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Ref Type Journal Article
PMID (30587557)
Authors Ghosh S, Sharma G, Travers J, Kumar S, Choi J, Jun HT, Kehry M, Ramaswamy S, Jenkins D
Title TSR-033, a Novel Therapeutic Antibody Targeting LAG-3, Enhances T-Cell Function and the Activity of PD-1 Blockade In Vitro and In Vivo.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 18 3 2019 Mar 632-641 Mol Cancer Ther
URL
Abstract Text Progressive upregulation of checkpoints on tumor-infiltrating lymphocytes promotes an immunosuppressive tumor microenvironment, severely compromising tumor immunity. Lymphocyte activation gene-3 (LAG-3) is a coinhibitory receptor associated with impaired T-cell function and is frequently coexpressed with programmed cell death protein-1 (PD-1) in the context of human cancers. Targeting LAG-3 in conjunction with PD-1 thus represents a strategy to amplify and broaden the therapeutic impact of PD-1 blockade alone. We have generated a high affinity and selective humanized monoclonal IgG4 antibody, TSR-033, which binds human LAG-3 and serves as a functional antagonist, enhancing in vitro T-cell activation both in mixed lymphocyte reactions and staphylococcal enterotoxin B-driven stimulation assays. In a humanized mouse non-small cell lung carcinoma model, TSR-033 boosted the antitumor efficacy of PD-1 monotherapy, with a concomitant increase in immune activation. Analogous studies in a murine syngeneic tumor model using surrogate antibodies demonstrated significant synergy between LAG-3 and PD-1 blockade-combination treatment led to a marked improvement in therapeutic efficacy, increased T-cell proliferation, IFNγ production, and elicited durable immunologic memory upon tumor rechallenge. 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
TSR-033 TSR033|TSR 033 LAG3 Antibody 18 TSR-033 is a humanized monoclonal antibody that targets LAG3 and inhibits binding of class II MHC molecules, potentially resulting in enhanced anti-tumor immune response, particularly in combination with other agents (PMID: 30587557).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References