Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on immune cells. Similar to other immune inhibitory receptors such as programmed death-1 (PD-1), LAG-3 ligation suppresses T-cell activation and cytokine production following antigen stimulation. Despite favorable response rates observed with PD-1 or PD-1 ligand blockade in the treatment of human cancers, there remain many patients who either derive little clinical benefit from such therapies (primary resistance) or suffer a relapse (acquired or adaptive immune resistance). LAG-3 has been implicated in tumor extrinsic resistance mechanisms, due in part to its upregulation following PD-1 blockade, suggesting that targeting this pathway in addition to PD-1 may engender stronger and more durable antitumor immune responses. TSR-033 is a potent and selective humanized monoclonal antibody of the IgG4/kappa isotype, generated through the use of a proprietary in vitro somatic hypermutation antibody discovery technology platform. TSR-033 binds to human LAG-3 and blocks the interaction between LAG-3 and its ligand, major histocompatibility complex class II, expressed on Daudi cells. When evaluated for C1q and CD16a binding, TSR-033 displays properties typical of a human IgG4 antibody, suggesting that it is unlikely to mediate appreciable complement-dependent cytotoxicity or antibody-dependent cell cytotoxicity. Functionally, TSR-033 enhanced T-cell activation in vitro in both SEB-driven and mixed lymphocyte reaction assays. The combination of TSR-033 with a ligand blocking anti-PD-1 antibody further augmented T-cell activation in both systems, as evidenced by increased cytokine production, relative to each individual reagent. Analogous studies using surrogate anti-mouse antibodies also demonstrated that combined blockade of PD-1 and LAG-3 significantly boosted IFNγ production in an in vitro model of murine CD4 T cell exhaustion. Furthermore, anti-LAG-3 combined with anti-PD-1 improved therapeutic efficacy in mouse syngeneic tumor models, eliciting durable immunologic memory upon tumor rechallenge and altering intratumoral and splenic T-cell populations, consistent with heightened immune activation. Taken together, the pharmacologic activity of TSR-033 demonstrates that it is a potent anti-LAG-3 therapeutic antibody and supports its clinical investigation in cancer patients.

Citation Format: Srimoyee Ghosh, Haley Laken, Jon Travers, Sujatha Kamar, H. Toni Jun, Marilyn R. Kehry, David Jenkins. Discovery of TSR-033, a novel, potent anti-human LAG-3 therapeutic antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A201.