Anti-Human LAG-3 (Relatimab) (IVMB0419)

LAG-3 (CD223) is an immune inhibitory receptor in activated T cells that inhibits T cell activation and proliferation, immune function, cytokine secretion, effector functions, and T cell homeostasis¹. LAG-3 functions by down-modulating TCR:CD3 intercellular signal transduction cascades and calcium fluxes in the immunological synapse. LAG-3 inhibitory activities are mediated by its ligands: major histocompatibility complex class II, galectin-3, liver secreted protein fibrinogen-like protein 1, and DC-specific intercellular adhesion molecule-3-grabbing non-integrin family member. Some of these LAG-3 ligand combinations are responsible for tumor immune evasion mechanisms¹ and LAG-3 is considered an aggressive progression marker in several hematological and solid tumor malignancies². As such, LAG-3 is a target of cancer immunotherapy.

Relatlimab is the first anti-LAG-3 monoclonal antibody to be clinically developed¹. It was generated using proprietary transgenic mice having human immunoglobulin miniloci in an endogenous IgH and Igκ knockout background³. The mice were immunized with recombinant human LAG-3-Fc protein, consisting of the LAG-3 extracellular domain (Leu23-Leu450) fused to the Fc portion of human IgG1. Hybridomas were generated by fusing spleen cells with P3×63Ag8.653 myeloma cells and screened for reactivity to hLAG-3-hFc. Clone 25F7 was chosen for grafting onto human κ and IgG4 constant region sequences, expressed in Chinese hamster ovary cells, and sequence optimized. The S228P stabilizing hinge was incorporated into the resulting antibody to prevent Fab-arm exchange. The binding epitope was experimentally determined to be in the N-terminal D1 insertion loop domain of LAG-3 within the H63-W70 peptide sequence.

Relatlimab binds to the LAG-3 receptor, blocking interaction with its ligands³ and consequently promotes T cell proliferation and cytokine secretion^{3, 4}. Relatlimab depletes leukemic cells and restores T cell and NK cell-mediated immune responses in vitro⁵. Relatlimab has also been developed as a combination therapy with an anti-PD-1 antibody for increased T cell activation and anti-tumor effects⁴.