<?xml version="1.0" encoding="UTF-8"?><rss version="2.0" xmlns:content="http://purl.org/rss/1.0/modules/content/" xmlns:wfw="http://wellformedweb.org/CommentAPI/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:atom="http://www.w3.org/2005/Atom" xmlns:sy="http://purl.org/rss/1.0/modules/syndication/" xmlns:slash="http://purl.org/rss/1.0/modules/slash/" > <channel> <title>Creative Biolabs ADC Blog</title> <atom:link href="https://www.creative-biolabs.com/blog/adc/feed/" rel="self" type="application/rss+xml" /> <link>https://www.creative-biolabs.com/blog/adc</link> <description>Antibody-Drug Conjugate (ADC) - Creative Biolabs</description> <lastBuildDate>Thu, 12 Sep 2024 03:52:31 +0000</lastBuildDate> <language>en-US</language> <sy:updatePeriod> hourly </sy:updatePeriod> <sy:updateFrequency> 1 </sy:updateFrequency> <generator>https://wordpress.org/?v=6.3.1</generator> <image> <url>https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2020/02/cropped-favicon-32x32.png</url> <title>Creative Biolabs ADC Blog</title> <link>https://www.creative-biolabs.com/blog/adc</link> <width>32</width> <height>32</height> </image> <item> <title>Fresh Game Plan for Developing Antibacterial Conjugates</title> <link>https://www.creative-biolabs.com/blog/adc/fresh-game-plan-for-developing-antibacterial-conjugates/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Thu, 12 Sep 2024 03:52:31 +0000</pubDate> <category><![CDATA[Antibody-drug Conjugates Research]]></category> <category><![CDATA[Antibacterial Conjugates]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=718</guid> <description><![CDATA[Bacterial infections are one of the most serious threats to human health, causing millions of deaths worldwide every year. However, due to the emergence of bacterial resistance, the antibacterial activity of many<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/fresh-game-plan-for-developing-antibacterial-conjugates/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">Bacterial infections are one of the most serious threats to human health, causing millions of deaths worldwide every year. However, due to the emergence of bacterial resistance, the antibacterial activity of many traditional antibiotics against many diseases caused by bacteria is weakened or even almost lost. In addition, the formation of bacterial biofilms, a group of microorganisms enclosed in an extracellular matrix, the main components of which are proteins and polysaccharides, undoubtedly exacerbates the current unoptimistic treatment situation. Therefore, research and development of new highly effective antibacterial drugs and new antibacterial strategies are of great significance for humans to get rid of this dilemma.</span></p> <p><span style="font-size: 15px;">Fortunately, there are many potential antibacterial agents under research, such as cationic photosensitizers, metabolic probes, metal nanomaterials, antimicrobial peptides (AMPs) and cationic polymers. As a new type of antibacterial material, amp has many advantages. Antimicrobial peptides, as an important component of the innate immune system of many animals and plants in the ecological environment, exhibit excellent antibacterial activity against both Gram-negative bacteria (Ge) and Gram-positive bacteria (Gþ). Its most widespread mode of action is to increase permeability or disrupt bacterial membranes, leading to extravasation of bacterial contents and bacterial death. Because of this, and because AMPs work differently than traditional antibiotics, it’s nearly impossible for bacteria to become resistant to them.</span></p> <p><span style="font-size: 15px;">HHC10 (KRWWKWIRW) is a peptide screened by an artificial neural network. It has certain antibacterial activity against Ge and G+ bacteria. Its antibacterial activity mainly comes from the destruction of bacterial membranes. Antimicrobial peptides have broad-spectrum antibacterial activity and are not prone to bacterial resistance, making them one of the promising antibacterial drugs that have been widely explored in recent years.</span></p> <p><span style="font-size: 15px;">Recently, researchers from Xiangya School of Pharmacy, Central South University, published an article titled “Harnessing antimicrobial peptide-coupled photosensitizer to combat drug-resistant biofilm infections through enhanced photodynamic therapy” in the journal Acta Pharm Sin B. This study reveals that it has conjugation of antimicrobial peptides with membrane-disrupting properties, and photosensitizers is a novel and effective strategy for treating bacterial infections.</span></p> <p><span style="font-size: 15px;">Bacterial biofilm-related infections are one of the most serious threats to human health. However, effective drugs against drug-resistant bacteria or biofilms are rarely reported. Here, we propose an innovative strategy to develop multifunctional antibacterial agents with broad-spectrum antibacterial activity by conjugating photosensitizers (ps) with antimicrobial peptides (amps).</span></p> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/09/ablog-202409-1.jpg"><img decoding="async" fetchpriority="high" class="aligncenter size-full wp-image-719" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/09/ablog-202409-1.jpg" alt="" width="652" height="442" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/09/ablog-202409-1.jpg 652w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/09/ablog-202409-1-300x203.jpg 300w" sizes="(max-width: 652px) 100vw, 652px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Fig. 1 CLSM images of <em>E. coli</em>, MDR <em>E. coli</em>, <em>P. aeruginosa</em>, and MRSA after incubation with TPI-CysHHC10.<sup>1</sup></span></p> <p><span style="font-size: 15px;">This strategy utilizes the ability of photosensitizers to generate reactive oxygen species (ROS) and the membrane targeting of AMPs (KRWWKWIRW, a peptide screened by artificial neural networks) to synergistically enhance antibacterial activity. In addition, unlike traditional aggregation-induced quenching (ACQ) photosensitizers, aggregation-induced emission (AIE) photosensitizers exhibit stronger fluorescence emission in the aggregated state, which helps visualize antibacterial mechanisms. <em>In vitro</em> antibacterial experiments show that the preparation has a good killing effect on both Gram-positive bacteria (G+) and Gram-negative bacteria (Ge). The ability to induce bacterial aggregation enhances the light-activated antibacterial activity against Ge bacteria. Notably, it showed significant effectiveness in destroying MRSA biofilms. It also has significant therapeutic effects on wound infections in mice.</span></p> <p><span style="font-size: 15px;">The excellent fluorescence properties of the fluorophore made it possible to visualize the interaction pattern between TPICysHHC10 and bacteria. In addition, the excellent singlet oxygen-generating ability of the fluorophore enhances the photodynamic antibacterial activity of TPI-CysHHC10. On the other hand, the destructive function of AMPs on bacterial outer membranes plays a crucial role in the antibacterial activity of TPI-CysHHC10 against Ge bacteria.</span></p> <p><span style="font-size: 15px;">The aggregation-inducing effect of TPI-CysHHC10 on Ge bacteria contributes to the efficient utilization of ROS generated by the conjugates encapsulated within bacterial aggregates. This local effect of ROS in a small range enhances the photodynamic antibacterial effect of TPICysHHC10. While killing planktonic bacteria, TPI-CysHHC10 also showed good results in inhibiting the formation of MRSA biofilms and destroying mature MRSA biofilms. This multifunctional antimicrobial agent has great potential to address the challenges posed by bacterial biofilm-related infections and drug-resistant bacteria.</span></p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/09/ablog-202409-2.jpg"><img decoding="async" class="aligncenter size-full wp-image-720" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/09/ablog-202409-2.jpg" alt="" width="652" height="318" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/09/ablog-202409-2.jpg 652w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/09/ablog-202409-2-300x146.jpg 300w" sizes="(max-width: 652px) 100vw, 652px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Fig. 2 The design mechanism of TPI-CysHHC10.<sup>1</sup></span></p> <p><span style="font-size: 15px;">In summary, the researchers proposed a new strategy to develop <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="/adc/antibody-design-and-conjugation.htm">antibacterial conjugates</a></strong></span> by combining PS with AMP, thereby generating a new class of broad-spectrum antibacterial drugs. In the treatment of mrsa infected wounds, TPI-CysHHC10 showed excellent photodynamic antibacterial effect and good biocompatibility. Conjugation of antimicrobial peptides with membrane-disrupting properties to photosensitizers is a novel and effective strategy for treating bacterial infections. This multifunctional antimicrobial agent has great potential to address the challenges posed by bacterial biofilm-related infections and drug-resistant bacteria. Further research and development of this drug may lead to substantial advances in the field of bacterial infection treatment.</span></p> <p><span style="font-size: 15px;">With our well-established DrugLnk<img src="https://s.w.org/images/core/emoji/14.0.0/72x72/2122.png" alt="™" class="wp-smiley" style="height: 1em; max-height: 1em;" /> and antibody engineering platforms, Creative Biolabs is dedicated to offering the best services to promote your antibody-antibiotic conjugate development. Our services include but are not limited to:</span></p> <ul> <li><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="/adc/antibody-discovery-services-for-bacterial-infection.htm">Antibody Discovery Services for Bacterial Infection</a></span></strong></span></li> <li><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="/adc/linker-design-and-synthesis.htm">Linker Design and Synthesis</a></span></strong></span></li> <li><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="/adc/antibiotic-synthesis.htm">Antibiotic Synthesis</a></span></strong></span></li> <li><span style="font-size: 15px;">Antibody-Antibiotic Conjugate</span></li> <li><span style="font-size: 15px;">AAC <em>In Vitro</em> Analysis</span></li> <li><span style="font-size: 15px;">AAC <em>In Vivo</em> Analysis</span></li> </ul> <p><span style="font-size: 15px;">Please <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="/adc/contact.htm">contact us</a></strong></span> for more information and a detailed quote.</span></p> <p><span style="font-size: 12px;">Reference:</span></p> <ol> <li><span style="font-size: 12px;">Fan, Duoyang, et al., “Harnessing antimicrobial peptide-coupled photosensitizer to combat drug-resistant biofilm infections through enhanced photodynamic therapy.” <em>Acta Pharmaceutica Sinica B</em>4 (2024): 1759-1771.</span></li> </ol> ]]></content:encoded> </item> <item> <title>Crafting Anti-nuclear “Missile” Therapy With Antibody-drug Conjugates</title> <link>https://www.creative-biolabs.com/blog/adc/crafting-anti-nuclear-missile-therapy-with-antibody-drug-conjugates/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Sat, 24 Aug 2024 05:45:44 +0000</pubDate> <category><![CDATA[Review]]></category> <category><![CDATA[ANADC]]></category> <category><![CDATA[Antibody-oligonucleotide Conjugates]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=713</guid> <description><![CDATA[In a new study, researchers from Yale School of Medicine hide tumor-fighting antibodies from cancer by disguising them in molecules that cancers use to nourish tumor growth, based on a new therapy<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/crafting-anti-nuclear-missile-therapy-with-antibody-drug-conjugates/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">In a new study, researchers from Yale School of Medicine hide tumor-fighting antibodies from cancer by disguising them in molecules that cancers use to nourish tumor growth, based on a new therapy from the Yale Cancer Center. defense system. This Trojan horse therapy has been shown to be effective in the laboratory against several cancer tumor types, including brain tumors that are difficult for drugs to reach because of the protection of the blood-brain barrier. Relevant research results were published online in the journal <em>ACS Central Science</em> on July 15, 2024, with the title “Cathepsin B Nuclear Flux in a DNA-Guided ‘Antinuclear Missile’ Cancer Therapy”<em>.</em></span></p> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/08/ablog-202407-1.jpg"><img decoding="async" class="aligncenter size-full wp-image-714" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/08/ablog-202407-1.jpg" alt="" width="343" height="220" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/08/ablog-202407-1.jpg 343w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/08/ablog-202407-1-300x192.jpg 300w" sizes="(max-width: 343px) 100vw, 343px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Fig. 1 The mechanism diagram of DNA-guided “antinuclear missile” cancer therapy.<sup>1</sup></span></p> <p><span style="font-size: 15px;">These successes are attributed to <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/one-stop-adc-development-service.htm">drug-carrying antibodies</a></strong></span> strategically redesigned from lupus to exploit their ability to target tumors while eliminating their effects on lupus. Scientists call such antibodies “antinuclear antibodies”, and they secretly hitch a ride on nucleic acid molecules that cancers pick up from the environment and use to synthesize new DNA to help tumors grow. Once inside the tumor, they effectively drop their camouflage and fire their anti-nuclear missile cargo to kill the cancer cells.</span></p> <p><span style="font-size: 15px;">Unlike other treatments that pair traditional antibodies with chemotherapy, the antibodies in this therapy don’t target cells by circulating through the bloodstream and looking for tumor cell surface markers, such as HER2 or PD-L1, but instead unknowingly target them. into the tumor environment. One promising effect that may arise from this very targeted therapy is that patients experience fewer toxic side effects.</span></p> <p><span style="font-size: 15px;">“Instead, the antinuclear antibody-drug conjugate (ANADC) looks for peptides floating around the tumor,” said James Hansen, corresponding author of the paper, a member of the Yale Cancer Center and director of radiation oncology at the Yale Gamma Knife Project. DNA fragments, meaning ANADC can track them even if tumors lack specific surface receptors that would prevent other, more traditional antibodies from finding them.”</span></p> <p><span style="font-size: 15px;">Hansen said ANADC was effective in mouse models of breast and colon cancer and even improved survival in mouse models of glioma. The authors are currently working to advance this therapy into clinical trials.</span></p> <p><span style="font-size: 15px;">“By targeting extracellular nucleic acids rather than surface receptors, ANADC can target essentially any type of necrotizing tumor, making it a tumor diagnostic therapy” and therefore has potential for use in other diseases, Hansen said.</span></p> <p><span style="font-size: 15px;">“This technology gives us the opportunity to use antinuclear antibodies to deliver drugs, proteins, or gene therapies to tumors or other sites of damage associated with increased DNA release, such as heart disease, stroke, or trauma,” Hansen said.</span></p> <p><span style="font-size: 15px;">View our comprehensive ADC services:</span></p> <ul> <li><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/adc-antibody-screening.htm">ADC Antibody Screening</a></span></strong></span></li> <li><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/druglnk-custom-synthesis.htm">DrugLnk<img src="https://s.w.org/images/core/emoji/14.0.0/72x72/2122.png" alt="™" class="wp-smiley" style="height: 1em; max-height: 1em;" /> Custom Synthesis</a></span></strong></span></li> <li><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/antibody-design-and-conjugation.htm">Antibody Design and Conjugation</a></span></strong></span></li> <li><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/adc-in-vitro-analysis.htm">ADC <em>In Vitro</em> Analysis</a></span></strong></span></li> <li><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/adc-in-vivo-analysis.htm">ADC <em>In Vivo</em> Analysis</a></span></strong></span></li> <li><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/adc-manufacturing.htm">ADC Manufacturing</a></span></strong></span></li> </ul> <p><span style="font-size: 12px;">Reference</span></p> <ol> <li><span style="font-size: 12px;">Cao, Fei, et al. “Cathepsin B Nuclear Flux in a DNA-Guided “Antinuclear Missile” Cancer Therapy.” <em>ACS Central Science</em>(2024).</span></li> </ol> ]]></content:encoded> </item> <item> <title>What’s New About Endometrial Cancer? An ADC Beyond Anticipation!</title> <link>https://www.creative-biolabs.com/blog/adc/whats-new-about-endometrial-cancer-an-adc-beyond-anticipation/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Tue, 23 Jul 2024 08:05:21 +0000</pubDate> <category><![CDATA[News]]></category> <category><![CDATA[ADC Therapy]]></category> <category><![CDATA[Endometrial Cancer]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=706</guid> <description><![CDATA[The highly anticipated 115th American Association for Cancer Research (AACR 2024) Annual Meeting opened in San Diego, USA. As the focus of the cancer research community, scientists, clinicians, and cancer researchers from<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/whats-new-about-endometrial-cancer-an-adc-beyond-anticipation/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The highly anticipated 115th American Association for Cancer Research (AACR 2024) Annual Meeting opened in San Diego, USA. As the focus of the cancer research community, scientists, clinicians, and cancer researchers from all over the world share here the latest advances in cancer research and treatment.</span></p> <p><span style="font-size: 15px;">Rebecca Porter, a researcher at Dana-Farber Cancer Institute, reported the latest clinical study data, a combination of a new ADC drug and an immune checkpoint inhibitor, in patients with previously treated refractory endometrium. Demonstrated significant therapeutic activity in cancer patients. In the study, six of the 16 treated patients saw their tumors shrink, including one case where the cancer disappeared. This result highlights the potential benefits of combining ADC drugs with immunotherapy.</span></p> <p><span style="font-size: 15px;">The study tested the ADC drugs Elahere (mirvetuximab soravtansine) and pembrolizumab (an anti-PD-1 monoclonal antibody) in patients with FRα-positive recurrent microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) serous endometrial cancer. The clinical trial met its primary endpoint, and the results support further research into this group of therapies.</span></p> <p><span style="font-size: 15px;">Serous endometrial cancer is an aggressive subtype of endometrial cancer with a poor prognosis, accounting for approximately 5% of endometrial cancer cases but 40% of deaths from the disease. About 30% of patients with serous endometrial cancer have tumors that express folate receptor α. The ADC drug targets folate receptor α by combining the <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/adc-development-services-targeting-folr1.htm">FRα-targeting monoclonal antibody</a></span></strong>—Mirvetuximab with the chemotherapy drug microtubule inhibitor <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/dm4-737.htm">DM4</a></span></strong>, thereby targeting and killing FRα-expressing cancer cells.</span></p> <p><span style="font-size: 15px;">View our pre-developed ADC products with DM4:</span></p> <table style="border-style: solid; border-color: #050505;"> <tbody> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>Catalog</strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>Product Name</strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>ADC Target</strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>ADC Linker</strong></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">ADC-W-1965</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/foravirumab-spdb-dm4-adc-2246.htm">Anti-Rabies Virus Glycoprotein (Foravirumab)-SPDB-DM4 ADC</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">Rabies Virus Glycoprotein</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">SPDB (N-succinimidyl-4-(2-pyridyldithio)butyrate)</span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">ADC-W-2067</span></p> <p> </td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/diridavumab-cr6261-spdb-dm4-adc-2348.htm">Anti-IAV HA (Diridavumab(CR6261))-SPDB-DM4 ADC</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">IAV HA</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">SPDB (N-succinimidyl-4-(2-pyridyldithio)butyrate)</span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">ADC-W-2115</span></p> <p> </td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/technetium-99mtc-pintumomab-spdb-dm4-adc-2396.htm">Anti-Adenocarcinoma antigen (Technetium (99 mTc) pintumomab)-SPDB-DM4 ADC</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">Adenocarcinoma antigen</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">SPDB (N-succinimidyl-4-(2-pyridyldithio)butyrate)</span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">ADC-W-2265</span></p> <p> </td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/racotumomab-spdb-dm4-adc-2552.htm">Anti-NGcGM3 (Racotumomab)-SPDB-DM4 ADC</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">NGcGM3</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">SPDB (N-succinimidyl-4-(2-pyridyldithio)butyrate)</span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">ADC-W-2301</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/ertumaxomab-spdb-dm4-adc-2588.htm">Anti-CD3E (Ertumaxomab)-SPDB-DM4 ADC</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">CD3E</span></p> <p> </td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">SPDB (N-succinimidyl-4-(2-pyridyldithio)butyrate)</span></p> <p> </td> </tr> </tbody> </table> <p><span style="font-size: 15px;">Previous preclinical studies have shown that this ADC drug may have a synergistic effect with immune checkpoint inhibitors. Immune checkpoint inhibitors release the brakes on the immune system, allowing anti-tumor T cells to attack cancer. ADCs can change immune cells in the tumor microenvironment and enhance T cell infiltration into tumors, thereby enhancing the effect of immune checkpoint inhibitors.</span></p> <p><span style="font-size: 15px;">The research team designed a two-phase clinical trial as a single-arm study, with all patients receiving the same treatment. The first phase enrolled 16 patients with recurrent or progressive FRα-positive, MSS/pMMR serous endometrial cancer who had received one to four prior therapies. Enrollment in the second phase will be based on at least two objective responses or six-month progression-free survival in two cases in the first phase.</span></p> <p><span style="font-size: 15px;">Of the 16 patients initially treated, 6 patients (37.5%) achieved an objective response, including 1 patient who achieved a complete response, another 5 patients who achieved a partial response, and an additional 5 patients who had stable disease. Therefore, the clinical trial met the primary endpoint, with more than 4 patients achieving objective response. In addition, 2 patients had progression-free survival of more than 6 months, one of whom was close to 12 months and the other more than 18 months.</span></p> <p><span style="font-size: 15px;">The study also observed that some patients had more rapid disease progression than others, and the research team will conduct additional analyses to determine if there are molecular changes in the characteristics of the tumor or microenvironment that could predict response or resistance to this combination therapy.</span></p> ]]></content:encoded> </item> <item> <title>Nature’s Breakthrough: ADCs and Base Editing Transform Blood Disease Treatment</title> <link>https://www.creative-biolabs.com/blog/adc/natures-breakthrough-adcs-and-base-editing-transform-blood-disease-treatment/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Fri, 21 Jun 2024 02:35:56 +0000</pubDate> <category><![CDATA[Review]]></category> <category><![CDATA[Blood Disease ADC]]></category> <category><![CDATA[CD45-targeted Therapy]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=701</guid> <description><![CDATA[Researchers from the University of Basel in Switzerland published a research paper titled “Selective haematological cancer eradication with preserved haematopoiesis” in the journal Nature. The entire hematopoietic system can be reconstructed by<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/natures-breakthrough-adcs-and-base-editing-transform-blood-disease-treatment/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">Researchers from the University of Basel in Switzerland published a research paper titled “Selective haematological cancer eradication with preserved haematopoiesis” in the journal Nature.</span></p> <p><span style="font-size: 15px;">The entire hematopoietic system can be reconstructed by transplantation of hematopoietic stem cells (HSCs). Currently, hematopoietic stem cell transplantation (HSCT) is a well-established clinical therapy. However, highly effective antigen-specific cell-depleting drug modalities, such as <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/classify-adc-toxins-6.htm">ADC drugs</a></strong></span> or CAR-T cell therapy, are expected to target depleted hematopoietic stem cells and tumor cells, potentially greatly improving hematopoietic stem cell transplantation (HSCT). Antigens co-expressed by tumor cells and other healthy cells (e.g., hematopoietic stem cells, T cells) pose a potential risk of toxicity. In addition, the diversity of hematopoietic cell types and the complexity and heterogeneity of hematologic tumor cells expressing hundreds of different cell surface antigens make target selection difficult.</span></p> <p><span style="font-size: 15px;">In view of these limitations, the research team changed the criteria for target selection. Instead of emphasizing the specificity of the cell type in which the antigen is expressed, they aimed to find a target that is widely expressed in all hematopoietic cells (including hematopoietic stem and progenitor cells, leukemia stem cells, and differentiated cells), but not in non-hematopoietic cells.</span></p> <p><span style="font-size: 15px;">CD45 is a target that meets this requirement, as it is expressed only by nucleated cells of hematopoietic origin and represents a pan-hematopoietic marker. Antibody-drug conjugates (ADCs) targeting mouse CD45 can effectively deplete long-term reconstituted hematopoietic stem cells (LT-HSCs), thereby enabling allogeneic hematopoietic stem cell transplantation.</span></p> <p><span style="font-size: 15px;">In addition to CD45, there are many ADC products with different targets to choose from</span></p> <table style="border-style: solid; border-color: #050505; width: 100%; height: 197px;"> <tbody> <tr style="height: 54px;"> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-ccr5-253.htm">CCR5</a></span></strong></span></td> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd180-8.htm">CD180</a></span></strong></span></td> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd19-9.htm">CD19</a></span></strong></span></td> </tr> <tr style="height: 54px;"> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd33-11.htm">CD33</a></span></strong></span></td> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd37-12.htm">CD37</a></span></strong></span></td> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd38-119.htm">CD38</a></span></strong></span></td> </tr> <tr style="height: 54px;"> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd40-122.htm">CD40</a></span></strong></span></td> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd40lg-123.htm">CD40LG</a></span></strong></span></td> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd44-13.htm">CD44</a></span></strong></span></td> </tr> <tr style="height: 35px;"> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd5-124.htm">CD5</a></span></strong></span></td> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd6-126.htm">CD6</a></span></strong></span></td> <td style="text-align: center; border-style: solid; border-color: #050505; width: 1px; height: 1px;" width="184"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-cd70-14.htm">CD70</a></span></strong></span></td> </tr> </tbody> </table> <p><span style="font-size: 15px;">However, because CD45+ cells are essential for hematopoiesis, immune defense, and many non-immune functions, highly effective CD45-targeted therapy is difficult to tolerate long-term without additional precautions. Knockdown of CD45 in hematopoietic stem and progenitor cells (HSPCs) results in severe combined immunodeficiency. The team’s previous study confirmed that replacing an amino acid in mouse CD45 eliminated its binding to the monoclonal antibody without affecting its expression and function. Since then, human HSPCs have been engineered to be immune to antigen-specific treatments, but retain their function, and maintain engraftment and multidirectional differentiation potential.</span></p> <p><span style="font-size: 15px;">Therefore, the goal of the study is to engineer CD45 to make it resistant to CD45-targeting ADCs while maintaining the function of hematopoietic stem cells, thus making targeted therapy possible.</span></p> <p><span style="font-size: 15px;">In this study, the research team developed a highly efficient antibody-drug conjugate (ADC) targeting CD45 and combined it with base editing technology to edit the CD45 of HSPCs for transplantation. This ensures that the CD45 retains its expression and function without being affected by the ADC drug, allowing for long-term reconstitution of the blood system after infusion into the body.</span></p> <p><span style="font-size: 15px;"><em>In vivo</em> experiments in mice demonstrated that antibody-drug conjugates (ADCs) targeting the pan-hematopoietic marker CD45 can specifically clear the entire hematopoietic system, including hematopoietic stem cells (HSCs). This ADC drug is then combined with a base-edited artificial blood stem cell transplant to selectively remove leukemia cells from the body while preserving the hematopoietic function of the transplanted hematopoietic stem cells.</span></p> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/06/ablog-202406-1.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-702" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/06/ablog-202406-1.jpg" alt="" width="419" height="252" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/06/ablog-202406-1.jpg 952w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/06/ablog-202406-1-300x180.jpg 300w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/06/ablog-202406-1-768x461.jpg 768w" sizes="(max-width: 419px) 100vw, 419px" /></a></span></p> <p><span style="font-size: 12px;">Fig. 1 Analysis of tumor clearance and Hematopoietic Protection of CIM053-SG3376 <em>in vitro</em><sup>1</sup></span></p> <p><span style="font-size: 15px;">Overall, the study combined CD45-targeted ADCs with genetically engineered hematopoietic stem cells (HSCs) to create an almost universal strategy for replacing the hematopoietic system, regardless of the etiology of the disease or the type of cell of origin. This approach is not only applicable to hematologic malignancies, but can also be applied to a wider range of hematologic diseases.</span></p> <p><span style="font-size: 12px;">Reference</span></p> <ol> <li><span style="font-size: 12px;">Garaudé, Simon, et al. “Selective haematological cancer eradication with preserved haematopoiesis.” <em>Nature</em> (2024): 1-8.</span></li> </ol> <p> </p> ]]></content:encoded> </item> <item> <title>ADCs in Cancer Therapy: Innovations, Challenges, and Outlooks</title> <link>https://www.creative-biolabs.com/blog/adc/adcs-in-cancer-therapy-innovations-challenges-and-outlooks/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Tue, 14 May 2024 08:16:40 +0000</pubDate> <category><![CDATA[Review]]></category> <category><![CDATA[ADC]]></category> <category><![CDATA[ADC resistance]]></category> <category><![CDATA[AJICAP technology]]></category> <category><![CDATA[Cancer Therapy]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=683</guid> <description><![CDATA[The emergence of antibody-drug conjugates (ADCs) as a potential cancer treatment pathway has attracted a great deal of attention. By combining the selective specificity of monoclonal antibodies with the cytotoxicity of drug<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/adcs-in-cancer-therapy-innovations-challenges-and-outlooks/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The emergence of antibody-drug conjugates (ADCs) as a potential cancer treatment pathway has attracted a great deal of attention. By combining the selective specificity of monoclonal antibodies with the cytotoxicity of drug molecules, the therapeutic index is improved, and cancer cells are selectively targeted while minimizing systemic toxicity.</span></p> <p><span style="font-size: 15px;">There are several challenges, including selecting the right target antigen, enhancing antibodies, <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="/adc/classify-adc-linkers-7.htm">linkers</a></strong></span>, and <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/adc/classify-adc-toxins-6.htm">payloads</a></span></strong>, as well as drug resistance mechanisms and side effect management. However, we can also use site-specific coupling techniques, new antibody formats, and combination therapy strategies to overcome these obstacles.</span></p> <ul> <li><span style="font-size: 15px;"><strong>ADC drugs approved by the FDA</strong></span></li> </ul> <p><span style="font-size: 15px;">As of 2023, the U.S. Food and Drug Administration (FDA) has approved 15 different antibody-drug conjugates (ADCs) targeting a variety of antigens for cancer treatment. These drugs target specific antigens such as <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/adc/target-cd33-11.htm">CD33</a></span></strong>, CD30, HER2, CD22, <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/adc/target-cd79b-17.htm">CD79b</a></span></strong>, B-cell maturation antigen (BCMA), <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/adc/target-nectin4-74.htm">Nectin-4</a></span></strong>, Tissue Factor (TF), <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/adc/target-egfr-30.htm">EGFR</a></span></strong>, and folate receptor alpha (FRα). Some of these antigens are targeted by multiple ADCs, demonstrating the critical focus on certain cancer markers.</span></p> <ul> <li><span style="font-size: 15px;"><strong>ADC drug composition</strong></span></li> </ul> <p><span style="font-size: 15px;">ADC drug typically consists of a monoclonal antibody, cytotoxic payload, and linker molecule.<a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-1.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-692" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-1.jpg" alt="" width="278" height="241" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-1.jpg 1500w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-1-300x260.jpg 300w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-1-1024x887.jpg 1024w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-1-768x665.jpg 768w" sizes="(max-width: 278px) 100vw, 278px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Fig. 1 ADC Structure.<sup>1</sup></span></p> <p><span style="font-size: 15px;">See cytotoxic payload products we provide</span></p> <table style="border-style: solid; border-color: #050505;"> <tbody> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>Catalog</strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>Product name</strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>CAS NO</strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>Purity</strong></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/auristatin-e-707.htm">ADC-P-004</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/auristatin-e-707.htm">Aurstatin E</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">160800-57-7</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">95%</span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/auristatin-f-708.htm">ADC-P-005</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/auristatin-f-708.htm">Auristatin F</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">163768-50-1</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">95%</span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/dolastatin-10-715.htm">ADC-P-012</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/dolastatin-10-715.htm">Dolastatin 10</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">110417-88-4</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">95%</span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/maytansinol-718.htm">ADC-P-015</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/maytansinol-718.htm">Maytansinol</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">57103-68-1</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">95%</span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/mmad-721.htm">ADC-P-018</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff; font-size: 15px;"><strong><a style="color: #0000ff;" href="/adc/mmad-721.htm">MMAD</a></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">203849-91-6</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">95%</span></td> </tr> </tbody> </table> <ul> <li><span style="font-size: 15px;"><strong>ADC is designed step-by-step using AJICAP technology</strong></span></li> </ul> <p><span style="font-size: 15px;">AJICAP technology can modify natural IgG antibodies to create ADCs. The steps include affinity peptide attachment to a lysine residue, antibody functionalization at the peptide binding site, and drug molecule conjugation. This enables targeted drug delivery and precision medicine applications.</span></p> <p><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-2.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-694" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-2.jpg" alt="" width="408" height="193" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-2.jpg 2032w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-2-300x142.jpg 300w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-2-1024x485.jpg 1024w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-2-768x364.jpg 768w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-2-1536x727.jpg 1536w" sizes="(max-width: 408px) 100vw, 408px" /></a></p> <p style="text-align: center;"><span style="font-size: 12px;">Fig. 2 The step of creating ADCs using the AJICAP technology.<sup>1</sup></span></p> <ul> <li><span style="font-size: 15px;"><strong>A general description of the mode of action of an antibody-drug conjugate</strong></span></li> </ul> <p><span style="font-size: 15px;">The mechanism of ADC drugs consists of several stages. First, the ADC attaches to a specific antigen in the cancer cells. This interaction causes receptor-mediated endocytosis, in which the intact ADC antigen complex is internalized by cancer cells. Some ADC-antigen complexes are recycled back to the cell surface, while the drug remains in the endonuclear body. If this complex follows the drug release pathway, endosomes mature into late endosomes, resulting in the degradation of cleavable linkers and the release of cytotoxic loads. The anaphase nucleosomes then fuse with lysosomes, and the ADC is broken down by lysosomal enzymes, which release cytotoxic drugs. In addition, free drugs may also have an effect on neighboring cancer cells, causing a bystander effect.</span></p> <p><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-3.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-695" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-3.jpg" alt="" width="312" height="225" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-3.jpg 1772w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-3-300x216.jpg 300w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-3-1024x737.jpg 1024w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-3-768x553.jpg 768w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-3-1536x1105.jpg 1536w" sizes="(max-width: 312px) 100vw, 312px" /></a></p> <p style="text-align: center;"><span style="font-size: 12px;">Fig. 3 Mode of action of ADC.<sup>1</sup></span></p> <ul> <li><span style="font-size: 15px;"><strong>Mechanisms of ADC resistance in HER2-positive breast cancer</strong></span></li> </ul> <p><span style="font-size: 15px;">Resistance mechanisms in breast cancer to ADCs include decreased antigen expression, impairments in antigen-ADC complex internalization, defective lysosomal degradation hindering payload release, and drug transporters eliminating payloads before cytotoxic effects initiate. These mechanisms reduce ADC efficacy, contributing to resistance.</span></p> <ul> <li><span style="font-size: 15px;"><strong>Clinical trials of bispecific ADCs</strong></span></li> </ul> <p><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-4.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-696" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-4.jpg" alt="" width="397" height="242" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-4.jpg 722w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/05/ablog-202405-4-300x183.jpg 300w" sizes="(max-width: 397px) 100vw, 397px" /></a></p> <p><span style="font-size: 15px;">As our understanding of the molecular mechanisms that drive cancer progression continues to expand, we look forward to the development of new ADCs that provide more effective and personalized treatment options for cancer patients.</span></p> <p><span style="font-size: 12px;">Reference</span></p> <ol> <li><span style="font-size: 12px;">Kumari, Shivangi, et al. “Antibody-drug conjugates in cancer therapy: innovations, challenges, and future directions.” <em>Archives of Pharmacal Research</em> 47.1 (2024): 40-65.</span></li> </ol> ]]></content:encoded> </item> <item> <title>It’s High Time For Next Generation Adcs To Set Out: 5 Ways To Go – Part II</title> <link>https://www.creative-biolabs.com/blog/adc/its-high-time-for-next-generation-adcs-to-set-out-5-ways-to-go-part-ii/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Sun, 21 Apr 2024 08:18:46 +0000</pubDate> <category><![CDATA[Review]]></category> <category><![CDATA[DAC]]></category> <category><![CDATA[ISAC]]></category> <category><![CDATA[PDC]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=670</guid> <description><![CDATA[Conditionally activated antibody prodrug conjugate (PDC) Traditional ADCs not only target receptors expressed on tumor cells but also those on certain healthy tissues, leading to inevitable off-tumor toxicity. Probody Drug Conjugates (PDCs)<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/its-high-time-for-next-generation-adcs-to-set-out-5-ways-to-go-part-ii/">Read More...</a>]]></description> <content:encoded><![CDATA[<h6><span style="font-size: 15px;"><strong>Conditionally activated antibody prodrug conjugate (PDC)</strong></span></h6> <p><span style="font-size: 15px;">Traditional ADCs not only target receptors expressed on tumor cells but also those on certain healthy tissues, leading to inevitable off-tumor toxicity. Probody Drug Conjugates (PDCs) can address this issue (Figure 3), inspired by the concept of prodrugs in small molecule therapeutics. The precursor antibody molecules in PDCs are IgGs that are either fused at their N-terminus with a cleavable linker to a self-masking group or designed with antigen-binding sites that undergo pH-dependent conformational changes, thereby reducing the IgG’s affinity for its target. Upon reaching the tumor microenvironment, these antibodies either shed their self-masking groups or undergo a change in the conformation of their antigen-binding sites in response to specific tumor-associated factors (such as protease abundance and acidic conditions), thereby locally restoring their original target-binding affinity and payload release. This innovative approach holds the promise of enhancing the therapeutic index of ADCs.</span></p> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-3.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-671" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-3.jpg" alt="" width="328" height="353" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-3.jpg 685w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-3-279x300.jpg 279w" sizes="(max-width: 328px) 100vw, 328px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 3. Conditionally activated antibody prodrug conjugates</span></p> <ul> <li><span style="font-size: 15px;">PDC with a protease sensitive self-masking group</span></li> </ul> <p><span style="font-size: 15px;">A study showed that the anti-CD71 PDC CX-2029 and its ADC equivalent (both containing the MMAE payload, DAR~2) demonstrated comparable levels of antitumor activity in various solid tumor mouse xenograft models. The preclinical maximum tolerated doses (MTDs) for the PDC and its equivalent ADC in non-human primates were 6 and 0.6 mg/kg, respectively, suggesting that the introduction of the masking fragment increased the therapeutic index by approximately tenfold. Building on this concept, researchers have developed several first-in-class PDCs, including CX-2051 (Phase I clinical trials), praluzatamab ravtansine (Phase II clinical trials), and CX-2029 (Phase I/II clinical trials). Praluzatamab ravtansine contains the microtubule inhibitor DM4 and an anti-CD166 antibody. CD166 is broadly expressed in many non-malignant tissues, making it an ideal target for a PDC. In a Phase I clinical trial, 99 patients with metastatic solid tumors, comprising breast cancer (46%), epithelial ovarian cancer (22%), and non-small cell lung cancer (13%), were treated with praluzatamab ravtansine, with tumor regression observed at doses ≥4mg/kg. CX-2029, an anti-CD71 PDC with an MMAE payload, is currently undergoing Phase I clinical trials involving patients with various advanced solid tumors, such as NSCLC (20%), HNSCC (18%), and colorectal cancer (16%).</span></p> <p> </p> <ul> <li><span style="font-size: 15px;">PDC with a pH reactive antigen binding site</span></li> </ul> <p><span style="font-size: 15px;">Tumor tissues (pH = 6.0–6.8) are typically slightly more acidic than most healthy tissues (pH = 7.3–7.4). The difference in pH values can be utilized for conditional activation of ADCs due to reversible conformational changes in the antigen-binding sites (Figure 3b). Incorporating weakly basic histidine residues into the antibody’s binding region is a common method to impart this pH-dependent activation. A prime example is the MMAE-based EGFR-targeting PDC, HTI-1511. The parent antibody of HTI-1511 exhibits more than tenfold higher binding affinity to EGFR at pH = 6.0–6.5 compared to pH = 7.4. HTI-1511 demonstrated good tolerability up to a dose of 8 mg/kg in cynomolgus monkeys, indicating potential clinical safety. In conclusion, the PDC platform holds significant promise for targeting antigens, yet the types of specific cancer subtypes effectively targeted by PDCs still need to be determined.</span></p> <h6><span style="font-size: 15px;"><strong>Immunostimulatory ADC (ISAC)</strong></span></h6> <p><span style="font-size: 15px;">ISACs enhance the immune response against tumors by activating the immune system. Compared to traditional ADCs that carry <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="adc/classify-adc-toxins-6.htm">cytotoxic payloads</a></span></strong>, ISACs offer the following potential advantages:</span></p> <ul> <li><span style="font-size: 15px;">ISAC-mediated antitumor responses can target a variety of tumor-associated damage-associated molecular patterns (DAMPs).</span></li> <li><span style="font-size: 15px;">ISAC-mediated immune stimulation can activate not only antigen-presenting cells but also other tumor-infiltrating immune cells, such as T cells.</span></li> <li><span style="font-size: 15px;">ISACs can induce immune memory effects that span the entire cellular immune response, thereby providing lasting antitumor effects and reducing the risk of recurrence.</span></li> </ul> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-4.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-672" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-4.jpg" alt="" width="311" height="428" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 4. Immunostimulatory ADCs</span></p> <ul> <li><span style="font-size: 15px;">ISAC with TLR7/TLR8/TLR9 agonist payload</span></li> </ul> <p><span style="font-size: 15px;">Among all TLRs identified so far, TLR7, TLR8, and TLR9 are the primary targets for most ISACs, with the activation of these endosomal TLRs promoting the presentation of tumor-associated DAMPs by APCs, generating robust antitumor effects through the activation of both innate and adaptive immune responses. In 2015, researchers announced the activity of an anti-CD20 ISAC developed by combining a TLR7 agonist with rituximab. <em>In vitro</em> tests showed that the combination did not impair the antigen-binding ability or specificity of rituximab, nor did it affect the TLR-stimulating activity of the agonist. This early study paved the way for the development of various ISACs activating TLR7/8. However, in the Phase I study (NCT04460456) and Phase I/II study (NCT05091528) of the HER2 TLR8 ISAC SBT6050, cytokine-related adverse events ultimately led to the termination of the study. Another ISAC targeting HER2, NJH395, containing a TLR7 agonist linked to an anti-HER2 antibody via a non-cleavable linker, was evaluated in a Phase I trial (NCT03696771). However, the study was also stopped after completing the single ascending dose part due to insufficient efficacy, among other reasons. Another HER2-targeting ISAC, BDC-1001, is a rituximab-based ISAC equipped with a TLR7/8 agonist via a non-cleavable linker (Figure 4b). BDC-1001 is currently being tested in a Phase I/II trial. Unlike SBT6050 and NJH395, BDC-1001 has shown promising preliminary results.</span></p> <ul> <li><span style="font-size: 15px;">ISAC with STING agonist payload</span></li> </ul> <p><span style="font-size: 15px;">When exposed to exogenous DNA from microbial pathogens and/or dying tumor cells, the cGAS-cGAMP-STING pathway is activated, leading to the production of type I interferons and the activation of innate immunity. Research has shown that STING signaling is critical for inducing T-cell-mediated antitumor immune responses and the infiltration of T cells into the tumor microenvironment (TME). An EGFR-targeting ISAC conjugating the cGAMP analog IMSA172 to an anti-EGFR antibody demonstrated good tolerability in EGFR-expressing mouse xenograft models, with dosing every three days for three doses at 200μg (approximately 8-10mg/kg), showing promising antitumor activity. The antitumor activity of these ISACs was further enhanced when combined with anti-PD-L1 antibodies. In summary, the multimodal antitumor immune actions provided by ISACs show potential for reducing the risk of acquired resistance and/or delaying its onset. With their unique mechanism of action, ISACs hold promise as a powerful tool for addressing the complex immune landscape in cancer treatment.</span></p> <h6><span style="font-size: 15px;"><strong>Protein degradation ADC (DAC)</strong></span></h6> <p><span style="font-size: 15px;">DACs leverage the cell’s protein degradation mechanisms to target specific proteins, offering an innovative approach to cancer treatment. This design concept is derived from PROTAC technology. PROTACs are heterobifunctional molecules connected by a linker, consisting of two ligands where one ligand targets a specific protein of interest and the other ligand binds to an E3 ubiquitin ligase. Unlike traditional inhibitors, the binding of these ligands to the target protein does not require antagonistic activity. Such a design enables the targeting of proteins previously considered “undruggable” as potential therapeutic targets.</span></p> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-5.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-673" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-5.jpg" alt="" width="351" height="359" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-5.jpg 685w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202402-2-5-293x300.jpg 293w" sizes="(max-width: 351px) 100vw, 351px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 5. Protein degradation of ADCs</span></p> <p><span style="font-size: 15px;">GNE-987 is a BET-PROTAC comprised of a BRD4 ligand and a VHL ligand, demonstrating effective degradation of BRD4 (DC50 = 0.03 nM) in EOL-1 cells and showing exceptional <em>in vitro</em> potency in two cell lines (IC50 = 0.02 nM in EOL-1 and IC50 = 0.03 nM in HL-60). However, drug metabolism and pharmacokinetics rendered it ineffective in <em>in vivo</em> models. To address this issue, researchers linked GNE-987’s hydroxyl group with six cysteines to an anti-CLL1 antibody, using an unstable carbonate linker to transform GNE-987 into a homogeneous DAC (Figure 5b). Data indicated that a single intravenous dose of 10 mg/kg DAC in subcutaneously transplanted HL-60 and EOL-1 AML mouse models could maintain sustained exposure <em>in vivo</em> and significantly inhibit tumor growth. Beyond BRD4, estrogen receptor-alpha (ERα), TGFβ receptor 2, and the chromatin regulator protein SMARCA2 (also known as BRM) have also been widely utilized as targets for DACs. However, DACs face the challenge that their payloads often possess high hydrophobicity, leading to overly hydrophobic overall structures. To ensure adequate cytotoxicity, a higher drug-to-antibody ratio (DAR) may be required, further exacerbating their hydrophobicity and adversely affecting the pharmacokinetics and toxicity profiles of these drugs. Thus, developing novel linker designs and improved degrader molecules to address these issues could significantly enhance the potential application of DACs in cancer therapy.</span></p> <h6><span style="font-size: 15px;"><strong>Dual-drug ADC</strong></span></h6> <p><span style="font-size: 15px;">Dual-drug ADCs, by incorporating two different payloads, address tumor resistance and heterogeneity through the combined mechanisms of action of multiple cytotoxic drugs. This strategy may exhibit enhanced activity against heterogeneous tumor cell populations and resistant clones. As a single therapeutic entity, dual-drug ADCs could produce synergistic effects and overcome resistance in tumors that are non-responsive to treatment through a simplified administration regimen. Researchers initially hypothesized that delivering two payloads (MMAE and MMAF) simultaneously would enhance and synergize activity. Experiments showed that such dual-drug ADCs demonstrated potent activity in a mouse xenograft model of CD30-expressing anaplastic large cell lymphoma (ALCL) resistant to multiple drugs, resulting in the complete eradication of cancer cells in 3 out of 5 mice. In contrast, an ADC with a DAR of 8 carrying only MMAF showed lower activity, eradicating all cancer cells in only 1 out of 5 mice, while the equivalent ADC carrying only MMAE had no antitumor activity.</span></p> <p><span style="font-size: 15px;">In a mouse xenograft model of Hodgkin’s lymphoma with heterogeneous CD30 expression, both the dual-drug ADC and the ADC carrying only MMAE completely inhibited tumor growth, likely due to MMAE-mediated bystander cell killing. Conversely, the equivalent ADC carrying only MMAF only moderately delayed tumor growth.</span></p> <p><span style="font-size: 15px;">While dual-drug ADCs show potential advantages in overcoming tumor heterogeneity and resistance, caution must be taken regarding the potential for synergistic toxicity. To this end, researchers have developed various orthogonal conjugation strategies to produce dual-drug ADCs with high homogeneity and precise drug-to-antibody ratios. These strategies not only ensure effective integration of the two payloads but also optimize their combined action to maximize therapeutic effects and minimize adverse reactions.</span></p> <p><span style="font-size: 15px;">More MMAE-linker complex product:</span></p> <table style="border-style: solid; border-color: #050505;"> <tbody> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>Catalog</strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>Product name</strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>CAS NO</strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><strong>Inquiry</strong></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">ADC-S-007</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/vc-mmae-892.htm">Vc-MMAE</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">646502-53-6</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/adc/form/order">I<strong><span style="color: #0000ff;">nquiry</span></strong></a></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">ADC-S-008</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/adc/osu-glu-vc-pab-mmae-893.htm"><span style="color: #0000ff;">O<strong>Su-Glu-vc-PAB-MMAE</strong></span></a></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">–</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/adc/form/order">I<strong><span style="color: #0000ff;">nquiry</span></strong></a></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">ADC-S-026</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><strong><span style="font-size: 15px; color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/mc-betaglucuronide-mmae-2-4660.htm">MC-betaglucuronide-MMAE-2</a></span></strong></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">–</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><strong><span style="font-size: 15px; color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></td> </tr> <tr> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">ADC-S-073</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px; color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/mdpr-val-cit-pab-mmae-4707.htm">m<strong>DPR-Val-Cit-PAB-MMAE</strong></a></span></td> <td style="border-style: solid; border-color: #050505;" width="138"><span style="font-size: 15px;">1491152-26-1</span></td> <td style="border-style: solid; border-color: #050505;" width="138"><strong><span style="font-size: 15px; color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></td> </tr> </tbody> </table> <p><span style="font-size: 12px;">Reference:</span></p> <p><span style="font-size: 12px;">Tsuchikama, Kyoji, et al. “Exploring the next generation of antibody–drug conjugates.” <em>Nature Reviews Clinical Oncology</em> (2024): 1-21.</span></p> ]]></content:encoded> </item> <item> <title>It’s High Time For Next Generation Adcs To Set Out: 5 Ways To Go</title> <link>https://www.creative-biolabs.com/blog/adc/its-high-time-for-next-generation-adcs-to-set-out-5-ways-to-go/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Fri, 19 Apr 2024 01:53:32 +0000</pubDate> <category><![CDATA[Review]]></category> <category><![CDATA[ADC design]]></category> <category><![CDATA[Next Generation ADC]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=664</guid> <description><![CDATA[Antibody-drug conjugates (ADCs) represent a highly promising approach to cancer treatment, capable of selectively delivering highly cytotoxic payloads to tumors. However, ADCs are currently facing a series of challenges, including resistance, tumor<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/its-high-time-for-next-generation-adcs-to-set-out-5-ways-to-go/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">Antibody-drug conjugates (ADCs) represent a highly promising approach to cancer treatment, capable of selectively delivering highly cytotoxic payloads to tumors. However, ADCs are currently facing a series of challenges, including resistance, tumor heterogeneity, and treatment-related adverse reactions. How can these challenges be addressed? On one hand, advancements in the components of ADCs (namely, the antibody, linker, and payload) are crucial for enhancing the efficacy and safety of the drugs. On the other hand, several emerging forms of ADCs, such as <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="/adc/bispecific-adcs-development.htm">bispecific ADCs</a></strong></span>, conditionally activated prodrug conjugates (also known as probody-drug conjugates, PDCs), immune-stimulating antibody conjugates (ISACs), protein degrading ADCs, and dual-drug ADCs, offer their own advantages and are equipped to tackle various challenges:</span></p> <ul> <li><span style="font-size: 15px;">Bispecific and dual-drug ADCs possess the dual potential to combat resistance and tumor heterogeneity.</span></li> <li><span style="font-size: 15px;">Combining immune-stimulating and protein degrading ADCs with current treatment strategies may achieve multimodal therapy through several different mechanisms of action.</span></li> </ul> <p><span style="font-size: 15px;">Recently, <em>Nature Reviews Clinical Oncology</em> published a review article that delves into the design of ADC molecules and how each component influences the drug’s properties. Furthermore, the article also highlights representative drugs of the aforementioned emerging ADC forms (bispecific ADCs, PDCs, ISACs, protein degrading ADCs, and dual-drug ADCs) that are in the preclinical/early clinical stages.</span></p> <h6><span style="font-size: 15px;"><strong>ADC molecular design</strong></span></h6> <p><span style="font-size: 15px;">As shown in Figure 1a, ADCs are composed of a monoclonal antibody, payload, and linker, combining the specificity of the antibody with the high cytotoxicity of the payload. The principle of ADC design has evolved through the optimization of each structural component (antibody, <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/adc/classify-adc-toxins-6.htm">payload</a></span></strong>, and linker).</span><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202404-1-1.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-665" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202404-1-1.jpg" alt="" width="293" height="355" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202404-1-1.jpg 863w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202404-1-1-248x300.jpg 248w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202404-1-1-846x1024.jpg 846w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202404-1-1-768x930.jpg 768w" sizes="(max-width: 293px) 100vw, 293px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 1. Composition, molecular properties, and new design of ADCs</span></p> <ul> <li><span style="font-size: 15px;">Selection of antibodies and targets</span></li> </ul> <p><span style="font-size: 15px;">The antibodies used in ADCs are typically chosen to be either humanized or directly human immunoglobulin G (IgG). When designing ADCs, there is a preference for using IgG1 antibodies, as on the one hand, IgG1 is overall stable in the bloodstream and can synergize with innate immune cells (such as NK cells and macrophages); on the other hand, using human IgG1 also helps to reduce the overall immunogenicity of the ADC, thereby minimizing the risk of hypersensitivity reactions and the formation of <a href="/adc/classify-anti-drug-abs-4.htm"><strong><span style="color: #0000ff;">anti-drug antibodies (ADAs)</span></strong></a>. Most current ADC structures are linked to N-glycans to facilitate binding to FcγRs. However, glycosylation may lead to nonspecific uptake of ADCs by hepatocytes, leading to liver toxicity. In the future, non-glycosylated monoclonal antibodies may be used. Ideally, antibodies should recognize antigens that are specifically expressed on the surface of cancer cells and not expressed at all in healthy tissues. However, most ADC targets, such as HER2 and TROP2, are expressed to some extent in healthy tissues. Thus, both target-dependent and target-independent toxicities may still occur. Research is currently exploring antibodies that can specifically recognize structural variations in antigens present in tumors. Furthermore, the rate of <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="/adc/adc-internalization-assay.htm">ADC internalization</a></strong></span> and recycling also significantly impacts efficacy. Optimization of binding affinity is a crucial step towards maximizing the effectiveness of ADCs. Paradoxically, overly strong antigen binding can result in ADC molecules lingering on the surface of tumor cells, limiting the degree of tissue penetration. Therefore, different parameters must be considered in the antibody framework of an ADC to ensure optimal performance.</span></p> <ul> <li><span style="font-size: 15px;">Payload</span></li> </ul> <p><span style="font-size: 15px;">The cytotoxic payloads of FDA-approved ADCs include antimitotics (MMAE, MMAF, and maytansinoid derivatives DM1 and DM4), DNA damaging agents (calicheamicins and pyrrolobenzodiazepine dimers), and topoisomerase I inhibitors (SN-38, DXd), among others. Other drugs currently under evaluation include microtubule inhibitors, DNA alkylating agents, topoisomerase II inhibitors, and RNA polymerase II inhibitors. Additionally, immunomodulators and protein degrader recruiters are gradually becoming promising new types of payloads. Most payload molecules possess a moderate-to-high level of hydrophobicity. Hydrophobic payloads can diffuse from the target-expressing tumor cells to adjacent cells with limited or no target expression, a phenomenon known as the bystander effect. Given that tumors with heterogeneity coexist with cells expressing the antigen and cells that do not, the bystander effect is crucial for the successful eradication of heterogeneous tumors. However, hydrophobic payloads can also negatively impact the efficacy of ADCs:</span></p> <ul> <li><span style="font-size: 15px;">Hydrophobic payloads can serve as good substrates for multidrug resistance proteins (such as MDR1, MRP1, and BCRP), reducing the efficacy of some ADCs against tumors that express these transport proteins.</span></li> <li><span style="font-size: 15px;">Hydrophobic ADCs tend to form aggregates, which may be rapidly cleared and could possess immunogenicity.</span></li> <li><span style="font-size: 15px;">Excessive hydrophobicity can promote liver uptake and cause hepatotoxicity.</span></li> </ul> <p><span style="font-size: 15px;">Therefore, while ensuring the bystander effect, it is necessary to regulate the hydrophobicity of ADCs. One current strategy is to lower the drug-to-antibody ratio (DAR), but reducing DAR leads to decreased antitumor activity, so it is essential to finely tune the DAR for each payload category to balance efficacy and toxicity. Another solution is to incorporate hydrophilic masking groups, such as long polyethylene glycol (PEG) chains, which allows for the construction of high DAR ADCs while avoiding some of the undesirable effects of high hydrophobicity.</span></p> <ul> <li><span style="font-size: 15px;">Linker</span></li> </ul> <p><span style="font-size: 15px;">As shown in Figure 1b, the linker plays a key role in keeping the cytotoxic payload attached to the antibody until it reaches the target. Linkers are classified into two categories: non-cleavable and cleavable. <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="/adc/non-cleavable-linker.htm">Non-cleavable linkers</a></strong></span> consist of stable chemical bonds that resist proteolytic degradation, providing excellent stability in the bloodstream. However, in ADCs with such linkers, the release of the payload requires the complete internalization and digestion of the antibody. In contrast, cleavable linkers are more widely used. These linkers can be degraded by tumor-associated factors (such as acidic and/or reductive conditions associated with most tumors or intracellular proteases). These linkers enable the effective release of the payload after internalization into cancer cells, thereby generating cytotoxicity, maximizing ADC efficacy, and facilitating the bystander effect. However, cleavable linkers carry the risk of premature payload release, leading to systemic toxicity and reduced efficiency of payload delivery. Therefore, striking a balance between stability and efficacy is crucial.</span></p> <ul> <li><span style="font-size: 15px;">Homogeneity</span></li> </ul> <p><span style="font-size: 15px;">In addition to the structural components discussed above, achieving homogeneity in conjugation is also crucial. As shown in Figure 1c, traditional ADCs often use cysteine-maleimide alkylation and lysine-amide coupling for construction, but these random conjugation methods result in heterogeneous ADC mixtures with variations in payload attachment sites and drug-to-antibody ratio (DAR). The heterogeneity of ADCs typically leads to reduced efficiency of payload delivery, thus necessitating strict control over production to minimize such variations. There are now numerous conjugation technologies available for generating ADCs with specific DARs, such as interchain disulfide alkylation (used for T-DXd and sacituzumab govitecan), THIOMAB technology, conjugation involving non-natural amino acids, cysteine re-bridging, Fc affinity tags, and site-specific conjugation using various enzymes (such as engineered glycosyltransferases, transglutaminases, formylglycine-generating enzymes, and sortase).</span></p> <h6><span style="font-size: 15px;"><strong>Bispecific ADC</strong></span></h6> <p><span style="font-size: 15px;">As previously mentioned, tumor heterogeneity and resistance can limit the antitumor activity of ADCs targeting a single antigen. To address this challenge, bispecific antibodies have emerged as a method capable of simultaneously binding two different target molecules and/or cells (Figure 2).</span></p> <p> </p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202404-1-2.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-666" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/04/ablog-202404-1-2.jpg" alt="" width="277" height="269" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 2. Representative bispecific ADCs</span></p> <ul> <li><span style="font-size: 15px;">Dual-epitope ADC</span></li> </ul> <p><span style="font-size: 15px;">Previous studies have indicated that the use of two anti-HER2 antibodies binding different epitopes can lead to internalization, lysosomal transport, and downregulation of the target receptor. Therefore, researchers hypothesized that a multivalent bispecific ADC targeting two different epitopes on HER2 might improve binding affinity and enhance payload delivery. To test this hypothesis, researchers created the tetravalent HER2-targeting ADC MEDI4276 (Figure 2a) by fusing the single-chain variable fragment of trastuzumab with the N-terminus of another anti-HER2 IgG1 antibody, 39S. As expected, this homogenous bispecific ADC demonstrated faster internalization kinetics and lysosomal transport compared to trastuzumab or the parent 39S antibody. Despite showing high levels of activity in preclinical models, MEDI4276 did not exhibit a favorable efficacy-safety profile in clinical trials. In breast cancer patients, the objective response rate (ORR) was low (9.4%). The maximum tolerated dose (MTD) of MEDI4276 was determined to be 0.75 mg/kg every three weeks, but among the 12 patients receiving this dose, seven experienced one or more clinically significant and/or grade 3 or higher adverse events. Zanidatamab zovodotin (also known as ZW49) is another bispecific HER2 ADC (Figure 2a), which, unlike MEDI4276’s tetravalent binding, allows for bivalent binding to HER2 with its asymmetric structure. Despite differences in binding modality, ZW49 also induces HER2 receptor clustering and rapid internalization. A phase I dose-escalation study of ZW49 showed manageable safety and promising antitumor activity in heavily pre-treated patients.</span></p> <ul> <li><span style="font-size: 15px;">Bispecific ADCs targeting two different antigens</span></li> </ul> <p><span style="font-size: 15px;">Bispecific ADCs, capable of simultaneously targeting two different antigens, offer multiple advantages:</span></p> <ul> <li><span style="font-size: 15px;">They can recognize and kill a broader range of tumor cells, including those from heterogeneous tumors.</span></li> <li><span style="font-size: 15px;">When targeting is optimal, bispecific ADCs can bind with higher tumor specificity, minimizing the risk of toxicity to healthy tissue.</span></li> <li><span style="font-size: 15px;">The involvement of multiple antigens and/or cells may produce synergistic effects.</span></li> </ul> <p><span style="font-size: 15px;">As shown in Figure 2b, researchers developed the bispecific ADC AZD9592, which targets EGFR and MET (a molecule preferentially co-expressed with EGFR on the surface of tumor cells). This drug demonstrated promising monotherapy and combination therapy activity with osimertinib in EGFR mutant and wild-type NSCLC, as well as in head and neck squamous cell carcinoma PDX models. Moreover, AZD9592 was well tolerated in monkeys. These positive preclinical results have led to its Phase I trial (NCT05647122). M1231 is another bispecific ADC targeting MUC1 and EGFR, with SC209 as its payload. Preclinical data suggest that, compared to monospecific bivalent ADCs, it shows stronger internalization, lysosomal transport, and therapeutic activity in non-small cell lung cancer and esophageal squamous cell carcinoma (ESCC) PDX models. Additionally, BL-B01D1 is a tetravalent bispecific ADC targeting EGFR and HER3, with the camptothecin derivative ED04 as its payload, connected through whole cysteine coupling with a DAR of 8. Preclinical evaluation confirmed the compound’s antitumor activity in pancreatic or colorectal cancer mouse xenograft models, and it has entered Phase III clinical trials. However, the application of bispecific ADCs also faces potential challenges. For example, the expression ratio of the two target antigens can vary across different tumors and patients, potentially increasing the complexity of identifying and selecting potential treatment responders. Thus, careful evaluation of the target epitopes, binding modalities, and their potential biological properties is crucial for effective treatment with bispecific ADCs. This requires researchers to consider various biological and clinical factors comprehensively when developing bispecific ADCs to optimize treatment strategies.</span></p> <p><span style="font-size: 12px;">Reference:</span></p> <p><span style="font-size: 12px;">Tsuchikama, Kyoji, et al. “Exploring the next generation of antibody–drug conjugates.” <em>Nature Reviews Clinical Oncology</em> (2024): 1-21.</span></p> ]]></content:encoded> </item> <item> <title>Optimization Strategies for ADC and Related Bioanalytical Methods</title> <link>https://www.creative-biolabs.com/blog/adc/optimization-strategies-for-adc-and-related-bioanalytical-methods/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Fri, 22 Mar 2024 05:49:27 +0000</pubDate> <category><![CDATA[Uncategorized]]></category> <category><![CDATA[ADC Bioanalysis]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=659</guid> <description><![CDATA[The emergence of antibody-drug conjugates (ADCs) as a potential therapeutic avenue in cancer treatment has garnered significant attention. By combining the selective specificity of monoclonal antibodies with the cytotoxicity of drug molecules,<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/optimization-strategies-for-adc-and-related-bioanalytical-methods/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The emergence of antibody-drug conjugates (ADCs) as a potential therapeutic avenue in cancer treatment has garnered significant attention. By combining the selective specificity of monoclonal antibodies with the cytotoxicity of drug molecules, ADCs aim to increase the therapeutic index, selectively targeting cancer cells while minimizing systemic toxicity. However, the manufacture of ADCs faces several challenges. These include identifying suitable target antigens, enhancing antibodies, suitable conjugation strategies, <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/linker-module.htm">linkers</a></strong></span>, and <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/drug-module.htm">payloads</a></strong></span>, and its complex in vivo metabolic processes pose difficulties for ADME. This review focuses on the optimization strategies used during ADC development and the technical approach used for ADME analysis.</span></p> <h6><span style="font-size: 15px;">Target and Antibody</span></h6> <p><span style="font-size: 15px;">ADCs have a broad range of targets, and while most can internalize following endocytosis mediated by receptors, some targets are found in the tumor vascular system or the cell surface. The optimal target should have high expression in tumor cells and low or non-existent expression in regular tissues and organs. The majority of the targets selected for current ADCs are antibody targets that have been successfully commercialized or developed based on pre-existing marketed monoclonal antibodies.</span></p> <p><span style="font-size: 15px;">Antibody modifications can be structural or functional. Although early ADCs were primarily synthesized as heterogeneous mixtures, they were found to have subpar pharmacokinetics, stability, and efficacy. Current efforts are geared towards creating homogeneous constructs with accurate drug loading and predetermined, regulated attachment sites. One major advancement in antibody modification is the engineering of antibodies with specific modification sites. Structural modifications are also a method to optimize antibodies, such as utilizing smaller antibodies to achieve high tumor penetration.</span></p> <p><span style="font-size: 15px;">The process of developing antibodies requires in vitro screening for efficacy evaluation. This includes primary screening of the antibody’s internalization ability and activity screening using the factor that antibodies can stimulate target degradation and directly kill tumor cells. Affinity of the antibody for the target antigen is also crucial. The ideal ADC drug’s KD value should not be lower than that of its bare antibody against the antigen. In recent years, ground-breaking ADCs have emerged based on platforms like PROTAC and LYTAC.</span></p> <p><span style="font-size: 15px;">The process for developing antibodies requires in vitro screening for efficacy evaluation. This includes primary screening for the antibody’s internalisation ability, using a fluorescein-labeled antibody, or screening for activity based on the fact that antibodies can stimulate target degradation and directly eliminate tumor cells. Frequently used tools range from laser confocal microscopy for co-localisation analysis and FACS assays for internalisation, to WB assays for target degradation and mechanism studies. Other activity assays include colony formation or CCK-8, complemented by high-throughput screening using high content live cell imaging systems. It’s crucial not to overlook the affinity of the antibody of a qualified ADC drug for the target antigen, as it’s vitally important. At present, the common tests are Elisa, SPR technology, and the KD value of an ideal ADC drug should not be lower than the KD value of its unaccompanied antibody against the antigen.</span></p> <h6><span style="font-size: 15px;">Linker and Payload</span></h6> <p><span style="font-size: 15px;">The potency of the ADC is directly determined by the payload. The most advanced ones include microtubule disrupting agents (MMAE, MMAF, DM1, DM4) and DNA-damaging agents. Non-cleavable alkyl linkers such as N-maleimidomethylcyclohexane-1-carboxylate (MCC, used in Kadcyla) are the most frequently used linkers, along with enzymatically cleavable linkers like the self-immolative para-aminobenzyl (PAB) group attached to a cathepsin-labile valine-citrulline dipeptide (vc, used in ADCETRIS), and acid-labile hydrazone linkers (AcBut, used in Mylotarg). Most approved ADCs use peptide-based linkers which are sensitive to lysosomal proteases. In contrast to the common chemical and enzymatic environment in vivo, <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/non-cleavable-linker.htm">non-cleavable linkers</a></span></strong> are inert, offering the advantage of reduced off-target toxicity, but compromising the bystander effect of the payload.</span></p> <p><span style="font-size: 15px;">The ideal linker prevents the payload’s premature release in plasma and also circumvents stability changes that lead to ADCs aggregation in vivo. Size exclusion chromatography (SEC-HPLC) is typically utilized to analyze the aggregation of antibodies and ADCs. Current strategies for linker improvement are as follows: Enhancing the hydrophilicity and chargeability of peptide-based linkers, creating branching linkers that enable ADC cleavage by tumour-specific/enhanced proteases, and developing branching linkers that can perform site-specific conjugation with different DARs.</span></p> <p><strong><span style="font-size: 15px;">See ADC linker Products:</span></strong></p> <table style="width: 132.449%; height: 923px;"> <tbody> <tr> <td style="border-style: solid; border-color: #050505; width: 15.5859%;" width="143"><span style="font-size: 15px;"><strong>Catalog</strong></span></td> <td style="border-style: solid; border-color: #050505; width: 49.9857%;" width="159"><span style="font-size: 15px;"><strong>Product name</strong></span></td> <td style="border-style: solid; border-color: #050505; width: 14.0728%;" width="143"><span style="font-size: 15px;"><strong>CAS NO</strong></span></td> <td style="border-style: solid; border-color: #050505; width: 11.6353%;" width="143"><span style="font-size: 15px;"><strong>Inquiry</strong></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; width: 15.5859%;" width="143"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/boc-phe-alloc-lys-pab-pnp-3414.htm">ADC-L-042</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 49.9857%;" width="159"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/boc-phe-alloc-lys-pab-pnp-3414.htm">Boc‐Phe‐(Alloc)Lys‐PAB‐PNP</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 14.0728%;" width="143"><span style="font-size: 15px;">1160844-44-9</span></td> <td style="border-style: solid; border-color: #050505; width: 11.6353%;" width="143"><span style="color: #0000ff; font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; width: 15.5859%;" width="143"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/4-s-2-s-2-amino-3-methylbutanamido-5-ureidopentanamido-benzyl-2-pyridin-2-yldisulfanyl-ethylcarbamate-3415.htm">ADC-L-043</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 49.9857%;" width="159"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/4-s-2-s-2-amino-3-methylbutanamido-5-ureidopentanamido-benzyl-2-pyridin-2-yldisulfanyl-ethylcarbamate-3415.htm">4-((S)-2-((S)-2-amino-3- methylbutanamido)-5- ureidopentanamido)benzyl 2-(pyridin- 2-yldisulfanyl)ethylcarbamate</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 14.0728%;" width="143"><span style="font-size: 15px;">1610769-13-5</span></td> <td style="border-style: solid; border-color: #050505; width: 11.6353%;" width="143"><span style="color: #0000ff; font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; width: 15.5859%;" width="143"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/n-succinimidyl-3-pyridin-2-yldithio-propionate-spdp-3416.htm">ADC-L-044</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 49.9857%;" width="159"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/n-succinimidyl-3-pyridin-2-yldithio-propionate-spdp-3416.htm">N-Succinimidyl 3-(pyridin-2-yldithio)-propionate (SPDP)</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 14.0728%;" width="143"><span style="font-size: 15px;">68181‐17‐9</span></td> <td style="border-style: solid; border-color: #050505; width: 11.6353%;" width="143"><span style="color: #0000ff; font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; width: 15.5859%;" width="143"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/perfluorophenyl-3-pyridin-2-yldisulfanyl-propanoate-3417.htm">ADC-L-045</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 49.9857%;" width="159"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/perfluorophenyl-3-pyridin-2-yldisulfanyl-propanoate-3417.htm">perfluorophenyl 3-(pyridin-2-yldisulfanyl)propanoate</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 14.0728%;" width="143"><span style="font-size: 15px;">160580-70-1</span></td> <td style="border-style: solid; border-color: #050505; width: 11.6353%;" width="143"><span style="color: #0000ff; font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; width: 15.5859%;" width="143"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/2-5-dioxopyrrolidin-1-yl-3-pyridin-2-yldisulfanyl-butanoate-3418.htm">ADC-L-046</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 49.9857%;" width="159"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/2-5-dioxopyrrolidin-1-yl-3-pyridin-2-yldisulfanyl-butanoate-3418.htm">2,5-dioxopyrrolidin-1-yl 3-(pyridin-2-yldisulfanyl)butanoate</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 14.0728%;" width="143"><span style="font-size: 15px;">107348-47-0</span></td> <td style="border-style: solid; border-color: #050505; width: 11.6353%;" width="143"><span style="color: #0000ff; font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; width: 15.5859%;" width="143"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/2-5-dioxopyrrolidin-1-yl-3-methyl-3-pyridin-2-yldisulfanyl-butanoate-3419.htm">ADC-L-047</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 49.9857%;" width="159"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/2-5-dioxopyrrolidin-1-yl-3-methyl-3-pyridin-2-yldisulfanyl-butanoate-3419.htm">2,5-dioxopyrrolidin-1-yl 3-methyl-3-(pyridin-2-yldisulfanyl)butanoate</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 14.0728%;" width="143"><span style="font-size: 15px;">–</span></td> <td style="border-style: solid; border-color: #050505; width: 11.6353%;" width="143"><span style="color: #0000ff; font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; width: 15.5859%;" width="143"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/n-succinimidyl-4-2-pyridyldithio-butanoate-3420.htm">ADC-L-048</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 49.9857%;" width="159"><span style="font-size: 15px;"><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/n-succinimidyl-4-2-pyridyldithio-butanoate-3420.htm">N-Succinimidyl 4-(2-pyridyldithio)butanoate</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; width: 14.0728%;" width="143"><span style="font-size: 15px;">115088-06-7</span></td> <td style="border-style: solid; border-color: #050505; width: 11.6353%;" width="143"><span style="color: #0000ff; font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></td> </tr> </tbody> </table> <h6><span style="font-size: 15px;">The conjugation and DAR</span></h6> <p><span style="font-size: 15px;">The number of drug molecules that can be attached to a single antibody depends on the conjugation chemistry. This quantity is characterized by the Drug to Antibody Ratio (DAR), which represents the average number of drug molecules per antibody molecule. In the case of Antibody-Drug Conjugates (ADCs), the DAR and its changes in vivo serve as critical parameters. They can influence the ADC’s physicochemical properties, effectiveness, safety, and pharmacokinetics. ADCs with high DARs are prone to aggregation and might exhibit an accelerated clearance rate or potentially pose a higher toxicity risk as compared to non-conjugated monoclonal antibodies (mAb) or antibodies with lower loads. Consequently, rigorous in vivo testing is essential to find the optimal DARs for specific targets and antibodies, in order to attain the most beneficial therapeutic window.</span></p> <p><span style="font-size: 15px;">As for determining the average DAR, the simplest method is to measure the concentration of both the drug and antibody using ultraviolet-visible (UV/VIS) spectroscopic measurements or calculating it using a Matrix-assisted Laser Desorption/Ionization Mass Spectrometer (MALDI-MS) or Electrospray Ionization Mass Spectrometer (ESI-MS). Several liquid-phase methods, like Hydrophobic Interaction Chromatography (HIC), Reversed-Phase Liquid Chromatography (RPLC), and Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS), are also useful for analyzing the DAR in homogeneous and non-homogeneous ADCs. However, the suitability of these methods in different sample types should be taken into consideration. This should be supplemented with in vivo and in vitro experiments to monitor the changes in half-life and thermal <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/adc-stability-analysis.htm">stability of ADCs</a></strong></span>.</span></p> <h6><span style="font-size: 15px;">ADME</span></h6> <p><span style="font-size: 15px;">The establishment of an ADME evaluation system is critical to the ADC development process. As previously mentioned, this is due to the variable physicochemical properties of ADCs, resulting from differences in linker, payload, conjugation strategy, and DARs. For a comprehensive assessment of a novel ADC’s ADME, it is necessary to characterize the disposition of both the intact molecule and its various components. This includes the target-mediated and catabolic clearance of the mAb, as well as the release, traditional small molecule distribution, metabolism, and excretion of the released drug. In ADC drug bioanalysis, the ligand binding assay (LBA) is the most commonly used bioanalytical method. It necessitates the use of platforms designed for different antibodies and load types. ELISA and ECLA, for instance, can be used to detect total antibodies and conjugated antibodies. Meanwhile, LC-HRMS serves as a more general detection method, and LC-MS/MS is mainly used to analyze free payload and metabolites for quantitative analysis.</span></p> <h6><span style="font-size: 15px;">Conclusions</span></h6> <p><span style="font-size: 15px;">The process of module optimization and ADME characterization for an ADC is complex, considering the need to account for both the mAb and small molecule components. The present review elucidates the experimental systems and strategies in current use, offering guidance to help researchers successfully develop novel ADCs with desirable ADME characteristics. As ADC technology is still under development, a continuous re-evaluation is necessary as the field matures in the coming years.</span></p> <p><span style="font-size: 15px;">Reference:</span></p> <p><span style="font-size: 15px;">1. Beaumont, Kevin, et al. “ADME and DMPK Considerations for the Discovery and Development of Antibody Drug Conjugates (ADCs).” <em>Xenobiotica</em>, vol. 52, no. 8, Aug. 2022, pp. 770–85.</span></p> ]]></content:encoded> </item> <item> <title>How to Screen an ADC Payload?</title> <link>https://www.creative-biolabs.com/blog/adc/how-to-screen-an-adc-payload/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Mon, 18 Mar 2024 03:28:41 +0000</pubDate> <category><![CDATA[Review]]></category> <category><![CDATA[ADC payload]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=654</guid> <description><![CDATA[Introduction of the Camptothecin Derivative Payload Camptothecin was first isolated from camptothecin stems in 1966 by Wall et al., mainly in the form of topological isomerase (topoI). In order to inhibit the<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/how-to-screen-an-adc-payload/">Read More...</a>]]></description> <content:encoded><![CDATA[<h6><span style="font-size: 15px;"><strong>Introduction of the Camptothecin Derivative Payload</strong></span></h6> <p><span style="font-size: 15px;">Camptothecin was first isolated from camptothecin stems in 1966 by Wall et al., mainly in the form of topological isomerase (topoI). In order to inhibit the synthesis of DNA as a target to exert an anti-cancer effect, its derivatives have been widely used in the treatment of related cancers in clinical practice, including irinotecan and topotecan. The success of DS-8201 has pushed the research of camptothecin to a climax. According to statistics, there have been 72 ADC drugs carrying camptothecin derivatives into the clinic. These 72 ADCs target a variety of different targets, including B7-H3, <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/adc-development-services-targeting-her3.htm">HER3</a></span></strong>, <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/adc-development-services-targeting-trop2.htm">TROP2</a></span></strong>, <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-nectin4-74.htm">Nectin4</a></span></strong>, FRα, Cldn18.2, MUC18, CDH6, <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/target-erbb2-37.htm">HER2</a></span></strong>, cMET, etc., and in addition, these ADCs also use up to 21 different linkers and 15 different payloads.</span></p> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/ablog-202403-2-1.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-655" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/ablog-202403-2-1.jpg" alt="" width="391" height="130" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/ablog-202403-2-1.jpg 664w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/ablog-202403-2-1-300x100.jpg 300w" sizes="(max-width: 391px) 100vw, 391px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 1. A Schematic View of the Camptothecin Analog</span></p> <h6><span style="font-size: 15px;"><strong>Considerations for the Modification of the Structure of Camptothecin</strong></span></h6> <p><span style="font-size: 15px;">Let’s take a look at how Zymeworks’ Payload was designed and screened, starting with determining the location of the modification based on the current research on camptothecin. In order to design a new camptothecin analog, the researchers analyzed more than 60 camptothecin structure-activity relationship (SAR) data. The camptothecin structure that is essential for activity includes the 20(S)-hydroxyl and lactone functional groups of the E ring, the pyridone D ring, and maintaining the planarity of the ABCDE ring system. The C-7 and C-9 positions can accommodate a variety of substituents, including additional fusion rings as seen in exatecan and its derivatives, while substitutions in the C-12 to C-14 regions significantly reduce activity. C-10 and C-11 can only accommodate small substituents, and 11-fluoroptothecin shows higher activity, which makes it possible to explore a wider variety of substituents at the C-7, C-9, and C-10 positions.</span></p> <p><span style="font-size: 15px;">Our Ready-To-Use Camptothecin Analog Products</span></p> <table style="width: 131.292%; border-color: #050505;"> <tbody> <tr> <td style="width: 19.0397%; border-style: solid; border-color: #050505;" width="94"><span style="font-size: 15px;">Cat.No.</span></td> <td style="width: 66.8874%; border-style: solid; border-color: #050505;" width="359"><span style="font-size: 15px;">Product Name</span></td> <td style="width: 43.1738%; border-style: solid; border-color: #050505;" width="66"><span style="font-size: 15px;">Price</span></td> </tr> <tr> <td style="width: 19.0397%; border-style: solid; border-color: #050505;" width="94"><span style="font-size: 15px;">ADC-W-372</span></td> <td style="width: 66.8874%; border-style: solid; border-color: #050505;" width="359"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/h1f6-glucuronide-camptothecin-analog-372.htm">Anti-CD70 (clone h1F6)-β-glucuronide-Camptothecin Analog ADC</a></span></strong></span></td> <td style="width: 43.1738%; border-style: solid; border-color: #050505;" width="66"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></span></td> </tr> <tr> <td style="width: 19.0397%; border-style: solid; border-color: #050505;" width="94"><span style="font-size: 15px;">ADC-W-349</span></td> <td style="width: 66.8874%; border-style: solid; border-color: #050505;" width="359"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/cac10-glucuronide-camptothecin-analog-349.htm">Anti-TNFRSF8 (CA10)-β-glucuronide-Camptothecin Analog ADC</a></span></strong></span></td> <td style="width: 43.1738%; border-style: solid; border-color: #050505;" width="66"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></span></td> </tr> <tr> <td style="width: 19.0397%; border-style: solid; border-color: #050505;" width="94"><span style="font-size: 15px;">ADC-W-2563</span></td> <td style="width: 66.8874%; border-style: solid; border-color: #050505;" width="359"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/anetumab-mc-vc-pab-sn38-adc-2844.htm">Anti-MSLN (Anetumab)-MC-Vc-PAB-SN38 ADC</a></span></strong></span></td> <td style="width: 43.1738%; border-style: solid; border-color: #050505;" width="66"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></span></td> </tr> <tr> <td style="width: 19.0397%; border-style: solid; border-color: #050505;" width="94"><span style="font-size: 15px;">ADC-W-1986</span></td> <td style="width: 66.8874%; border-style: solid; border-color: #050505;" width="359"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/sevirumab-mc-vc-pab-sn38-adc-2267.htm">Anti-Phosphatidylserine (Sevirumab)-MC-Vc-PAB-SN38 ADC</a></span></strong></span></td> <td style="width: 43.1738%; border-style: solid; border-color: #050505;" width="66"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></span></td> </tr> <tr> <td style="width: 19.0397%; border-style: solid; border-color: #050505;" width="94"><span style="font-size: 15px;">ADC-W-2154</span></td> <td style="width: 66.8874%; border-style: solid; border-color: #050505;" width="359"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/talizumab-mc-vc-pab-sn38-adc-2435.htm">Anti-IgE Fc (Talizumab)-MC-Vc-PAB-SN38 ADC</a></span></strong></span></td> <td style="width: 43.1738%; border-style: solid; border-color: #050505;" width="66"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></span></td> </tr> </tbody> </table> <h6><span style="font-size: 15px;"><strong>Preliminary Screening of Candidates for Payload</strong></span></h6> <p><span style="font-size: 15px;">Based on the above study, Zymeworks focused on the modification of the C-7 (R1) and C-10 (R3) positions of the camptothecin backbone, while keeping the 11-fluorosubstituent unchanged and C-9 unsubstituted. His research focuses on analogs with hydrophilic functional groups (e.g., amines, carbonates, urea, sulfonamides) with a linkable hydroxyl group at the C-7 position and a methyl or methoxy group at the C-10 position. In addition, the investigators also sought to evaluate camptothecin analogs with an amino group at the C-10 position, providing an alternative for linker connection. Ultimately, a library of approximately 100 paclitaxel small molecules was synthesized and evaluated in vitro for cytotoxicity in a range of HER2-expressing cell lines, including SK-BR-3, Calu-3, SK-OV-3, and ZR-75-1.</span></p> <p><span style="font-size: 15px;">Structure-activity relationship analysis of these synthesized small molecules revealed that most compounds with methyl groups at the C-10 position had a pIC50 ≥ 8.0 (i.e., IC50 < 10 nM) with large variability in their hydrophobic profiles (cLogD range of -1 to 3). analogs with an amine group at the C-10 position are comparatively more effective and more hydrophilic. In contrast, camptothecin with a C-10 methoxy substituent was less active and had no significant improvement in hydrophobicity.</span></p> <h6><span style="font-size: 15px;"><strong>Payload-linker Combination Filtering</strong></span></h6> <p><span style="font-size: 15px;">From this library, seven derivatives were selected for further study with methyl or amine groups at the C-10 position and covering a wide range of activity, hydrophilicity, and structural diversity at the C-7 position. Subsequently, these seven different derivatives were studied with different linkers and different positions, and the linker is a cleavable tetrapeptide sequence GGFG, which is combined with maleimide containing PEG or maleimide-triethylene glycol (MT) propionyl group. In addition, DL7 and DL8 were prepared for direct comparison with ADCs carrying clinically validated DXd vectors.</span></p> <h6><span style="font-size: 15px;"><strong>Comprehensive Screening of Druggability</strong></span></h6> <p><span style="font-size: 15px;">This was followed by a comprehensive evaluation of the different drug candidates, including hydrophilicity, in vitro target-dependent efficacy, stability (blood stability, stability of PH7 buffer species), bystander effect, efficacy in animal models, including 3D tumor model efficacy, ADME/DMPK properties, tolerability in non-human primates, etc., and finally determining the candidate Payload ZD06519 (FD1).</span></p> <h6><span style="font-size: 15px;"><strong>Summary</strong></span></h6> <p><span style="font-size: 15px;">The success of DS-8201 completely detonated the research on ADCs, and at the same time, it also put the camptothecin derivative DXd in the spotlight and attracted countless imitations from later generations. Payload’s modification is a systematic project, and any small changes will not only affect the compound itself but may also affect the final efficacy. This article introduces in detail the process of ZD06519 (FD1) modification screening, including the consideration of modification location, the consideration of substitution group, the consideration of physical and chemical properties, the consideration of metabolism and pharmacodynamics, etc., which not only provides a reference for the modification of camptothecin derivatives, but also provides a direction for the development of other payloads.</span></p> ]]></content:encoded> </item> <item> <title>Several Ways to Sort Out Sulfhydryl-Conjugated ADCs</title> <link>https://www.creative-biolabs.com/blog/adc/several-ways-to-sort-out-sulfhydryl-conjugated-adcs/</link> <dc:creator><![CDATA[bioadc]]></dc:creator> <pubDate>Mon, 18 Mar 2024 03:00:49 +0000</pubDate> <category><![CDATA[Review]]></category> <category><![CDATA[ADCs]]></category> <category><![CDATA[Sulfhydryl-Conjugated]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=642</guid> <description><![CDATA[The popularity of sulfhydryl groups in ADC preparation can be traced back to three factors: (a) thiols are the most nucleophilic amino acid side-chain functional group (much more nucleophilic than amines); (b)<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/several-ways-to-sort-out-sulfhydryl-conjugated-adcs/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The popularity of sulfhydryl groups in ADC preparation can be traced back to three factors: (a) thiols are the most nucleophilic amino acid side-chain functional group (much more nucleophilic than amines); (b) the relatively small number of cysteines (8 for IgG1 and IgG4) in the antibody suitable for conjugation; and (c) the fact that stability of the antibody is not critical, allowing for relatively controlled customization of the DAR; Interchain cysteines are present in the hinge region and connect the heavy chain (HC) and light chain (LC), appearing to favor “hiding” hydrophobic <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/classify-adc-toxins-6.htm">payloads</a></strong></span> after conjugation. It must be noted that a reduction step is always required prior to conjugation to release free thiols.</span></p> <p><span style="font-size: 15px;">The vast majority of thiol-conjugated ADCs are maleimide-based (see Figure 1). Alkylation occurs between the primary interstrand cysteine (see Figures 1A and B) and the engineered cysteine (see Figure 1C). The exception is ADCs prepared by nucleophilic aromatic substitution. Other chemistries, such as disulfide exchange, are also being developed for some preclinical assets.</span></p> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-1.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-643" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-1.jpg" alt="" width="334" height="268" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-1.jpg 617w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-1-300x240.jpg 300w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-1-600x480.jpg 600w" sizes="(max-width: 334px) 100vw, 334px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 1. Groups based on maleimide chemically coupled ADC thiols<sup>1</sup></span></p> <h6><span style="font-size: 15px;"><strong>Reaction with Maleimide</strong></span></h6> <p><span style="font-size: 15px;">Maleimide is susceptible to alkylation by the nucleophilic Michael addition reaction of the thiol group to form a stable thioether bond (Figure 2). In the pH range of 6.5–7.5, the maleimide reaction is specific for thiols and reacts 1000 times faster with amines than at pH 7.0, so complete transformation can be achieved with only a small amount of excess reagent. The main drawback of the maleimide alkylation reaction is the reversibility of the Michael addition reaction, the rate of which has a lot to do with the pKa of the specific cysteine residue linked. This reverse Michael reaction may lead to the premature release of the linker payload in the bloodstream and may lead to adverse effects, which is also an important driver for the development of more stable maleimide variants.</span></p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-2.jpg"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-644" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-2.jpg" alt="" width="720" height="113" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-2.jpg 720w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-2-300x47.jpg 300w" sizes="(max-width: 720px) 100vw, 720px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 2. Alkylation of various maleimide reagents with cysteine<sup>1</sup></span></p> <p><span style="font-size: 15px;">As mentioned above, cysteines in monoclonal antibodies require a reduction step to release the thiol group prior to conjugation. As a result, a number of free thiol groups (up to 8 for IgG1 and IgG4) can be released by carefully optimizing the amount of reducing agent (typically TCEP or DTT) prior to the addition of maleimide-functionalized payloads. ADCs prepared by conjugation with cysteine include Adcetriss, Polivys, Padcevs, Enhertu, Blenrep, Trodelvys, Zynlontat, and others. Due to the lack of site specificity, these ADCs are typically produced as random mixtures with an average DAR of 2.3–4. However, there are two notable exceptions, Enhertu and Trodelvys, which, due to the relatively low toxicity of the camptothecin toxins carried, are produced by (near) quantitative conjugation of all interchain cysteines, with DARs of 7.7 and 7.6, respectively, and therefore can also be considered so-called site-directed coupling.</span></p> <p><span style="font-size: 15px;">It is important to note that maleimide (mc) linkers are used in the vast majority of cases, although some ADCs use more electron-poor β-aminoethyl or ethylene glycol spacers. Some phenyl-substituted maleimides have also been reported to be more stable and are currently in preclinical development.</span></p> <p><span style="font-size: 15px;">In 2008, it was reported that site-specific conjugation of the cytotoxic <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/classify-drug-linker-complexes-8.htm">linker payload</a></strong></span> to monoclonal antibodies with specific cysteine may improve the therapeutic index of ADCs compared to randomized ADCs. Since then, a variety of site-specific ADCs have entered the clinic, such as SGNCD19B, CD123A, and CD352A (all HC-S239C mutations), RG7861/DSTA4637S (LC-V205C mutations), IMGN632 (S442C mutations), and BAT8003 (A114C mutations), and even bicysteine-based ADCs such as PF-06804103 (LC-K183C+). HC-K290C)。 In addition, two complementary technologies have been developed, namely cysteine insertion (e.g., MEDI2228 (HC-i239C)) and fusion of HC-terminal peptide tags (e.g., ALT-P7 (C-terminal ACGHAACGHA)). Unfortunately, the use of cysteine-engineered antibodies does not guarantee clinical success, as some of these assets have been abandoned (e.g., BAT8003 and all three Seagen ADCs mentioned above).</span></p> <p><span style="font-size: 15px;">The inverse Michael reaction can be inhibited by hydrolyzing the original thioether-succinimide adduct to provide a maleamide acid derivative. This hydrolysis can be achieved by prolonged treatment of ADCs at pH 9. Such conditions may apparently result in additional post-translational modifications of the antibody, such as deamidation or pyroglutamic acid formation. In response to this problem, Seagen has developed an effective solution by adding aminomethyl maleimide, which is based on 2,3-diaminopropionic acid (DPR technology), to the α position of the N-alkyl chain (see figure below). The amino group induces spontaneous autohydrolysis of the succinimide conjugate, thereby blocking the inverse Michael reaction. The ADC product SGN-CD48A (now abandoned) was the first to feature DPR technology, as was SGN-CD228A.</span></p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-3.jpg"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-645" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-3.jpg" alt="" width="634" height="277" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-3.jpg 634w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-3-300x131.jpg 300w" sizes="(max-width: 634px) 100vw, 634px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 3. Cysteine is alkylated with a diaminopropionic acid (DPR)-based aminomethyl maleimide reagent and then autohydrolyzed to obtain maleic acid conjugates.<sup>1</sup></span></p> <p><span style="font-size: 15px;">Our drug-linker complex products:</span></p> <table style="border-style: solid; border-color: #050505; width: 102.814%;"> <tbody> <tr> <td style="border-style: solid; border-color: #050505; text-align: center; width: 17.5497%;" width="94"><span style="font-size: 15px;">Cat.No.</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 43.543%;" width="182"><span style="font-size: 15px;">Product name</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 19.0397%;" width="138"><span style="font-size: 15px;">CAS NO</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 22.5166%;" width="138"><span style="font-size: 15px;">Price</span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; text-align: center; width: 17.5497%;" width="94"><span style="font-size: 15px;">ADC-S-024</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 43.543%;" width="182"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/dbm-mmaf-4658.htm">DBM-MMAF</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 19.0397%;" width="138"><span style="font-size: 15px;">–</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 22.5166%;" width="138"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; text-align: center; width: 17.5497%;" width="94"><span style="font-size: 15px;">ADC-S-025</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 43.543%;" width="182"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/mc-betaglucuronide-mmae-1-4659.htm">MC-betaglucuronide-MMAE-1</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 19.0397%;" width="138"><span style="font-size: 15px;">–</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 22.5166%;" width="138"><strong><span style="font-size: 15px; color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; text-align: center; width: 17.5497%;" width="94"><span style="font-size: 15px;">ADC-S-026</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 43.543%;" width="182"><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/adc/mc-betaglucuronide-mmae-2-4660.htm"><span style="color: #0000ff;"><strong>MC-betaglucuronide-MMAE-2</strong></span></a></span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 19.0397%;" width="138"><span style="font-size: 15px;">–</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 22.5166%;" width="138"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></span></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; text-align: center; width: 17.5497%;" width="94"><span style="font-size: 15px;">ADC-S-027</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 43.543%;" width="182"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/sgd-1910-mc-val-ala-pbd-4661.htm">SGD-1910 (Mc-Val-Ala-PBD)</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 19.0397%;" width="138"><span style="font-size: 15px;">1342820-51-2</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 22.5166%;" width="138"><strong><span style="font-size: 15px; color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></td> </tr> <tr> <td style="border-style: solid; border-color: #050505; text-align: center; width: 17.5497%;" width="94"><span style="font-size: 15px;">ADC-S-028</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 43.543%;" width="182"><span style="color: #0000ff;"><strong><span style="font-size: 15px;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/mc-pbd-4662.htm">MC-PBD</a></span></strong></span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 19.0397%;" width="138"><span style="font-size: 15px;">–</span></td> <td style="border-style: solid; border-color: #050505; text-align: center; width: 22.5166%;" width="138"><strong><span style="font-size: 15px; color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/form/order">Inquiry</a></span></strong></td> </tr> </tbody> </table> <h6><span style="font-size: 15px;"><strong>Other Cysteine Alkylation Reagents</strong></span></h6> <p><span style="font-size: 15px;">For example, the high reactivity of α-haloacetamide reagents is well known, and in the case of 2-iodoacetamide, it is an indisputable choice for blocking free cysteine in proteins or protein mixtures (e.g., cell lysates). Importantly, the resulting thioether bond is completely irreversible and therefore superior to thiol-maleimide ether in terms of stability. In fact, Alley et al. reported in 2008 that the use of a-bromoacetamide hexanoyl linkers could provide a thioether ADC with excellent plasma stability, with no measurable systemic drug release within 2 weeks of mouse dosing and a 25% increase in intratumoral drug exposure within 7 days. However, despite the differences in stability between bromoacetamide and maleimide-based ADCs, there were no significant differences in their potency, activity, or toxicity properties. The reason for this surprising lack of distinction is likely to be that for this particular maleimide-based ADC, the half-life of the ADC’s linker and the half-life of the ADC clearance are similar. Since ADC concentrations decrease over time, prolonging the junction half-life beyond the pharmacokinetic half-life is unlikely to have a significant effect on drug exposure.</span></p> <p><span style="font-size: 15px;">Based on the discovery that methylsulfonylbenzothiazole (MSBT) is a selective thiol blocker, Barbas et al. developed a series of aromatic methylsulfonone reagents for the alkylation of thiol-containing proteins, mainly oxazinazole and benzothiazole. Similarly, methylsulfonate reacts with thiols through a nucleophilic aromatic substitution mechanism (see figure below), a concept that is applied in SKB264/BT001035.</span></p> <p><span style="font-size: 15px;">Researchers at Glythera have reported highly stable thioether ADCs obtained by incubating free cysteine thiols with 4-vinylpyridine, a technique known as PermaLinks. The resulting ADC is significantly stable and is not easily degraded.</span></p> <p><span style="font-size: 15px;">The last technology worth mentioning is the phosphoamide coupling technology developed at the University of Berlin, which is still in its early stages but is currently being commercially used by Tubulis. Studies have shown that aryl phosphonate with electron-deficient triple bonds has excellent cysteine-selective reactivity, and the resulting (Z)-vinyl sulfide has excellent stability compared to traditional maleimide linkages.</span></p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-4.jpg"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-646" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-4.jpg" alt="" width="660" height="305" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-4.jpg 660w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-4-300x139.jpg 300w" sizes="(max-width: 660px) 100vw, 660px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 4. Alternative techniques for cysteine alkylation<sup>1</sup></span></p> <h6><span style="font-size: 15px;"><strong>Alkylation/Crosslinking with Bismaleimide or Bismaleamide Acid</strong></span></h6> <p><span style="font-size: 15px;">The ability to alkylate maleimide has also been applied to various cross-linked bismaleimide reagents. Each reagent captures two free cysteine thiol groups, resulting in the formation of DAR4 ADCs after the complete reduction of all eight interchain disulfide bonds. It is important to note that although mixtures are generated due to interchain cross-linking between thiol groups (e.g., from HC-226C to HC-229C), the resulting ADCs have a narrow DAR distribution. NewBio’s NBT828 uses a bismaleimide crosslinker. Bisuccinimide conjugates may also be hydrolyzed to carbamate derivatives upon the nucleophilic addition of a thiol group, providing a conjugate that cannot undergo reverse Michael degradation.</span></p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-5.jpg"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-647" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-5.jpg" alt="" width="660" height="195" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-5.jpg 660w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-5-300x89.jpg 300w" sizes="(max-width: 660px) 100vw, 660px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 5. Bismaleimide reagent cross-linked cysteine<sup>1</sup></span></p> <p><span style="font-size: 15px;">Researchers from AstraZeneca reported rebridging cysteine-engineered antibodies with bismaleimide-modified payloads (PBDs) to obtain DAR1 ADCs.</span></p> <h6><span style="font-size: 15px;"><strong>THIObridget Conjugation</strong></span></h6> <p><span style="font-size: 15px;">A novel coupling reagent originally reported by Del Rosario et al. and Wilbur et al., taking advantage of the high nucleophilicity and susceptibility to Michael addition reactions of free thiols, was further developed by Poly-Therics (now known as Abzena, with THIObridget technology) for ADCs. This rebridging technique enhances the stability of the reducing antibody by using the thiol formed by religating the dithiol reaction group, more effectively maintaining the conformational integrity of the final conjugate. Close-to-the-molecular-scale dithiol reactive groups are well suited for this purpose, as they can be seamlessly integrated into the protein structure without disrupting subunit interactions. The a-toluenesulfonyl methyl-a,b-unsaturated ketone reagent was applied to the reducing antibody, which was generated <em>in situ</em> from a precursor of bis-a,a-toluenesulfonyl methyl ketone, triggering a series of reactions including Michael addition, b-elimination toluenesulfonic acid, and subsequent Michael addition to produce a stable conjugated product.</span></p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-6.jpg"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-648" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-6.jpg" alt="" width="816" height="323" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-6.jpg 816w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-6-300x119.jpg 300w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-6-768x304.jpg 768w" sizes="(max-width: 816px) 100vw, 816px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 6. THIObridget technology<sup>1</sup></span></p> <h6><span style="font-size: 15px;"><strong>Alkylation/Conjugation by Bisbromomethyl Aromatic Reagents</strong></span></h6> <p><span style="font-size: 15px;">Concortis (now Sorrento) developed a third coupling method for DAR4 ADCs, called C-lockt technology. The C-lockt technique combines the nucleophilic nature of thiols with the propensity of the benzyl bromide population to undergo nucleophilic SN2 substitution reactions. Thus, by reducing the interchain disulfide bonds, which then react with a bisbromomethyl aromatic reagent (e.g., bisbromomethylquinoxaline), an irreversible cross-linking reaction occurs to form a thioether. Interestingly, it was reported that the clinical ADC (CD38-ADC) prepared using the C-lockt technique was not DAR4 but DAR3 (averaged).</span></p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-7.jpg"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-649" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-7.jpg" alt="" width="788" height="139" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-7.jpg 788w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-7-300x53.jpg 300w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-7-768x135.jpg 768w" sizes="(max-width: 788px) 100vw, 788px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 7. Cysteine crosslinking by diaalkylation of bisbromomethylquinoxaline<sup>1</sup></span></p> <h6><span style="font-size: 15px;"><strong>Use Dibromopyridine Dione for Conjugation</strong></span></h6> <p><span style="font-size: 15px;">Inspired by the use of dibromomaleimide groups to re-bridging reduced disulfide bonds, Chudasama et al. developed a rebridging coupling technique based on the pyridine dione (PD) core structure. Unlike maleimide derivatives, pyridine dione rings are more stable and do not open the rings by hydrolysis, resulting in a more homogeneous binder. The authors prepared monobromo-PD (MBPD) and dibromo-PD (DBPD) derivatives and demonstrated that both react specifically with thiol groups at pH 8.0, even in the presence of amines. DBPD reactive groups have been used to develop a range of crosslinking and modification reagents that incorporate other reaction sites, such as alkynes for click chemistry and even derivatives containing reducing agents, for one-step antibody reduction and conjugation. The use of DBPD thiols to rebridge chemistry with antibody binding has been applied to create highly fixed-point ADCs, such as trastuzumab for DAR4 MMAE.</span></p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-8.jpg"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-650" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-8.jpg" alt="" width="660" height="319" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-8.jpg 660w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-8-300x145.jpg 300w" sizes="(max-width: 660px) 100vw, 660px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 8. Cross-linking of antibody thiol groups with dibromoazadione derivatives<sup>1</sup></span></p> <h6><span style="font-size: 15px;"><strong>Disulfide bond coupling</strong></span></h6> <p><span style="font-size: 15px;">Disulfide bonds have been used since the early days of ADCs, such as in MLN2704, CMD-401, BIWI-1, and IMGN242. A linker design containing a disulfide bond is located somewhere between the cytotoxic payload and the antibody and can facilitate a reversible linkage that can be cleaved by glutathione reduction within tumor cells to release the toxin. However, the reality is that premature severing of circulating disulfide bonds often occurs due to the presence of free cysteine, which results in the release of the payload before the tumor cells enter. The addition of a protective group, such as a methyl or dimethyl group, to the carbon adjacent to the disulfide bond has been used to increase stability in circulation by creating steric hindrance around the disulfide bond, but in many cases, it also reduces the rate of toxin release from tumor cells. In addition, even though the increased steric hindrance improves the stability of disulfide bonds, these ADCs are not as effective as conjugating drugs to engineered cysteine residues at optimal locations in the antibody sequence.</span></p> <p><span style="font-size: 15px;">For the first time, Pillow et al. directly conjugated a small molecule drug to an engineered cysteine antibody at different locations to generate a sterically unhindered disulfide bond-Mertansine ADC. The results were compared with ADCs with different sterically hindered disulfide bonds conjugated to lysine residues. The authors identified the engineered cysteine located at LC-K149C as the most stable binding site for drug attachments containing disulfide bonds. ADCs created using the LC-K149C locus show excellent circulatory stability while allowing potent glutathione (GSH)-mediated cleavage within tumor cells and thus have the highest potency against mouse human non-Hodgkin lymphoma xenografts of all mutants evaluated.</span></p> <p><span style="font-size: 15px;"> <a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-9.jpg"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-651" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-9.jpg" alt="" width="800" height="139" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-9.jpg 800w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-9-300x52.jpg 300w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2024/03/Ablog-202403-9-768x133.jpg 768w" sizes="(max-width: 800px) 100vw, 800px" /></a></span></p> <p style="text-align: center;"><span style="font-size: 12px;">Figure 9. Disulfide bonds are produced by engineering cysteines to prepare antibody conjugates<sup>1</sup></span></p> <p><span style="font-size: 15px;">Reference:</span></p> <ol> <li><span style="font-size: 15px;">van Delft, Floris, and John M. Lambert, eds. Chemical Linkers in Antibody-Drug Conjugates (ADCs). Vol. 81. Royal Society of Chemistry, 2021.</span></li> </ol> ]]></content:encoded> </item> </channel> </rss>