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

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.