A Bispecific Antibody Targeting Cd28h And Pdl-1 Is A Novel And Potent Immunomodulator Of T Cell Responses

The success of immune checkpoint inhibitors CTLA4 and PD-1 monoclonal antibody, both FDA approved cancer therapies, specifically counteracts inhibitory pathways to activate antigen-specific T cells. However, their success is limited by the fact that not all patients respond to immunotherapy and a variety of adverse events due to non specific and systemic T cell activation limits their administration. A newly identified B7 family receptor, CD28H/TMIGD2, is constitutively expressed on T, pDCs and innate lymphoid cells including NK and ILCs. CD28H is also detected in TILs including the CD8+ tissue resident memory T cells (TRM), a T cell subset that correlates with better prognosis and response to immune checkpoint inhibitor therapy. Functionally, CD28H provides costimulatory function to T cells in the context of TCR signaling events during activation. We engineered a bispecific antibody (Bis mAb) targeting CD28H and PDL1 aimed to augment T cell costimulation and NK activation. The CD28H-PDL1 Bis mAb potentiates T cell proliferative and cytokine responses in antigen-specific human T cell assays and induces human NK -mediated redirected killing of PDL1+ tumor cells. In T cells, the mechanism of action of the Bis mAb requires intracellular signaling domain of the CD28H which downmodulates SHP phosphorylation upon CD3 activation. Intriguingly, we found that the Bis mAb increases induction of CD8 TRM cells in vitro. In human TILs, where CD28H is mostly expressed on CD8 TRM in tumors, the Bis mAb enables higher cytokine responses over PDL1 mAb alone. Given the recent relevance of TRM cells as an important pool of anti-tumor T cell immunity, the rationale for targeting this population via CD28H in the context of blocking PDL1 may prove to be a therapeutic tool for enhancing responses to checkpoint inhibitor therapy. Citation Format: Madhu Ramaswamy, Taeil Kim, Desmond Jones, Hormas Ghadially, Tamer Mahmoud, Andrew Garcia, Susan Wilson, Jeffrey Riggs, Darren Schofield, GIanluca Carlesso. A bispecific antibody targeting CD28H and PDL-1 is a novel and potent immunomodulator of T cell responses [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4438.