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How relatlimab intends to work in NSCLC

1

Figure 1: LAG-3 biology and pathway1

LAG-3 is a cell-surface molecule expressed on T cells and other immune cells. Interaction of LAG-3 with its ligands triggers inhibitory activity that reduces the function of effector T cells, leading to an impaired ability to fight tumor cells and an increased potential for tumor growth.
  • LAG-3 is a cell-surface molecule expressed on T cells and other immune cells.2,3
  • Interaction of LAG-3 with its ligands, triggers inhibitory activity that reduces the function of effector T cells, leading to an impaired ability to fight tumor cells and an increased potential for tumor growth.2,4
  • LAG-3 has diverse inhibitory biologic effects on the function of T cells.2,3
  • Increased expression of LAG-3 on CD8+ and CD4+ TILs, especially in the context of PD-1 expression, inhibits effector T-cell function.2,5
  • LAG-3 reduces T-cell activation and proliferation and may attenuate pro-inflammatory responses.3,6
  • In addition to activated CD4+ and CD8+ T cells, LAG-3 is expressed on several immune cell types, including memory T cells, Tregs, and natural killer cells.7,8
  • RELA is a LAG-3–blocking antibody that binds to the LAG-3 receptor on T cells, preventing its interaction with MHC II, as well as other emerging ligands (e.g., FGL1).9
  • Preclinical studies indicate that the LAG-3 antibody may promote proinflammatory response and enhance the number and effect of CD8+ cells, culminating in increased antitumor response.3

2

Figure 2: LAG-3 and PD-1 dual inhibition

Dual blockade of PD-1 and LAG-3 with NIVO and RELA10

LAG-3 and PD-1 dual inhibition. LAG-3 and PD-1, 2 distinct immune checkpoints that are often co-expressed on TILs, contribute to tumor-mediated T-cell dysfunction1 Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors
  • LAG-3 and PD-1, 2 distinct immune checkpoints that are often co-expressed on TILs, contribute to tumor-mediated T-cell dysfunction.2
  • Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production.  Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors.11
  • NIVO is a human IgG4 monoclonal antibody that binds to the PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2 and reduces PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.11
  • NIVO + RELA combination therapy enables T-cell activation and proliferation, leading to the initiation of an improved immune response and promoting tumor cell death.5,12

Abbreviations

APC = antigen-presenting cell; LAG-3 = lymphocyte activation gene-3; MHC = major histocompatibility complex; TCR = T-cell receptor; PD-1 = programmed Death-1; CD = cluster of differentiation; IFN ɣ = interferon gamma; NIVO = nivolumab; PD-L1/2 = programmed death - ligand 1/2; RELA = relatlimab; TCR = T-cell receptor; Th1 = T-cell helper 1; Treg = regulatory T cells; TIL= tumor-infiltrating lymphocyte; FGL1= fibrinogen-like protein 1

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  1. Lipson EJ, Tawbi HA, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047)
  2. Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer. 2018;9(5 6):176-189. doi:10.18632/genesandcancer.180
  3. Grosso JF, Kelleher CC, Harris TJ, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. Journal of Clinical Investigation. 2007;117(11):3383-3392. doi:10.1172/JCI31184
  4. Wang, Sanmamed, Datar, et al. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell. 2019;176(1):334-347. doi:10.1016/j.cell.2018.11.010
  5. Woo S-R, Turnis ME, Goldberg MV, et al. Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape. Cancer Res. 2012;72(4):917 927. doi:10.1158/0008-5472.CAN-11-1620
  6. Workman CJ, Dugger KJ, Vignali DAA. Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-3. J Immunol. 2002;169(10):5392-5395. doi:10.4049/jimmunol.169.10.5392
  7. Anderson AC, Joller N, Kuchroo VK. LAG-3, TIM-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44(5):989-1004
  8. Workman CJ, Cauley LS, Kim I-J, Blackman MA, Woodland DL, Vignali DAA. Lymphocyte Activation Gene-3 (CD223) Regulates the Size of the Expanding T Cell Population Following Antigen Activation In Vivo. J Immunol. 2004;172(9):5450-5455. doi:10.4049/jimmunol.172.9.5450
  9. Thudium K, Selby M, Zorn JA, et al. Preclinical Characterization of Relatlimab, a Human LAG-3–Blocking Antibody, Alone or in Combination with Nivolumab. Cancer Immunol Res. 2022;10(10):1175-1189. doi:10.1158/2326 6066.CIR-22-0057
  10. Sangro B, Yau T, Harding JJ, et al. RELATIVITY-106: a phase 1/2 trial of nivolumab and relatlimab in combination with bevacizumab in first-line hepatocellular carcinoma. Poster at ASCO-GI. 2023;5
  11. OPDUALAG® [prescribing information]. Princeton, NJ: Bristol Myers Squibb Company; 2022
  12. Vilgelm AE, Johnson DB, Richmond A. Combinatorial approach to cancer immunotherapy: strength in numbers. J Leukoc Biol. 2016;100(2):275-290. doi:10.1189/ jlb.5RI0116-013RR

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