American Association for Cancer Research
15357163mct180836-sup-205994_3_supp_5163489_pw7333.pdf (14.3 kB)

Supplementary Table 2 from 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

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journal contribution
posted on 2023-04-03, 15:04 authored by Srimoyee Ghosh, Geeta Sharma, Jon Travers, Sujatha Kumar, Justin Choi, H. Toni Jun, Marilyn Kehry, Sridhar Ramaswamy, David Jenkins

A Bio-Layer Interferometry (BLI)-based method (Forte Bio Octet Red 96) for determining binding rate constants (kon, koff, KD) was utilized to provide kinetic data on the interaction between the monoclonal antibodies (human IgG1 reference standard and TSR-033) and human CD16a



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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