Agonistic antibodies to co-stimulatory members of the TNF Receptor Superfamily (TNFRSF) have demonstrated impressive antitumor immune responses in murine tumor models and are currently under investigation in the clinic. In order to induce efficient co-stimulatory signaling, the majority of TNFRSF members require supermolecular cluster formation on the immune cell surface. Recent studies have revealed that agonistic antibodies achieve this in part by Fcγ receptor (FcγR) mediated cross-linking, enabling antibodies to cluster the TNFRSF member expressed on the opposing immune cell. Agonistic antibodies to OX40 (CD134; TNFRSF4), which primarily target T cells are currently in clinical trials for cancer immunotherapy. However, as OX40 needs clustering for efficient signaling, these antibodies can only function in microenvironments where FcγR bearing cells are abundant. To overcome this limitation, we generated multimeric anti-human-OX40 antibodies, which cluster OX40 independent of FcγR mediated cross-linking. In vitro, we found that multimeric anti-OX40 induces robust signaling independent of FcγR. Compared to the bivalent antibodies, multimeric anti-OX40 generated superior immune responses in vaccination and tumor settings, in vivo. Together, multimeric antibody platforms have important implications for effective targeting of OX40 and possibly other TNFRSF members.

Citation Format: Shravan Madireddi, Yanli Yang, Sherry Yeh, Chen Gu, Patricia L. Sanchez, Randall Brezski, Henry Chiu, Hans Erickson, Rafael A. Cubas, Gregory Lazar, Jeong Kim. Multimeric anti-human OX40 induces robust immune responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A29.