Development of 5T4-based Bispecific ADCs

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.

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.

Crystal structure of human 5T4. 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.

Tumor-targeted immunomodulators. Fig.2 Tumor-targeted immunomodulators. (Dahlén, 2018)

What Can We Do for You?

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.

Reference

  1. Dahlén, E.; et al. Veitonmäki N, Norlén P. Bispecific antibodies in cancer immunotherapy. Therapeutic advances in vaccines and immunotherapy. 2018, 6(1): 3-17.

For Research Use Only. NOT FOR CLINICAL USE.


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