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Preclinical Characterization of Relatlimab, a Human LAG-3–Blocking Antibody, Alone or in Combination With Nivolumab

Kent Thudium, Mark Selby, Julie A. Zorn, Gregory Rak, Xi-Tao Wang, Roderick Todd Bunch, Jason M. Hogan, Pavel Strop, Alan J. Korman
doi: https://doi.org/10.1101/2022.01.24.477551
Kent Thudium
1Bristol Myers Squibb, Princeton, NJ, USA
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  • For correspondence: kent.thudium@bms.com
Mark Selby
2Walking Fish Therapeutics Inc, San Francisco, CA, USA
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Julie A. Zorn
1Bristol Myers Squibb, Princeton, NJ, USA
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Gregory Rak
3Kallyope Inc, New York, NY, USA
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Xi-Tao Wang
1Bristol Myers Squibb, Princeton, NJ, USA
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Roderick Todd Bunch
1Bristol Myers Squibb, Princeton, NJ, USA
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Jason M. Hogan
1Bristol Myers Squibb, Princeton, NJ, USA
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Pavel Strop
4Tallac Therapeutics, Burlingame, CA, USA
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Alan J. Korman
5Vir Biotechnology Inc, San Francisco, CA, USA
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Abstract

Novel therapeutic approaches combining immune checkpoint inhibitors are needed to improve clinical outcomes for patients with cancer. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint molecule that inhibits T-cell activity and antitumor immune responses, acting through an independent mechanism from that of programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4). Here, we describe the development and preclinical characterization of relatlimab, a human antibody that binds to human LAG-3 with high affinity and specificity to block the interaction of LAG-3 with the ligands MHC II and fibrinogen like protein-1, and to reverse LAG-3–mediated inhibition of T-cell function in vitro. Consistent with previous reports, in mouse models, the combined blockade of LAG-3 and PD-1 with surrogate antibodies resulted in enhanced anti-tumor activity greater than the individual blockade of either receptor. In toxicity studies in cynomolgus monkeys, relatlimab was generally well tolerated when combined with nivolumab. These results are consistent with findings from the RELATIVITY-047 phase 2/3 trial showing that relatlimab combined with nivolumab is a well-tolerated regimen that demonstrated superior progression-free survival compared with nivolumab monotherapy in patients with unresectable or metastatic melanoma.

Synopsis Preclinical studies demonstrate that relatlimab specifically blocks the interaction between LAG-3 and its ligands, and provide a biological rationale for combining relatlimab with the anti−PD-1 antibody nivolumab as an effective cancer immunotherapeutic strategy.

Competing Interest Statement

KT, JZ, XW, RTB, and JH are employed by, and own stock in, Bristol Myers Squibb. KT also reports being co-inventor in patents US 11,001,630; US 10,683,357; US 10,155,813; and US 8,263,073. MS is employed by, and owns equity in, Walking Fish Therapeutics. GR, PS, and AK were employed by Bristol Myers Squibb at the time the work that led to this manuscript was performed and currently own stock in Bristol Myers Squibb.

Footnotes

  • ↵# Bristol Myers Squibb at the time the work was performed

  • Funding: This study was funded by Bristol Myers Squibb.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 25, 2022.
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Preclinical Characterization of Relatlimab, a Human LAG-3–Blocking Antibody, Alone or in Combination With Nivolumab
Kent Thudium, Mark Selby, Julie A. Zorn, Gregory Rak, Xi-Tao Wang, Roderick Todd Bunch, Jason M. Hogan, Pavel Strop, Alan J. Korman
bioRxiv 2022.01.24.477551; doi: https://doi.org/10.1101/2022.01.24.477551
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Preclinical Characterization of Relatlimab, a Human LAG-3–Blocking Antibody, Alone or in Combination With Nivolumab
Kent Thudium, Mark Selby, Julie A. Zorn, Gregory Rak, Xi-Tao Wang, Roderick Todd Bunch, Jason M. Hogan, Pavel Strop, Alan J. Korman
bioRxiv 2022.01.24.477551; doi: https://doi.org/10.1101/2022.01.24.477551

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