The overall therapeutic benefit of blocking the first generation of immune checkpoint pathways (PD-1 and CTLA-4) has been demonstrated across multiple tumor types, yielding long term protection in some patients. However, most patients do not respond to these single-agent approaches. Thus, collaborative strategies that seek to engage novel pathways and cell types may provide therapeutic options for patients wherein pre-existing host and tumor microenvironment factors do not favor current immunotherapeutic agents or in tumors where adaptive resistance has occurred.

In recent years, the CD226 (DNAX Accessory Molecule-1 [DNAM-1]) axis has emerged as a relevant regulatory node in for natural killer (NK) and T cells - particularly in the context of tumor immunology. Similar to the competitive interplay between CTLA-4/CD28 and B7 (CD80/86), inhibitory receptors within the axis (e.g., CD96 [TACTILE]) effectively compete with the co-stimulatory receptor CD226 for binding to shared ligands (e.g., CD155), thereby impairing the initiation and/or promotion of ongoing antitumor immune responses. Indeed, genetic or monoclonal antibody (mAb)-based co-inhibition of CD96 with other immune checkpoints has proven efficacious in several nonclinical tumor models.

CD96 has been shown to impact both T cell and NK cell function, offering a level of versatility as a target for cancer immunotherapy. For example, in the setting of anti-PD-1 neoadjuvant treatment, significantly improved survival of pancreatic ductal adenocarcinoma (PDAC) tumor-bearing mice was observed following enhancement of NK cell activity by CD96 antibody treatment. Equally, pronounced effects on primary tumor growth following anti-PD-1, -TIGIT, and -CD96 mAb treatment in a colorectal carcinoma tumor model (CT26) was found to be dependent on CD8+ T cells.

GSK6097608 is a clinical-stage fully-human immunoglobulin G1 (IgG1)κ mAb that targets the inhibitory immune receptor CD96. GSK6097608 was identified, in part, for its ability prevent and disrupt CD96:CD155 interactions, thereby promoting T and NK cell function. GSK6097608 demonstrated concentration-dependent rescue of human immune cell activity following exposure to plate-bound recombinant CD155 (cognate receptor/ligand); an effect that was improved with concomitant TIGIT blockade. Notably, functional activity was found to be dependent on intact Fc-FcγR co-engagement, as potentiation of primary human T and NK cell function was lost when GSK6097608 was grafted on an Fc-attenuated backbone. Here, we describe some of the biophysical and functional characteristics that support the rationale for clinical evaluation of GSK6097608.

Citation Format: Yan Degenhardt, Jun Guan, Peter Morley, David Jones, Michael Conner, Stephen Eastman, Wei Wang, Andrew Sanderson, Anand Ravindran, Julie Krueger, Iris Roth, James Smothers, Jeremy D. Waight. Discovery and characterization of the CD96 antibody GSK6097608, a high-affinity, antagonistic anti-CD96 antibody for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6268.