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

Abstract

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 data provide evidence to support the rationale for clinical development of FS118, a LAG-3/PD-L1 mAb2, for the treatment of human cancers. Citation Format: Matthew Kraman, Natalie Fosh, Katarzyna Kmiecik, Katy Everett, Carlo Zimarino, Mustapha Faroudi, Mateusz Wydro, Alexander Koers, Lesley Young, Daniel Gliddon, Michelle Morrow, Jacqueline Doody, Mihriban Tuna, Neil Brewis. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2719.

Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4

“…Other LAG-3 inhibitory antibodies MK-4280, REGN3767 [71], TSR-033 [72], BI754111 [73], and Sym022 [74] have also been investigated at various stages of clinical development. To capitalize on synergistic effects of co-blockade PD-1 and LAG-3 pathways in preclinical models [75], some bispecific anti-LAG-3/PD-(L)1 antagonistic mAbs have also been developed, such as FS118 [76] and MGD013 [77]. To date, at least 10 kinds of LAG-3 blockade agents have been developed and studied in clinical trials, yet their results are not available now.…”

Development of bispecific antibodies in China: overview and prospects

“…MGD013 was showed to enhance cytokine production upon antigenic rechallenge of prior superantigen-stimulated T cells in vitro, and to increase CD8:Treg ratio and to induce loss of LAG3 surface expression on T cells in vivo [ 135 ]. Furthermore, anti-PD-1 × anti-LAG-3 bsAb may offer clinical opportunities to checkpoint naïve patients as well as to checkpoint experienced patients who have progressed on prior therapy with PD-1/PD-L1 inhibitors [ 94 , 135 , 136 ].…”

Bispecific Antibodies for the Treatment of Cancer

“…In comparison, binding to PD-L1 showed greater dissociation (3.90) than association (0.38), resulting in a larger K D value of 1.00 nM. This has indicated that FS118 has high affinity and potent binding to LAG-3, with moderate affinity to PD-L1 [61].…”

“…To investigate target binding of FS118, a Surface Plasmon Resonance (SPR) assay was undertaken [61]. This procedure involved one ligand (e.g.…”