148P HexaBody-OX40: A novel Fcγ receptor crosslinking-independent OX40-targeting antibody, exhibits agonistic activity in vitro and antitumor activity in vivo

• DOI: 10.1016/j.iotech.2023.100620
• Publication Date: 2023-12-08T11:09:58Z
• Authors: K. Kemper; M. Köhne; M. van der Kroef; K.B.B. Nuermberger; M. Russier; G. Zom; A-L. Krause; P. de Goeje; F. Gieseke; A. Gorlani; A. Muik; L. Guelen; D. Satijn; S. Fellermeier-Kopf; T. Ahmadi; Ö. Türeci; E. Breij; U. Sahin
• Keywords: Agonistic behaviour

Clustering of the costimulatory TNF receptor superfamily member OX40 on activated T cells activates signaling pathways that enhance T-cell activation, survival, and proliferation. agonists in development requiring FcγR-mediated crosslinking to induce agonism have demonstrated limited clinical activity. We present preclinical characterization HexaBody-OX40 (GEN1055/BNT315), a novel agonist antibody designed cluster independent antitumor responses. Target binding characteristics agonistic activity were analyzed vitro using assays, cell-based reporter functional assays primary human cells. Antitumor pharmacodynamics assessed vivo MC38 tumor-bearing knock-in mice. bound OX40-expressing In contrast other agonists, induced FcγR-independent based assay. an assay polyclonally stimulated PBMCs, enhanced proliferation activation CD4+ CD8+ cells, cytokine secretion. this assay, depended presence Furthermore, antigen-specific overexpressing OX40. syngeneic model mice was associated with peripheral increased percentages tumor-specific intratumoral increase Granzyme B+ studies, exhibited FcγR-crosslinking-independent activity, unique mechanism action is distinct from agonists. showed vivo. A first-in-human trial planned evaluate safety preliminary efficacy patients advanced solid tumors.