Abstract 2719: Dual blockade of PD-L1 and LAG-3 with FS118, a unique bispecific antibody, induces CD8+ T-cell activation and modulates the tumor microenvironment to promote antitumor immune responses

Background Despite advances with therapies targeting the PD-1/PD-L1 pathway, many patients are refractory or relapse following treatment. LAG-3 expression on exhausted T cells and T-regulatory cells (Tregs) in the tumor may be responsible for this resistance and provides a rationale for co-treatment with antibodies targeting LAG-3 and PD-L1. An alternative approach is the development of a bispecific antibody encompassing binding sites for two antigens. FS118 is a bispecific antibody targeting LAG-3 and PD-L1 that provides dual pathway blockade with the potential to drive unique biology via co-binding of PD-L1 and LAG-3. Methods FS118 was evaluated in vitro for antigen binding and de-repression of LAG-3 and PD-L1 function in both a D011.10 T-cell activation system and a super-antigen stimulated peripheral blood mononuclear cells (PBMC) assay. FS118 was also assessed in a human CD8 specific MHC I restricted antigen recall assay. Anti-tumor activity of a murine-specific molecule, mLAG-3/PD-L1 mAb2, was evaluated in vivo in the MC38 mouse tumor model and associated immunophenotypic changes were evaluated using flow cytometry. Results In murine in vitro assay systems, mLAG3/PD-L1 mAb2 recapitulates the function of FS118 in human systems. Furthermore, FS118 was shown to provide increased activation of human CD8+ T-cells compared to a PD-L1 mAb alone in response to stimulation with MHC Class I restricted peptides. In vivo, studies performed in MC38 tumor-bearing mice studies indicated that mLAG-3/PD-L1 could result in significant anti-tumor activity equivalent to a combination of antibodies targeting LAG-3 and PD-L1. Pharmacodynamic assessment demonstrated changes in the immunophenotype of tumor-infiltrating lymphocytes in the tumor of mLAG3/PD-L1 mAb2 treated mice. These changes were observed in cohorts which received the anti-mouse LAG-3/PD-L1 mAb2 and revealed a both a loss of LAG-3 surface expression on CD4+ and CD8+ T cells, as well as an increase in the CD8:Treg ratio. Conclusions Dual blockade of LAG-3 and PD-L1 with a bispecific antibody results in T-cell activation at least comparable to a combination of antibodies targeting LAG-3 and PD-L1 in primary T-cell assays and murine tumor models. Taken together, the human PBMC based assays and mouse tumor model data demonstrate that a LAG-3/PD-L1 mAb2 can not only potently suppress the checkpoint inhibitor LAG-3 at the tumor site, but does this in part through stimulating a CD8+ T cell mediated response. These