The bispecific tumor antigen-conditional 4-1BB x 5T4 agonist, ALG.APV-527, mediates strong T cell activation and potent anti-tumor activity in preclinical studies.

4-1BB (CD137) is an activation-induced co-stimulatory receptor that regulates immune responses of activated CD8 T and NK cells, by enhancing proliferation, survival, cytolytic activity and IFN production. The ability to induce potent anti-tumor activity by stimulating 4-1BB on tumor-specific cytotoxic T cells makes 4-1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4-1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built based on the ADAPTIR™ bispecific platform with optimized binding domains to 4-1BB and 5T4 originating from the ALLIGATOR-GOLD® human single chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4-1BB using X-ray crystallography. As demonstrated in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4-1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust anti-tumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4-1BB-mediated anti-tumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as demonstrated by robust activity in preclinical in vitro and in vivo models. Based on the combined preclinical dataset, ALG.APV-527 has potential as a promising anti-cancer therapeutic for the treatment of 5T4-expressing tumors.