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	<title>adc research &#8211; Creative Biolabs ADC Blog</title>
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	<title>adc research &#8211; Creative Biolabs ADC Blog</title>
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		<title>The Success of Seattle Genetics/Wutian ADC Adcetris for Phase III Clinical Surgery of Peripheral T Cell Lymphoma (PTCL)</title>
		<link>https://www.creative-biolabs.com/blog/adc/antibody-drug-conjugate-adcetris/</link>
		
		<dc:creator><![CDATA[bioadc]]></dc:creator>
		<pubDate>Fri, 26 Oct 2018 03:59:50 +0000</pubDate>
				<category><![CDATA[Antibody-drug Conjugates Research]]></category>
		<category><![CDATA[News]]></category>
		<category><![CDATA[adc clinical trials]]></category>
		<category><![CDATA[adc research]]></category>
		<category><![CDATA[Adcetris]]></category>
		<category><![CDATA[antibody drug conjugates]]></category>
		<category><![CDATA[mmae]]></category>
		<category><![CDATA[protease-sensitive crosslinker]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=163</guid>

					<description><![CDATA[October 03, 2018 &#8211; Seattle Genetics and Takeda recently announced the evaluation of antibody conjugates Adcetris (brentuximab vedotin) for the treatment of peripheral T-cell lymphoma (PTCL, also known as mature Phase III<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/antibody-drug-conjugate-adcetris/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">October 03, 2018 &#8211; Seattle Genetics and Takeda recently announced the evaluation of antibody conjugates Adcetris (brentuximab vedotin) for the treatment of peripheral T-cell lymphoma (PTCL, also known as mature Phase III clinical study of T-cell lymphoma, MTCL) reached the primary endpoint of ECHELON-2. Based on data of the research, Seattle Genetics has planned to submit Adcetris&#8217; Supplementary Biological License (sBLA) to the US FDA in the near future.</span><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/10/Adcetris-adc.jpg"><img decoding="async" fetchpriority="high" class="size-full wp-image-173 aligncenter" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/10/Adcetris-adc.jpg" alt="" width="600" height="350" /></a></p>
<h6>PTCL Clinal Program Introduction</h6>
<p><span style="font-size: 15px;">ELON-2 is the largest randomized, double-blind, phase III study to date in PTCL patients enrolled in previously untreated CD30-positive PTCL patients, which evaluated for Adcetris in combination with chemotherapy regimen CHP (cyclophosphamide + A) and the efficacy and safety of CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) in first-line treatment compared to the currently accepted first-line standard care regimen for PTCL. The primary endpoint of the study was progression-free survival (PFS) assessed by the Independent Review Body (IRF).</span></p>
<p><span style="font-size: 15px;">The results of the study showed that the Adcetris+CHP regimen achieved a statistically significant improvement in PFS (HR=0.71, p=0.0110) compared to the CHOP regimen, reaching the primary endpoint of the study. In addition, the Adcetris+CHP regimen also demonstrated superiority in key secondary endpoint overall survival (OS) compared to the CHOP regimen (HR=0.66, p=0.0244). In other key secondary endpoints, the Adcetris+CHP regimen also showed statistically significant advantages, including: PFS, complete response rate (CRR), and objective response rate (ORR) in patients with intersystem degenerative large cell lymphoma (sALCL). In this research, the Adcetris+CHP scheme has comparable security to the CHOP scheme. Detailed data will be announced at the annual meeting of the American Society of Hematology (ASH) in early December.</span></p>
<h6>Antibody-drug Conjugate (Adcetris)</h6>
<p><span style="font-size: 15px;">Adcetris is an <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/services.htm">antibody-conjugated drug (ADC) </a></span></strong>that is coupled by a monoclonal antibody that targets the CD30 protein and a microtubule disrupter (<span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/auristatins.htm">monomethyl auristatin E, MMAE</a></strong></span>) via a <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/peptide-linker.htm">protease-sensitive crosslinker</a></strong></span>. The coupling technology is the proprietary technology of Seattle Genetics. CD30 protein is a clear marker of classical Hodgkin&#8217;s lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), while Auristatin E blocks cell division by inhibiting the polymerization of tubulin. Adcetris is stable in the blood and releases MMAE after internalization by CD30-positive tumor cells.</span></p>
<p><span style="font-size: 15px;">Adcetris was developed by Seattle Genetics, and in 2009, Takeda reached a licensing agreement and obtained commercial rights to the drug in other countries except the US and Canada. By far, Adcetris has been approved by more than 70 countries around the world.</span></p>
<p><span style="font-size: 15px;">Currently, Takeda and Seattle Genetics are actively promoting a large phase III clinical development project to make Adcetris as a basic care drug for the treatment of CD30-positive lymphoma and to redefine the clinical first-line treatment of lymphoma.</span></p>
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		<title>Celldex plans Life After Glembatumumab, Cutting 2 More Drugs From Pipeline</title>
		<link>https://www.creative-biolabs.com/blog/adc/celldex-plans-life-glembatumumab-cutting-2-more-drugs-pipeline/</link>
		
		<dc:creator><![CDATA[bioadc]]></dc:creator>
		<pubDate>Fri, 15 Jun 2018 03:58:40 +0000</pubDate>
				<category><![CDATA[News]]></category>
		<category><![CDATA[adc clinical trials]]></category>
		<category><![CDATA[adc research]]></category>
		<category><![CDATA[antibody drug conjugate pepline]]></category>
		<category><![CDATA[antibody drug conjugates]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=97</guid>

					<description><![CDATA[Still reeling from the failure of its lead breast cancer candidate glembatumumab vedotin last month, Celldex has culled another two pipeline projects and now says it will focus its R&#38;D efforts mainly<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/celldex-plans-life-glembatumumab-cutting-2-more-drugs-pipeline/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size:15px">Still reeling from the failure of its lead breast cancer candidate glembatumumab vedotin last month, Celldex has culled another two pipeline projects and now says it will focus its R&amp;D efforts mainly on two cancer antibodies.</span></p>
<p><span style="font-size:15px">The New Jersey biotech says it has decided to discontinue work on CDX-014 was in phase 1 testing for renal cell and clear cell ovarian carcinomas.</span></p>
<p><span style="font-size:15px">Like glembatumumab, CDX-014  is an <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/services.htm" target="_blank" rel="noopener">antibody-drug conjugate</a></span></strong> and Celldex said it will be expensive to develop further. Also for the chop is CDX-1401, an off-the-shelf dendritic cell-targeting vaccine that completed a phase 1 trial in 2012 as an immunotherapy for NY-ESO-1-expressing tumor cells.</span></p>
<p><span style="font-size:15px">The revamp leaves Celldex’ in-house pipeline headed by ErbB3-targeting antibody CDX-3379, which is in a phase 2 trial in head and neck cancer in combination with Eli Lilly’s Erbitux (cetuximab), and CD40 antibody CDX-1140 currently in a phase 1 trial pitting it against multiple solid tumors.</span></p>
<p><span style="font-size:15px">It also has two candidates under development at partners, with Bristol-Myers Squibb taking the lead on varlilumab—a CD27 antibody in phase 2 as a duo with checkpoint inhibitor Opdivo (nivolumab)—and CDX-301, a dendritic cell growth factor in an investigator-led pilot study with radiation therapy in patients with advanced non-small cell lung cancer (NSCLC).<br />
The update to the pipeline was delivered alongside Celldex’ first-quarter results, which revealed that it is sitting on around $123 million in cash and spent $28 million in the first three months of the year—although that figure is expected to decline dramatically after it cut 20% of its workforce last month.</span></p>
<p><span style="font-size:15px">The cutbacks came just a few days after the company’s CEO Anthony Marucci decided to scrap glembatumumab based on midstage data showing it couldn’t improve on chemotherapy with Genentech’s Xeloda (capecitabine) in patients with metastatic triple-negative breast cancers who overexpress glycoprotein NMB. It wasn’t the first big setback for Celldex, which in 2016 also abandoned cancer vaccine Rintega (rindopepimut) following a failed phase 3 glioblastoma trial.</span></p>
<p><span style="font-size:15px">“Based on our progress to date, we believe our cash on hand combined with proceeds from our established ATM [with Cantor] will support the continued development of our pipeline through 2020,” said Marucci. “This extended runway will provide for multiple inflection points, and we are solely focused on executing along these lines.&#8221;</span></p>
<p>Source: https://www.fiercebiotech.com/biotech/celldex-plans-life-after-glembatumumab-cutting-two-more-drugs-from-pipeline</p>
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		<title>Understanding Cancer Heterogeneity May Help Avoid Harmful Effects of Chemotherapy</title>
		<link>https://www.creative-biolabs.com/blog/adc/cancer-heterogeneity-avoid-harmful-effects-chemotherapy/</link>
		
		<dc:creator><![CDATA[bioadc]]></dc:creator>
		<pubDate>Fri, 15 Jun 2018 03:47:48 +0000</pubDate>
				<category><![CDATA[News]]></category>
		<category><![CDATA[adc research]]></category>
		<category><![CDATA[antibody drug conjugates]]></category>
		<category><![CDATA[chemical therapy]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=91</guid>

					<description><![CDATA[“Understanding cancer heterogeneity could further reduce chemo use,” says cancer research expert Antonio Giordano, MD, PhD, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University. “Further study<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/cancer-heterogeneity-avoid-harmful-effects-chemotherapy/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size:15px">“Understanding cancer heterogeneity could further reduce chemo use,” says cancer research expert Antonio Giordano, MD, PhD, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University. “Further study of cases that can successfully be treated with hormone- and immunotherapy, and how to identify them, will unlock this potential.”</span></p>
<p><span style="font-size:15px">Giordano refers to the TAILORx study, published by The New England Journal of Medicine this week, which describes treatment outcomes in breast cancer comparing cases receiving both endocrine therapy and chemotherapy, versus those receiving only endocrine therapy. Under certain conditions, including the early-stage development of tumor size, and the tumor not having spread to any peripheral lymph nodes, endocrine therapy alone resulted in nearly identical rates of survival and recurrence as endocrine- and chemotherapy combined.</span></p>
<p><span style="font-size:15px">&#8220;It is important to underscore that this specific study refers to patients with small tumors and no lymph node infiltrations,&#8221; says Giordano. &#8220;Women with early-stage breast cancer may be able to avoid chemotherapy, which is exciting, because there are pros and cons associated with it. The treatments have unavoidable effects on healthy cells as well as cancer cells&#8221;</span></p>
<p><span style="font-size:15px">&#8220;The goal of precision medicine moving forward,&#8221; Giordano says, &#8220;is to identify more sophisticated approaches to this problem of cancer heterogeneity. Every type of cancer, at the molecular level, can have a cell environment that changes and evolves through the course of the disease. Or from patient to patient.&#8221;</span></p>
<p><span style="font-size:15px">&#8220;Only by understanding specific targets or molecules responsible for key cellular processes will we be able to understand, with precision, new options of therapeutic target that could replace chemotherapy altogether,&#8221; Giordano says.</span></p>
<p><span style="font-size:15px">&#8220;The precision target is not yet precise enough,&#8221; Giordano says. &#8220;But the option to spare many patients the potential harmful effects of chemo is a sign we are moving in the right direction.&#8221;</span></p>
<p>Source:https://shrodotorg.wordpress.com/</p>
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		<title>Forward I Phase III Trial of Mirvetuximab Sorvtansine in Platinum-resistant Ovarian Cancer Completes Full Enrollment</title>
		<link>https://www.creative-biolabs.com/blog/adc/phase-iii-trial-of-mirvetuximab-enrollment/</link>
		
		<dc:creator><![CDATA[bioadc]]></dc:creator>
		<pubDate>Fri, 15 Jun 2018 03:31:58 +0000</pubDate>
				<category><![CDATA[Antibody-drug Conjugates Research]]></category>
		<category><![CDATA[News]]></category>
		<category><![CDATA[adc clinical trials]]></category>
		<category><![CDATA[adc research]]></category>
		<category><![CDATA[antibody drug conjugate pepline]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=85</guid>

					<description><![CDATA[The FORWARD I Phase III registration trial (NCT02631876) evaluating the antibody-drug conjugate or ADC mirvetuximab soravtansine as a single-agent therapy for the treatment of platinum-resistant ovarian cancer, has completed full enrollment and<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/phase-iii-trial-of-mirvetuximab-enrollment/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">The FORWARD I Phase III registration trial (NCT02631876) evaluating the antibody-drug conjugate or ADC mirvetuximab soravtansine as a single-agent therapy for the treatment of platinum-resistant ovarian cancer, has completed full enrollment and will continue as planned without modification.</span></p>
<p><span style="font-size: 15px;">Mirvetuximab soravtansine, also known as IMGN853, is the first FRα-targeting ADC. The drug, which is being developed by clinical-stage biotechnology company Immunogen, uses a humanized FRα-binding antibody to target the ADC specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill these targeted cancer cells.</span></p>
<p><span style="font-size: 15px;">Mirvetuximab is also being assessed in combination regimens for both platinum-resistant and platinum-sensitive disease in the Phase Ib/II FORWARD II trial.</span></p>
<p><span style="font-size: 15px;">The decision follows a recommendation by the <em>Independent Data Monitoring Committee </em>(IDMC) based upon successful completion of a pre-specified interim futility analysis after 80 progression-free survival (PFS) events as determined by blinded, independent central review.</span></p>
<p><span style="font-size: 15px;">Completed full enrollment of the trial was realized two months ahead of schedule. Researchers are expecting top-line results from FORWARD I sometime during the first half of 2019.</span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/06/mirvetuximab-soravtansine-clinial-trial.png"><img decoding="async" class="size-full wp-image-86 aligncenter" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/06/mirvetuximab-soravtansine-clinial-trial.png" alt="mirvetuximab soravtansine clinial trial" width="600" height="351" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/06/mirvetuximab-soravtansine-clinial-trial.png 600w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/06/mirvetuximab-soravtansine-clinial-trial-300x176.png 300w" sizes="(max-width: 600px) 100vw, 600px" /></a></span></p>
<p style="text-align: center;">The Phase III, open label, randomized FORWARD I study (NCT02631876) was designed to compare the safety and efficacy of mirvetuximab soravtansine, also known as IMGN853, to that of selected single-agent chemotherapy (Investigator’s choice) in women with platinum-resistant FR-alpha positive advanced EOC, primary peritoneal cancer and/or fallopian tube cancer.</p>
<p>&nbsp;</p>
<p style="text-align: left;">“We are encouraged that the IDMC recommended FORWARD I proceed as planned and are pleased that the trial has reached full enrollment earlier than expected. We look forward to assessing top-line data in the first half of 2019,” noted Anna Berkenblit, MD., vice president and chief medical officer of ImmunoGen.</p>
<p style="text-align: left;"><strong>Ovarian Cancer</strong><br />
<span style="font-size: 15px;">“Ovarian cancer is the leading cause of death from gynecological cancers, and patients diagnosed with this life-threatening disease have limited treatment options, especially once they develop platinum-resistant disease,” Berkenblit explained.</span></p>
<p><span style="font-size: 15px;">It is estimated that 22,000 women are diagnosed annually with ovarian cancer in the US. With more than 14,000 deaths each year, ovarian cancer accounts for more deaths than any other cancer of the female reproductive system.</span></p>
<p><span style="font-size: 15px;">Standard first-line therapy for ovarian cancer is a platinum-based combination regimen. Once the cancer becomes platinum-resistant, treatment options include single-agent cytotoxic therapies such as pegylated liposomal doxorubicin, paclitaxel, or topotecan, and combination therapies that include bevacizumab.</span></p>
<p><span style="font-size: 15px;">There is a significant need for more effective, better-tolerated therapies for recurrent ovarian cancer. It is estimated that approximately 19,000 women in the US and approximately 24,000 women in the EU have platinum-resistant ovarian cancer requiring second-line or later treatment.</span></p>
<p><span style="font-size: 15px;">ImmunoGen estimates that 60% of ovarian cancer cases have medium or high FRα expression.</span></p>
<p><span style="font-size: 15px;"><strong>Trial design</strong></span><br />
FORWARD I is an ongoing Phase III trial designed to randomize 333 patients 2:1 to receive either mirvetuximab soravtansine or the physician’s choice of single-agent chemotherapy (pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel). Eligibility criteria include patients with platinum-resistant ovarian cancer that express medium or high levels of folate receptor alpha (FRα) who have been treated with up to three prior regimens. The primary endpoint of this study is PFS, which is being assessed in the entire study population and in the subset of patients with high FRα expression. Enrollment was initially planned to be completed by the end of June.</p>
<p><span style="font-size: 15px;">ImmunoGen is partnering with the Gynecologic Oncology Group Foundation Inc., a leader in clinical research in gynecologic malignancies, on FORWARD I, which is being conducted in North America and Europe. This trial is intended to support full marketing approval of mirvetuximab soravtansine for patients with platinum-resistant ovarian cancer.</span></p>
<p>&nbsp;</p>
<p>Source: https://adcreview.com/news/forward-i-phase-iii-trial-of-mirvetuximab-soravtansine-in-platinum-resistant-ovarian-cancer-completes-full-enrollment/</p>
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		<title>Antibody–drug Conjugates: Historical Developments</title>
		<link>https://www.creative-biolabs.com/blog/adc/antibody-drug-conjugates-developments/</link>
		
		<dc:creator><![CDATA[bioadc]]></dc:creator>
		<pubDate>Fri, 11 May 2018 07:13:12 +0000</pubDate>
				<category><![CDATA[Antibody-drug Conjugates Research]]></category>
		<category><![CDATA[adc research]]></category>
		<category><![CDATA[antibody drug conjugates]]></category>
		<category><![CDATA[FDA approved ADC]]></category>
		<category><![CDATA[mmae]]></category>
		<category><![CDATA[PtLnX]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=78</guid>

					<description><![CDATA[A Simple Concept of Antibody-drug Conjugates (ADCs) Developing new anticancer chemotherapeutic drugs showing superior antitumor efficacy with reduced toxicity is continuing to be a challenging endeavor. Antibody-drug conjugates (ADCs) are an emerging<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/antibody-drug-conjugates-developments/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><strong><span style="font-size: 18px;">A Simple Concept of Antibody-drug Conjugates (ADCs)</span></strong></p>
<p><span style="font-size: 15px;">Developing new anticancer chemotherapeutic drugs showing superior antitumor efficacy with reduced toxicity is continuing to be a challenging endeavor. Antibody-drug conjugates (ADCs) are an emerging class of targeted anticancer drug delivery agent that confer selective and sustained cytotoxic drug delivery to tumors. More than a century ago, in 1906, Paul Ehrlich came up with the original concept of linking a cytotoxic payload to a protein with affinity and selectivity to a tumor, like an antibody (Ab) to achieve selective delivery of chemotherapeutic agents in a tumoral environment. Thus, the idea of antibody–drug conjugates (ADC) was born (Figure. 1).</span></p>
<p><span style="font-size: 15px;"><img decoding="async" class="size-full wp-image-79 aligncenter" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/05/basic-earlyantibody-drug-conjugate-concept-illustration.png" alt="basic earlyantibody-drug conjugate concept illustration" width="612" height="428" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/05/basic-earlyantibody-drug-conjugate-concept-illustration.png 612w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/05/basic-earlyantibody-drug-conjugate-concept-illustration-300x210.png 300w" sizes="(max-width: 612px) 100vw, 612px" /></span></p>
<p style="text-align: center;">Figure. 1 Basic early antibody-drug conjugate concept illustration. (A) An antibody specific to a tumor-associated antigen recognizes the cell surface of a tumor cell, leaving normal tissue untouched. Then, drug release and action through various mechanisms leading to cell death. (B) In comparison, the free drug is toxic against both normal and cancer tissues, therefore, showing no selectivity between tumors and healthy tissue.</p>
<p><span style="font-size: 15px;">Many monoclonal Ab (mAb), such as avastin, rituximab, and cetuximab, are well known as standard treatments for solid tumors and hematological cancers. By contrast, pristine chemodrugs, such as vinblastine, doxorubicin, and paclitaxel, have limited use for cancer treatment because of their nonspecific toxicity, thus narrowing the therapeutic window and increasing drug resistance. Discovery of ADCs bridged the gap between the Ab and cytotoxic drug, creating highly specific anticancer agents with an improved therapeutic window. This simple concept was thought to be a particularly attractive solution to the challenge of finding a way to increase the therapeutic window of the cytotoxic agent. Furthermore, conjugation of a small molecular weight cytotoxic agent to a large hydrophilic antibody is expected to restrict penetration of the cytotoxic compound across cellular membranes of antigen-negative normal cells, providing an additional mechanism by which the therapeutic index of the small molecule cytotoxin is widened, beyond that of targeted delivery (Figure. 2).</span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/05/increasing-therapeutic-index.png"><img decoding="async" loading="lazy" class="size-full wp-image-80 aligncenter" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/05/increasing-therapeutic-index.png" alt="increasing therapeutic index" width="628" height="399" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/05/increasing-therapeutic-index.png 628w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/05/increasing-therapeutic-index-300x191.png 300w" sizes="(max-width: 628px) 100vw, 628px" /></a></span></p>
<p style="text-align: center;">Figure. 2 Increasing the therapeutic index of cytotoxic drugs by conjugation to antibodies.</p>
<p><strong><span style="font-size: 18px;">Advances in ADC Development</span></strong></p>
<p><strong><span style="font-size: 15px;">First-generation ADCs</span></strong></p>
<p><span style="font-size: 15px;">Since the breakthrough discovery of the first FDA-approved ADC, gemtuzumab ozogamicin (trade name, Mylotrag), anticancer therapy research has diversified, resulting in the development of several novels, safer ADCs. Advances in the development of ADCs towards targeted anticancer drug delivery is described by Creative Biolabs here. After the first generation of ADC had caused acute adverse effects and morbidity in patients, several parameters were pointed out that cannot be bypassed while developing an ADC:</span></p>
<p><span style="font-size: 15px;">What We Learned From First-generation ADCs</span></p>
<ul>
<li>Insufficient potency of ADC in patients: due to low concentrations of antibody both in serum and moreover in tumor environment. The low concentration of mAb in plasma cannot allow to achieve the appropriate therapeutic range, and only &lt;1% of the injected dose is able to reach the tumor localization.</li>
<li>Nature of the antibody: nonhuman antibodies were used in first ADC, leading for example to an immune response through the generation of human anti-murine antibodies (HAMA), preventing repeated exposure of the ADC to patients, thus limiting its efficacy.</li>
<li>Linker stability: first linkers were designed to be cleaved under acidic conditions, nevertheless this kind of linker proved to be quite unstable even in plasma, leading to unexpected toxicity due to the early uncontrolled release of the toxic payload.</li>
<li>Limited expression of the antigen: before delivering and releasing the payload inside the cancer cell, the ADC should first bind to its specific antigen at the tumor cell surface. Because of the limited expression of this antigen at the surface, which should be of an average of 10,000 receptors per cancer cell, the ADC can only deliver a limited number of payloads that could be insufficient to reach the necessary concentration to achieve cell death.</li>
<li>Limited internalization: not all the targeted antigen can allow an optimal clathrin dependent internalization of the antigen-mAb complex.</li>
<li>Optimized average DAR = 4: this value should be the best one to achieve in order to build an optimized ADC, having in mind the compromise between a sufficient number of carried drugs and a limited modification of the native structure of the mAb.</li>
</ul>
<p>&nbsp;</p>
<p><strong><span style="font-size: 15px;">Second-generation ADCs</span></strong></p>
<p><span style="font-size: 15px;">The limitations and failures of first-generation ADCs were eliminated in second-generation ADCs. The premature release of drugs because of the unstable hydrazone linker in Mylotrag® has been avoided in second-generation FDA approved ADCs, by using different linkers, such as the valine-citrulline (cathepsin cleavable) linker in Adcetris® and a thioester (noncleavable) linker in Kadcyla ®. The cytotoxic payloads used in second-generation ADCs are also more potent than in first-generation ADCs. For example, tubulin-targeting agents, such as <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/blog/adc/payload-adc-mmae-mmaf/">MMAE</a></span></strong> used in Adcetris® is approximately 100–1000-fold stronger than DNA-intercalating doxorubicin of BR96 Dox. The IC50 of MMAE is approximately 1 nM in different human cancer cell lines, whereas doxorubicin IC50 is in the 1–6 uM range. Despite the improvement in cytotoxic payloads and the introduction of stable linkers, second-generation ADCs have significant limitations in terms of their heterogeneous DAR, resulting from stochastic coupling strategies between the Ab and drug. Typically, chemical conjugation between the drug and antibody occurs via the lysine or cysteine residue of the mAb, which generates DAR (range 0–8) with an average value of 3–4. Therefore, heterogeneous ADCs can contain a mixture of unconjugated, partially conjugated, and overconjugated antibodies and, therefore, there will be competition between unconjugated antibodies and drug-conjugated species for antigen binding that can diminish the activity of the ADC. By contrast, overconjugation of the drug to the Ab can result in antibody aggregation, a decrease in stability, and incremental increases in nonspecific toxicity, and a reduction in the half-life of ADCs in the circulation. Overall, heterogeneous ADCs have a limited therapeutic index and tumor penetration abilities, which are associated with the induction of drug resistant in the tumor microenvironment.</span></p>
<p><span style="font-size: 15px;">What We Learned From Second-generation ADCs</span></p>
<ul>
<li>Mode of action and potency of the payload: only DNA alkylating agents and tubulin polymerization inhibitors with subnanomolar activities proved to be useful for targeted delivery through ADC technology, due to limited antigen expression and limited delivered amount of ADC available in the tumor. Such drug cannot be used in monotherapy due to high cytotoxicity and narrow therapeutic window.</li>
<li>Nature of the linker and delivery mechanism: cleavable linkers finally have a broader efficacy than noncleavable ones. Indeed, although ADC incorporating either cleavable or noncleavable linker requires internalization to release the free drug, ADCs with cleavable linkers may also be active even when they are poorly internalized. The explanation can be found in the overexpression of some intracellular enzymes, like cathepsin B, that can leave lysosomes then cytosol to reach the extracellular media to promote metastasis or cell invasion, leading to cleavage of the linker in extracellular matrix, the free drug subsequently permeates the cell to reach its target [16].</li>
<li>Conjugation site on the mAb: it can also affect potency, stability and PK properties of the ADC.</li>
<li>Parameters to choose a good AG target: homogeneity/heterogeneity of tumor expression, high level of expression inside a tumor and selective expression for tumor tissues should be all well assessed for a given AG to be considered as a suitable target for ADC payload delivery.</li>
</ul>
<p><strong><span style="font-size: 15px;">Third-generation ADCs</span></strong></p>
<p><span style="font-size: 15px;">The aforementioned concerns regarding the heterogeneous DARs of second-generation ADCs have been addressed in third-generation ADCs. Site-specific conjugation has been introduced to produce homogenous ADCs with well-characterized DARs and desired cytotoxicities [62]. The site-specific conjugation of the drug to Ab provides a single isomer ADC with a uniform DAR value. Such ADCs can be made using bioengineered antibodies containing site-specific amino acids, such as cysteine, glycan, or peptide tags [63]. For example, precise site-specific conjugation of MMAE to human IgG was developed by replacing the Ala114 amino acid of the CH1 domain of the IgG with cysteine to create a selectively engineered antibody, called <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/EnCys-mAb-based-conjugation.htm">THIOMAB</a></span></strong>. Alternative approaches to site-specific drug conjugation include: (i) a thio-bridge approach that links drugs to the interchain disulfide bond of Abs (four per mAb) [14]; (ii) introduction of unnatural amino acids, such as p-acetylphenylalanine, or noncanonical amino acids. Based on above techniques, Creative Biolabs has developed a novel ADC conjugation platform-<strong>P<strong>tLnX<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;" /></strong></strong><strong>. </strong><strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="https://www.creative-biolabs.com/adc/ptlnx.htm">PtLnX</a></span> </strong>is a technical platform developed by <strong>Creative Biolabs</strong> and one of our collaborators that uses bis(ethylenediamine) platinum chloride [Pt(en)Cl<sub>2</sub>] as a linker core for ADC development.</span></p>
<p><span style="font-size: 15px;">Wisely chosen targeted antigen, novel linker technology and original mode of drug action continue to be investigated to fully optimized ADC-based targeted therapy in order to improve the therapeutic index of an overall ADC. Extensive research is ongoing to improve all the components of ADCs that can enhance their targetability and therapeutic efficacy against tumors. A better understanding of ADC-targeting strategies can speed up the FDA approval rate of ADCs and drastically increase the number of clinical trials, especially in solid tumors.</span></p>
<p><strong> </strong></p>
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		<title>The Expanding Field of Antibody-Drug Conjugates (ADCs)</title>
		<link>https://www.creative-biolabs.com/blog/adc/expanding-field-antibody-drug-conjugates/</link>
		
		<dc:creator><![CDATA[bioadc]]></dc:creator>
		<pubDate>Thu, 01 Mar 2018 07:12:13 +0000</pubDate>
				<category><![CDATA[Antibody-drug Conjugates Manufacturing]]></category>
		<category><![CDATA[Antibody-drug Conjugates Research]]></category>
		<category><![CDATA[News]]></category>
		<category><![CDATA[adc clinical trials]]></category>
		<category><![CDATA[adc research]]></category>
		<category><![CDATA[antibody drug conjugate pepline]]></category>
		<category><![CDATA[antibody drug conjugates]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/adc/?p=58</guid>

					<description><![CDATA[Antibody-drug conjugates or ADCs have emerged as a powerful and strategic tool in the targeted treatment of cancer. These relatively novel agents combine the ability of monoclonal antibodies to specifically target tumor cells,<a class="moretag" href="https://www.creative-biolabs.com/blog/adc/expanding-field-antibody-drug-conjugates/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/03/blog3.jpg"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-59" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/03/blog3.jpg" alt="blog3" width="960" height="290" srcset="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/03/blog3.jpg 960w, https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/03/blog3-300x91.jpg 300w" sizes="(max-width: 960px) 100vw, 960px" /></a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/adc/services.htm" rel="noopener"><span style="color: #0000ff;"><strong>Antibody-drug conjugates</strong></span></a> or ADCs have emerged as a powerful and strategic tool in the targeted treatment of cancer. These relatively novel agents combine the ability of monoclonal antibodies to specifically target tumor cells, which express specific antigens on their surface, with the highly potent killing activity of a cytotoxic drug with payloads which is generally too toxic for systemic administration. In contrast to conventional, standard, treatments, antibody-drug conjugates cause less damage to healthy tissues.</span></p>
<p><span style="font-size: 15px;">This approach, has, over the last two decades led to a paradigm shift in cancer chemotherapy.</span></p>
<p><span style="font-size: 15px;">Today, a number of different ADC-based treatments options are available for both including hematological malignancies and solid tumors. These options have dramatically increased the efficacy of treatment and are now considered among the most promising strategies used for targeted therapy of patients with a variety of malignancies.</span></p>
<p><span style="font-size: 15px;">Although much progress has been made, the therapeutic success of future antibody-drug conjugates depends on closely choosing the target antigen, increasing the potency of the cytotoxic cargo, improving the properties of the linker, and reducing drug resistance.</span></p>
<p><span style="font-size: 15px;"><strong>Approved drugs</strong></span><br />
<span style="font-size: 15px;">Today, there are 4 antibody-drug conjugates approved and commercially available in the United States. Until the summer of 2017 <em>brentuximab vedotin</em> (Adcetris®; Seattle Genetics) and ado-trastuzumab entansine (Kadcyla®; Genetech/Roche) were the only commercially available ADCs. Then, on August 17, 2017, the U.S. Food and Drug Administration (FDA) approved <em>inotuzumab ozogamicin</em> (Besponsa<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;" />, Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.) for the treatment of adults with relapsed or refractory B-cell precursor <em>acute lymphoblastic leukemia</em> (ALL) and only weeks later, <em>gemtuzumab ozogamicin</em> (Mylotarg<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;" />, previously known as CMA-676; Wyeth Pharmaceuticals, a subsidiary of Pfizer) for the treatment of adults with newly diagnosed CD33-positive <em>acute myeloid leukemia</em> or AML, and adults and children 2 years and older with relapsed or refractory CD33-positive AML was again approved, bringing the number of commercially available ADCs to four.</span></p>
<p><span style="font-size: 15px;">In addition, there are nearly 175 investigational ADCs in development – from early discovery to pivotal, late stage, clinical phase III studies.</span></p>
<p><span style="font-size: 15px;"><strong>J.P. Morgan Healthcare Conference</strong></span><br />
<span style="font-size: 15px;">Earlier this year, during the <em>36th Annual J.P. Morgan Healthcare Conference</em> in San Francisco, Seattle Genetics highlighted the progress of its pipeline of antibody-drug conjugates.</span></p>
<p><span style="font-size: 15px;">Through both internal efforts and efforts of its collaborators, Seattle Genetics’ Antibody-drug Conjugate technology is being employed in more than 20 clinical trial programs.  Some of these study programs include a number of late-stage development programs across both hematologic malignancies and solid tumors.</span></p>
<p><span style="font-size: 15px;"><strong>Important therapeutic modality</strong></span><br />
<span style="font-size: 15px;">“ADCs continue to advance as an important therapeutic modality, both as single agents and as part of various combination regimens, across hematologic malignancies and solid tumors,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.</span></p>
<p><span style="font-size: 15px;">“We are the industry leader in ADC technology driven by our scientific expertise in monoclonal antibodies, drug payloads and stable linker technologies. Our leadership is further illustrated by the continued clinical and commercial expansion of <em>brentuximab vedotin</em> (Adcetris®; Seattle Genetics), progress with our late-stage programs <em>enfortumab vedotin</em> and <em>tisotumab vedotin</em>, and the breadth of our pipeline of other ADCs and empowered antibodies,” Siegall further noted.</span></p>
<p><span style="font-size: 15px;">Addressing the success of the company’s partners, Siegal observed: “Our collaborators are making significant advances with several programs using our technology. Antibody0drug Conjugates ADCs are an integral part of an evolving cancer treatment paradigm, and we are committed to bringing important new treatments to patients in need,”</span></p>
<p><span style="font-size: 15px;"><strong>CD30-Expressing Lymphomas</strong></span><br />
<span style="font-size: 15px;">Overexpression of CD30, a 120-kDa type I trans-membrane glycoprotein belonging to the tumor necrosis factor (TNF) receptor superfamily, has been reported in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). Treatment with CD30-targeted <span class="highlight">antibody-drug</span> <span class="highlight">conjugates, including <em>brentuximab vedotin</em> </span>can lead to promising clinical benefit.</span></p>
<p><span style="font-size: 15px;"><em>Brentuximab vedotin, </em>which is developed by <em>Seattle Genetics</em> and <em>Takeda Pharmaceuticals</em> on a 50:50 basis is commercially available in 70 countries worldwide and generated more than $600 million in global sales in 2017.</span></p>
<p><span style="font-size: 15px;">On January 2, 2018 the U.S. Food and Drug Administration (FDA) accepted Seattle Genetics’ filing for supplemental <em>Biologics License Application</em> (BLA) of <em>brentuximab vedotin</em> in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.</span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/03/blog3-1.png"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-60" src="https://www.creative-biolabs.com/blog/adc/wp-content/uploads/2018/03/blog3-1.png" alt="blog3-1" width="900" height="527" /></a></span></p>
<p><span style="font-size: 15px;"><em><strong>Schematic:</strong> The ECHELON-1 trial is a Phase III trial in Frontline Therapy of Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490).</em></span></p>
<p><span style="font-size: 15px;">The FDA granted <em>Priority Review</em> for the application, and the <em>Prescription Drug User Fee Act</em>(PDUFA) target action date is May 1, 2018. The submission of the supplemental BLA is based on positive results from a phase III clinical trial called ECHELON-1. In October 2017, the FDA granted Breakthrough Therapy Designation (BTD) for <em>brentuximab vedotin</em> in frontline advanced Hodgkin lymphoma based on the ECHELON-1 study results.</span></p>
<p><span style="font-size: 15px;"><strong>Enfortumab vedotin</strong></span><br />
<span style="font-size: 15px;">In addition to advancing <em>brentuximab vedotin</em>, Seattle Genetics and its collaborator Astellas have initiated a pivotal phase II clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with <em>checkpoint inhibitor</em> (CPI) therapy. The study is designed to support potential registration under the FDA’s accelerated approval regulations.</span></p>
<p><span style="font-size: 15px;">Seattle Genetics, in collaboration with its development partner Genmab, also plans to initiate a phase II clinical trial of <em>tisotumab vedotin</em> for patients with recurrent and/or metastatic cervical cancer. This study is intended to support potential registration under the FDA’s accelerated approval regulations.</span></p>
<p><span style="font-size: 15px;"><strong>Late stage trials</strong></span><br />
<span style="font-size: 15px;">A number of companies, including GlaxoSmithKline, Genentech/Roche and AbbVie are including Seattle Genetics’ proprietary ADC-technologies in the development of their ADC-programs. These programs include:</span></p>
<ul>
<li><em>GSK2857916</em>, an ADC being developed by GlaxoSmithKline (GSK) for multiple myeloma. GSK recently reported encouraging data from the program at the 59th American Society of Hematology (ASH) annual meeting in December 2017;</li>
<li><em>Polatuzumab vedotin</em>, an ADC being developed by Genentech/Roche. Positive results were presented at ASH from a phase 2 trial in advanced-stage diffuse large B-cell lymphoma. A phase 3 trial is underway; and,</li>
<li><em>Depatuxizumab mafodotin</em>, an ADC for glioblastoma in development by AbbVie. Encouraging data have been reported from this ADC, which is currently in a phase 3 clinical trial.</li>
</ul>
<p><span style="font-size: 15px;">Genentech/Roche’s Polatuzumab vedotin and GlaxoSmithKline’s GSK2857916 have both received <em>Breakthrough Therapy Designation</em> from the FDA and <em>PRIority MEDicines</em> (PRIME) designations from the <em>European Medicines Agency</em>. These designations signify the importance of therapies such as these in addressing the significant unmet medical need.</span></p>
<p><span style="font-size: 15px;">“Through our robust internal development efforts and our strong licensing and co-development agreements, we are extending the potential of ADCs globally. We look forward to future results of studies that include Seattle Genetics’ novel technologies both as monotherapies, as well as in combination with checkpoint inhibitors and other agents,” said Siegall concluded.</span></p>
<p><span style="font-size: 15px;"><strong>Anti-CD30-LDM ADC</strong></span><br />
<span style="font-size: 15px;">The development of novel antibody-drug conjugates is rapidly expanding. Researchers at Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, are working on the development of a novel enediyne-integrated antibody-drug conjugate.[2]</span></p>
<p><span style="font-size: 15px;">This development involves lidamycin or LDM, which consists of an apoprotein LDP and an active enediyne chromaphore AE. Lidamycin is a member of the enediyne antibiotic family and one of the most potent antitumor agents. Researchers consider lidamycin to be an ideal payload for the preparation of ADCs.</span></p>
<p><span style="font-size: 15px;">In one study, the researchers demonstrated that the anti-CD30-LDM ADC, a novel ADC consisting of the intact anti-CD30 antibody and lidamycin, is highly cytotoxic to Hodgkin lymphoma and anaplastic large cell lymphoma cell lines with IC50 values of 5~50 pM. In using a Karpas299 xenograft model, the ADC inhibited tumor growth by 87.76% in mice treated with the investigational agent. Interestingly, the researchers did not observe discernible adverse effects.</span></p>
<p><span style="font-size: 15px;">Based on the results of their study, the researchers concluded that the anti-CD30-LDM offers attractive tumor targeting capability and anti-tumor efficacy both <em>in vitro</em> and <em>in vivo</em> and could be a promising candidate for the treatment of CD30+ lymphomas.</span></p>
<p><span style="font-size: 15px;"><strong>Other programs</strong></span><br />
<span style="font-size: 15px;">Although the first-generation ADCs have been commercialized, researchers around the globe are concerned that the amount of the cytotoxic payload that can be loaded onto a single antibody molecule is still relatively low. Their concern also includes the fact that synthetic linkers used in some antibody-drug conjugates may be unstable, and, that as a result the cytotoxic payload may become detached, leading to the onset of adverse drug reactions. As such, ADC technologies are still evolving, and many companies are currently working to develop next-generation ADC technologies.</span></p>
<p><span style="font-size: 15px;">Among these next generation ADCs is <em>trastuzumab deruxtecan</em> (also known as <em><span class="highlight">DS-8201</span></em>), being developed by Daiichi Sankyo. Trastuzumab deruxtecan is an antibody-drug conjugate comprised of a humanized antibody against HER2, a novel enzyme-cleavable linker and irinotecan, a topoisomerase I inhibitor, payload, which stimulates DNA synthesis.</span></p>
<p><span style="font-size: 15px;">Daiichi Sankyo’s ADCs also utilize proprietary technologies characterized by a structure of unique linkers connecting the drug and the antibody. The technology being developed also allows for the linker and the payload to be combined with various antibodies. By capitalizing on this characteristic, researchers at the company aim to maximize the value of these technologies through internal efforts and possibly through external collaboration</span></p>
<p><span style="font-size: 15px;"><strong>Mersana’s Dolaflexin </strong></span><br />
During the 2018 36th Annual J.P. Morgan Healthcare Conference, Anna Protopapas, President and Chief Executive Office of Mersana Therapeutics outlined her company’s goals. The company is a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody drug conjugates (ADCs) based on its Dolaflexin® and other proprietary platforms.</p>
<p><span style="font-size: 15px;">“2017 was a year of exceptional execution as we positioned the company for achieving key clinical milestones in 2018 and beyond. Last year, we advanced two lead ADC product candidates, XMT-1522 and XMT-1536, into the clinic and supported our partner Takeda in selecting its first Dolaflexin-based ADC for initiation of IND enabling studies,” Protopapas said.</span></p>
<p><span style="font-size: 15px;">“We’re looking forward to 2018, as we plan to complete the dose escalation phase of the Phase I study for XMT-1522 and present the data at a scientific conference, as well as substantially complete recruitment of the dose expansion cohorts for XMT-1522. We also expect to continue dose escalation for XMT-1536 and select our next ADC candidate for clinical development. We will persist in building a strong organization that is passionately dedicated to scientific excellence, focused execution and addressing patient needs,” she added.</span></p>
<p><span style="font-size: 15px;">Mersana’s pipeline includes two compounds in Phase I clinical trials:</span></p>
<ul>
<li><em>XMT-1522</em>, a Dolaflexin ADC targeting HER2-expressing breast cancer, non-small cell lung cancer (NSCLC) and gastric cancer, which, in  dose escalation studies, has been administered to six dose cohorts with the sixth dose cohort currently in safety evaluation.  Preclinical data on XMT-1522 presented at AACR 2017 supported potential synergy with immune checkpoint inhibitors, and</li>
<li><em>XMT-1536</em>, a first-in-class Dolaflexin ADC targeting NaPi2b, a clinically validated ADC target broadly expressed in epithelial ovarian cancer and non-squamous NSCLC, as well as a number of other tumor types. In dose escalation studies, XMT-1536 has enrolled and cleared the first dose level.</li>
</ul>
<p><span style="font-size: 15px;">Protopapas explained that she expects to continue the dose escalation study to establish Maximum Tolerated Dose (MTD) for XMT-1522, and will be able to select Recommended Phase II Dose (RP2D) and substantially enroll dose expansion cohorts. She also expects to continue the dose escalation study to establish MTD for XMT-1536.</span></p>
<p><span style="font-size: 15px;"><strong>New platform technologies</strong></span><br />
<span style="font-size: 15px;">In addition to the results of these investigational agents, Protopapas confirmed that the company has ongoing, robust research programs in place, which positions Mersana to deliver an additional investigational new drug (IND) every 12-24 months.  She expects that the company will be able to disclose pre-clinical data of the next ADC clinical candidate at an upcoming scientific meeting. More excitedly, she also hopes to disclose new proprietary platform technologies at an upcoming scientific meeting.</span></p>
<p>Source: https://adcreview.com/news/expanding-field-antibody-drug-conjugates/</p>
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