7yxu | pdb_00007yxu
Crystal structure of agonistic antibody 1618 fab domain bound to human 4-1BB.
Structural highlights
FunctionTNR9_HUMAN Receptor for TNFSF9/4-1BBL. Possibly active during T cell activation. Publication Abstract from PubMed4-1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNgamma production. The ability to induce potent antitumor 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 on the basis of 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 shown 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 antitumor 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 antitumor 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 shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors. The Bispecific Tumor Antigen-Conditional 4-1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies.,Nelson MH, Fritzell S, Miller R, Werchau D, Van Citters D, Nilsson A, Misher L, Ljung L, Bader R, Deronic A, Chunyk AG, Schultz L, Varas LA, Rose N, Hakansson M, Gross J, Furebring C, Pavlik P, Sundstedt A, Veitonmaki N, Ramos HJ, Sall A, Dahlman A, Bienvenue D, von Schantz L, McMahan CJ, Askmyr M, Hernandez-Hoyos G, Ellmark P Mol Cancer Ther. 2023 Jan 3;22(1):89-101. doi: 10.1158/1535-7163.MCT-22-0395. PMID:36343381[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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