5T4 based Bispecific ADC Development Service

A bispecific antibody can bind two different targets or two distinct epitopes on the same target. 5T4, specifically overexpressed on the cell surface of various tumors and internalized rapidly when bound to antibody, may be used as an attractive target to develop effective immunotherapy such as bispecific antibody-drug conjugate (ADC). Having accumulated rich experience in antibody discovery and bio-conjugation for many years, Creative Biolab is competent to develop high-affinity and fast-internalizing anti-5T4 antibody which could be applied in the bispecific ADC development. Armed with our perfect conjugation platform, we are capable of providing high-quality anti-5T4 bispecific ADC development services for our honor clients.

Background

The Overview of 5T4

5T4, also known as trophoblast glycoprotein, is a 72-kDa, N-glycosylated transmembrane protein. The extracellular domain contains leucine-rich repeats, which are commonly associated with protein-protein interactions. 5T4 is a well-defined tumor antigen expressed on many different types of malignancies, including non-small cell lung, renal, pancreas, breast, prostate, colorectal, gastric, ovarian, and cervical cancers. Conversely, 5T4 has limited expression on normal tissues, making it an attractive target for cancer immunotherapy.

Fig.1 Crystal structure of human 5T4.

• Antibody-based Therapeutics Targeting 5T4

To date, several ADCs targeting 5T4 have been reported. For instance, PF-06263507 comprises a humanized anti-5T4 mAb linked to the tubulin inhibitor MMAF via a non-cleavable maleimidocaproyl linker. PF-06263507 has been investigated in a phase I clinical trial (NCT01891669). MEDI-0641 is an ADC conjugated with PBD dimer via a valine-alanine dipeptide linker. However, MEDI-0641 does not seem to have yet entered clinical development as it is not mentioned neither under clinicaltrials.gov nor in the company's website. The third anti-5T4 ADC is H6-DM4. It is composed of a chimeric anti-5T4 mAb linked to an antimitotic cytotoxin, the maytansinoid DM4, through a cleavable N-succinimidyl 4-(2-pyridylothio) butyrate (SPDB) linker. H6-DM4 was cytotoxic against a panel of gastrointestinal cancer cell lines, including colorectal CSCs and colorectal cancer cells resistant to platinum compounds.

Encouraged by therapeutics based on traditional ADC, bispecific antibodies and its conjugates have attracted a lot of attention. For 5T4 target, APV-527 bispecific antibody is a promising immunotherapeutic candidate for the treatment of a variety of 5T4-expressing solid tumors. It is designed to simultaneously target 5T4 and the co-stimulatory receptor 4-1BB (CD137) to promote potent, tumor-directed immune T-cell activation. This enables the immune-activating effect of APV-527 to be directed specifically to the tumor and not against normal tissue.

Fig.2 Tumor-targeted immunomodulators.¹

Our Service

5T4-based Bispecific ADCs Services

The design of bispecific ADC is much more complicated than a simple linkage of a mAb to a payload. The considerations include target characterization and combination, antibody properties, payload, and linker. All these components of an ADC need to be optimized to achieve the best combination for bispecific ADC development. Creative Biolabs is capable of generating anti-5T4 bispecific antibodies (4-1BB x 5T4, 5T4 × CD3) with higher affinity and fast internalization. These bispecific antibodies could be further conjugated with potent payload through our featured DrugLnkTM Service Platform. Once the bispecific ADC conjugate is prepared, comprehensive bispecific ADC analysis services are available for you. For more information, please do not hesitate to contact us.

Highlights

• Customized Conjugation Techniques: Our customized conjugation techniques provide precise linkage of antibodies to potent payloads, maximizing therapeutic efficacy while minimizing off-target effects and toxicity in normal tissues.
• Expertise in 5T4 Targeting: With extensive experience in 5T4 targeting, Creative Biolabs develops bispecific ADCs that selectively bind to tumor cells, offering superior treatment options for various cancers.
• Comprehensive ADC Optimization: Creative Biolabs offers comprehensive optimization services for bispecific ADCs, including target selection, antibody engineering, payload choice, and linker design to achieve the best therapeutic outcomes.
• Advanced Analytical Services: We provide advanced analytical services for bispecific ADCs, ensuring high quality, efficacy, and safety through rigorous in vitro and in vivo evaluations.
• Expertise in Antibody Discovery: With years of experience in antibody discovery and bio-conjugation, Creative Biolabs offers customized bispecific ADC development, ensuring optimal therapeutic efficacy and selectivity for various cancer types.

FAQ

1. Q: Why is 5T4 an attractive target for bispecific ADC development?

   A: 5T4, a trophoblast glycoprotein, is overexpressed on the cell surface of various tumors and internalizes rapidly upon antibody binding. Its limited expression on normal tissues makes it an ideal target for cancer immunotherapy, including the development of bispecific ADCs, which can deliver cytotoxic drugs selectively to cancer cells.

2. Q: What are some examples of 5T4-targeting ADCs currently in development?

   A: Several ADCs targeting 5T4 have been reported, such as PF-06263507, MEDI-0641, and H6-DM4. These ADCs have shown promise in preclinical and clinical studies for their ability to selectively target and kill cancer cells, demonstrating the potential of 5T4 as a valuable target in cancer therapy.

3. Q: What makes APV-527 a promising bispecific antibody for 5T4-expressing tumors?

   A: APV-527 is designed to target 5T4 and the co-stimulatory receptor 4-1BB (CD137), promoting potent, tumor-directed immune T-cell activation. This dual-targeting approach enhances the immune response specifically against 5T4-expressing tumors, minimizing effects on normal tissues and improving therapeutic efficacy.

4. Q: What services does Creative Biolabs offer for anti-5T4 bispecific ADC development?

   A: Creative Biolabs offers comprehensive services for anti-5T4 bispecific ADC development, including the generation of bispecific antibodies (e.g., 4-1BB x 5T4, 5T4 × CD3), payload conjugation through their DrugLnkTM Service Platform, and extensive bispecific ADC analysis to ensure high quality and efficacy of the final product.

5. Q: How does Creative Biolabs evaluate the efficacy of their 5T4-based bispecific ADCs?

   A: Creative Biolabs conducts comprehensive in vitro and in vivo evaluations of their bispecific ADCs. These analyses include assessing the binding affinity, internalization rates, cytotoxicity, and therapeutic efficacy in preclinical models, ensuring that the bispecific ADCs are highly effective and safe for potential clinical use.

Published Data

In this experiment, 5T4-based bispecific antibody-drug conjugates (ADCs) were utilized to target high-risk subclones of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The 5T4 protein is overexpressed in these high-risk subclones, particularly in those with high minimal residual disease (MRD) post-induction therapy. The study demonstrated that 5T4-positive cells had a greater ability to overcome the xenograft barrier in NOD-scid IL2Rγnull (NSG) mice, preferentially localized to bone marrow, and reconstituted the original clonal composition upon engraftment. Treatment with the 5T4-targeted ADC, A1mcMMAF, significantly improved survival in mice engrafted with 5T4-positive cells without overt toxicity. Additionally, combining A1mcMMAF with dexamethasone sequentially in the MRD setting significantly enhanced survival compared to either treatment alone, supporting the potential of 5T4-based bispecific ADCs in improving outcomes for patients with high-risk BCP-ALL.

Fig.3 A1mcMMAF monotherapy of HR08 B-cell acute lymphoblastic leukemia patient-derived xenotransplant challenge.²

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Anti-5T4 ADC