Harnessing TNFR2 Antibodies: A New Frontier in Immuno-Oncology for T Cell Modulation

Recent research has highlighted the potential of TNFR2 as a target for developing treatments in the field of Immuno-Oncology. The presence of TNFR2 on various T cells within the tumor environment has been linked to T cell exhaustion and a lack of response to certain immune therapies. In an effort to counter this, researchers have developed antibodies against human TNFR2 with the aim of creating new anti-cancer drugs.

Utilizing a microfluidic single cell platform, several antibodies were identified following mouse immunization with a recombinant human TNFR2 extracellular domain. Two antibodies, HFB3-1 and HFB3-14, showed high affinity for human TNFR2 and were chosen for further study. They were found to target distinct domains of TNFR2, with HFB3-1 binding to the CRD2 domain and HFB3-14 to the CRD3 region. Both antibodies were selective for TNFR2, cross-reactive with non-human primate orthologs, and capable of enhancing the binding of human TNFα to TNFR2 and activating T cells.

The humanized versions of these antibodies, HFB3-1hz6 and HFB3-14hz1c, maintained the binding and cross-reactivity profiles of their parent antibodies. They were found to bind preferentially to activated primary CD8 and CD4 T cells, enhancing their activation and proliferation. The mechanism of action involves a co-stimulatory effect that is independent of cross-linking and is associated with the enhancement of NFκB signaling and the induction of NFκB target genes.

These antibodies have shown promising developability, with good stability under various conditions and adequate plasma exposure in mice. In vivo efficacy and toxicology studies are ongoing. The antibodies' functional characteristics, along with their favorable profiles for development and pharmacokinetics, suggest they could offer a new therapeutic approach for cancer treatment.

Citation: Wei S, Yang G, Li J, et al. Discovery and characterization of novel TNFR2 antibodies to modulate T cell activities in immunosuppressive environment [abstract]. Cancer Res 2020;80(16 Suppl):Abstract nr 2282.