HFB10-1E1, a novel OX-40 agonistic antibody with a unique pharmacological profile and biomarker strategy
Andreas Raue1, Yun-Yueh Lu1, Ouyang Li1, Minmin Lu1, Joyce Pi1, Jia Wu1, Mingfang Feng1, Qian Zhang1, Surendar Arumugam1, Ruina Jin2, Yuan Wang2, Ross Fulton1, Matthieu Delince1, Juliana Crivello1, Zachary Duda1, Alexandra Staskus1, Charina Ortega1, Pascaline Mary1, Hongkai Zhang2, Nicola Beltraminelli1, Francisco Adrian1, Liang Schweizer1
1HiFiBiO Therapeutics, Cambridge, MA, United States
2Nankai University, China
Agonistic antibodies against the co-stimulatory receptor OX-40 have shown promising activity in preclinical models, but clinical activity has only been observed in isolated cases. While co-stimulation of T cells is described as the primary pharmacological mechanism of these antibodies, high expression of OX-40 on tumor-infiltrating regulatory T cells has also been observed and discussed as a potentially confounding factor in a clinical setting.

We present HFB10-1E1, a novel OX-40 agonistic antibody with an optimized pharmacological profile. HFB10-1E1 binds specifically to a unique epitope on human OX-40 and cross-reacts with cynomolgus monkey OX-40. Upon cross-linking, HFB10-1E1 induces NFκB signaling in a reporter cell line and leads to co-stimulation of T cells in vitro. The agonistic activity of HFB10-1E1 is further enhanced in the presence of the endogenous ligand OX-40L. In contrast to other anti-OX-40 antibodies, treatment with HFB10-1E1 does not result in reduced expression of OX-40 on T cells, which will ease the prediction of clinical dose-schedule and potentially lead to better activity. HFB10-1E1 demonstrates more potent in vivo anti-tumor activity in human OX-40 knock-in mice bearing MC-38 syngeneic tumors as compared to a previously published anti-OX-40 antibody. HFB10-1E1 has a favorable developability profile, and stable cell lines with high production yield have been obtained.

Further, we present a novel concept for identifying potential responding patients to HFB10-1E1 using HiFiBiO’s proprietary Drug Intelligent Science (DIS™) platform. The DIS approach for discovery of predictive response biomarkers combines high-throughput single-cell profiling of a patient’s T cell repertoire with functional read-outs to characterize tumor-specific T cell clones responsive to HFB10-1E1. Our results provide the foundation for the implementation of the DIS™ platform to guide the clinical development of HFB10-1E1 for selected patients that are most likely to benefit from the treatment.

HFB10-1E1 is being developed as a potential novel treatment option for cancer coupled with a patient stratification biomarker.

Session: Therapeutic Antibodies 1 (Virtual Poster Session)
Category: IMMUNOLOGY: Preclinical and Clinical