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

Background

Clustering of the costimulatory TNF receptor superfamily member OX40 on activated T cells activates signaling pathways that enhance T-cell activation, survival, and proliferation. OX40 agonists in development requiring FcγR-mediated crosslinking to induce OX40 agonism have demonstrated limited clinical activity. We present the preclinical characterization of HexaBody-OX40 (GEN1055/BNT315), a novel OX40 agonist antibody designed to cluster OX40 independent of FcγR-mediated crosslinking to enhance antitumor T-cell responses.

Methods

Target binding characteristics and agonistic activity of HexaBody-OX40 were analyzed in vitro using binding assays, cell-based reporter assays, and functional assays using primary human T cells. Antitumor activity and pharmacodynamics of HexaBody-OX40 were assessed in vivo in MC38 tumor-bearing human OX40 knock-in mice.

Results

HexaBody-OX40 bound to activated OX40-expressing T cells. In contrast to other OX40 agonists, HexaBody-OX40 induced FcγR-independent OX40 agonist activity in a T-cell based reporter assay. In an assay using polyclonally stimulated human PBMCs, HexaBody-OX40 enhanced proliferation and activation of CD4⁺ and CD8⁺ T cells, and cytokine secretion. In this assay, OX40 agonistic activity in CD8⁺ T cells depended on the presence of CD4⁺ T cells. Furthermore, HexaBody-OX40 enhanced proliferation of antigen-specific CD8⁺ T cells overexpressing OX40. In vivo antitumor activity of HexaBody-OX40 in a syngeneic MC38 model in human OX40 knock-in mice was associated with peripheral T-cell proliferation and activation, increased percentages of tumor-specific CD8⁺ T cells, and an intratumoral increase in CD4⁺ T cells and Granzyme B⁺ cells.

Conclusions

In preclinical studies, HexaBody-OX40 exhibited FcγR-crosslinking-independent OX40 agonist activity, a unique mechanism of action that is distinct from other OX40 agonists. HexaBody-OX40 enhanced T-cell activation and proliferation in vitro and showed antitumor activity in vivo. A first-in-human clinical trial is planned to evaluate clinical safety and preliminary efficacy of HexaBody-OX40 in patients with advanced solid tumors.

Legal entity responsible for the study

The authors.

Funding

Genmab BV, BioNTech SE.

Disclosure

K. Kemper, M. van der Kroef, G. Zom, A. Gorlani, L. Guelen, D. Satijn, T. Ahmadi, E. Breij: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab BV. M. Köhne, K.B.B. Nuermberger, A. Krause, F. Gieseke, A. Muik, S. Fellermeier-Kopf, î Türeci, U. Sahin: Financial Interests, Personal, Full or part-time Employment: BioNtech SE; Financial Interests, Personal, Stocks/Shares: BioNTech SE. M. Russier, P. de Goeje: Financial Interests, Personal, Stocks/Shares: Genmab BV; Financial Interests, Personal, Full or part-time Employment: Genmab BV.