Abstract 4248: HFB200603, a novel anti-BTLA monoclonal antibody that provides therapeutic potential for immune escape and synergizes with anti-PD-1 treatment

Abstract BTLA is a co-inhibitory immune checkpoint molecule sharing sequence and structural homology with PD-1 and CTLA4. Ligation of HVEM with BTLA induces recruitment of SHP1 and SHP2, and triggers inhibition of T cell proliferation and cytokine production. In melanoma, HVEM is described to have a broader expression than PD-L1 and constituted a negative prognostic marker; in PD-L1 negative NSCLC, the expression of HVEM has been shown to contribute to immune escape. Therefore BTLA-HVEM axis could play an important role in the immune escape, thus BTLA blockade in combination with PD-1/PD-L1 blockade could represent an effective therapeutic option. Using our proprietary microfluidic-based single cell platform CelliGO™, we identified a series of anti-human BTLA antibodies that were characterized for their binding affinity, cross-reactivity, selectivity and functional activity. Amongst them, HFB200603 was identified as a single-digit nanomolar binder to human and cynomolgus BTLA, capable of reversing HVEM-mediated immune suppression in a BTLA-HVEM reporter system and in a primary CD4+ T cell proliferation assay. HFB200603 showed synergistic effect with anti-PD-1 to enhance IFN-γ production in an MLR assay, and demonstrated favorable developability and pharmacokinetic profiles. Profiling of tumor infiltrating lymphocytes demonstrated that BTLA+PD-1+ T cells are present in melanoma, NSCLC, and HCC. Blockade of the BTLA-HVEM interaction with HFB200603 alone or in combination with anti-PD-1 led to increases in IFN-γ, CXCL9, IP-10 and other proinflammatory cytokines in primary dissociated tumor cultures. Based on its favorable pharmacological activity and excellent developability, HFB200603 is currently being developed as a potential novel immunotherapy coupled with a patient biomarker strategy derived from HiFiBiO’s Drug Intelligent Science (DIS™) single-cell immune profiling platform. Citation Format: Juying Li, Qian Zhang, Bingqing Shen, Manan Shah, Mingjie Chen, Sharon Li, Ling Dong, Francisco Adrian, Liang Schweizer. HFB200603, a novel anti-BTLA monoclonal antibody that provides therapeutic potential for immune escape and synergizes with anti-PD-1 treatment [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 4248.