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Relatlimab
Opdualag
LAG-3 checkpoint inhibitor (anti-LAG-3 monoclonal antibody)
Evidence Score
20
Relatlimab (BMS-986016; Bristol-Myers Squibb) is a fully human IgG4 monoclonal antibody that binds LAG-3 (Lymphocyte Activation Gene 3; CD223) on the surface of exhausted tumor-infiltrating T cells, blocking LAG-3 interactions with its ligands — primarily MHC class II molecules on antigen-presenting cells and on tumor cells expressing MHC-II. LAG-3 co-expression with PD-1 defines the most deeply exhausted, functionally impaired TIL subset; dual blockade of both checkpoints with relatlimab + nivolumab (Opdualag) produces a synergistic restoration of T-cell effector function exceeding either agent alone. **SDH-specific mechanistic rationale — succinate-driven T-cell exhaustion axis (theoretical):** SDH loss → constitutive succinate accumulation in the SDH-deficient tumor microenvironment. Gudgeon et al. (Cell Rep 2022, PMID 35977513) demonstrated that extracellular succinate directly suppresses CD8⁺ T-cell cytolytic activity — establishing succinate as an active immunosuppressive oncometabolite at concentrations relevant to the SDH-deficient TME, independent of its epigenetic (TET/KDM4 inhibition) roles. Pfefer T et al. (Immunol Lett 2026 review, PMID 41724335) extended this line of evidence, reporting that succinate promotes T-cell exhaustion in the TME and drives expansion of cancer-associated fibroblasts — a dual immunosuppressive-stromal mechanism. T-cell exhaustion programs are characterised by progressive upregulation of co-inhibitory checkpoint receptors including LAG-3, PD-1, TIM-3, and TIGIT. In SDH-deficient tumors, chronic constitutive succinate overproduction from the blocked ETC complex II may sustain persistent T-cell exhaustion and LAG-3 upregulation, creating a theoretical therapeutic opportunity for LAG-3 blockade. This mechanistic chain (SDH loss → succinate accumulation → T-cell exhaustion → LAG-3 upregulation) is theoretical: the individual steps are supported by PMID 35977513 and PMID 41724335, but the complete chain has not been demonstrated in SDH-deficient tumor cell lines, animal models, or patient tissue. This direction is mechanistically distinct from the existing immunotherapy entries in this engine: - PMID 35977513 (succinate T-cell suppression) and PMID 41724335 (succinate T-cell exhaustion) are the direct mechanistic anchors. - PD-1/PD-L1 axis (existing entry): HIF-1α transcriptionally activates CD274 (PD-L1) → T-cell suppression via PD-1. Relatlimab targets LAG-3, the co-inhibitory receptor that works in parallel with PD-1 on exhausted TILs — mechanistically complementary and non-redundant. - Oleclumab (existing entry): anti-CD73 IgG1; targets the upstream adenosine-generating enzyme on tumor cells. A completely different immunosuppression axis (CD73→adenosine→ADORA2A/A2B) not involving LAG-3 or T-cell exhaustion. - Etrumadenant (existing entry): dual ADORA2A/ADORA2B oral antagonist; targets adenosine receptors on T cells. Again a distinct axis. **Clinical data:** - NCT03470922 (RELATIVITY-047; Phase 2/3; Bristol-Myers Squibb; unresectable/metastatic melanoma; relatlimab 160 mg + nivolumab 480 mg [Opdualag] vs. nivolumab 480 mg; n=714; primary endpoint: progression-free survival): Tawbi HA et al. (NEJM 2022, PMID 34986285) reported significantly improved median PFS (10.1 vs. 4.6 months; HR 0.75, 95% CI 0.62–0.92; p=0.006) for dual LAG-3 + PD-1 blockade vs. PD-1 alone; FDA approved Opdualag (relatlimab 160 mg + nivolumab 480 mg fixed-dose combination) for unresectable or metastatic melanoma in March 2022 — the first LAG-3 checkpoint inhibitor approved globally. The clinical trial ID is NCT03470922 (RELATIVITY-047). **Key limitation:** No published data test relatlimab or any anti-LAG-3 agent in SDH-deficient GIST, PPGL, RCC, or pituitary adenoma. LAG-3 expression on TILs in SDH-deficient tumor tissue has not been quantified by IHC or flow cytometry in patient cohorts. The succinate-to-exhaustion-to-LAG-3 chain (PMID 35977513, PMID 41724335) supports the upstream mechanism (succinate suppresses T cells; a review notes it can promote exhaustion) but does not directly demonstrate LAG-3 upregulation in SDH-null models. Required next step: LAG-3 IHC on SDH-deficient GIST and PPGL TMA panels; RNA-seq for LAG3 expression in SDH-null vs. SDH-intact isogenic cell lines; in vitro succinate treatment of T cells co-cultured with SDH-deficient cancer cells and assessment of LAG-3 upregulation by flow cytometry. Evidence_score 20 (theoretical): mechanistic rationale rests on PMID 35977513 and PMID 41724335 supporting the upstream succinate-T-cell-suppression and exhaustion steps (LAG-3 upregulation is inferred, not shown); no SDH-specific LAG-3 or relatlimab data exist; FDA-approved agent with robust Phase 3 data in melanoma (NCT03470922); score placed at 20 reflecting well-reasoned but unvalidated mechanistic extrapolation and complete absence of SDH-specific preclinical data.
SDH loss creates an immunosuppressive tumor microenvironment through two distinct succinate-dependent mechanisms: (1) extracellular succinate is directly taken up by tumor-infiltrating T cells via MCT1 (SLC16A1), impairing TCA-cycle glucose oxidation in T cells and suppressing IFN-γ secretion and degranulation — demonstrated in human CD4+/CD8+ T cells at tumor-associated succinate concentrations (Gudgeon et al., Cell Rep 2022, PMID 35977513), with RNA-seq of SDH-deficient pheochromocytoma/paraganglioma confirming profound in-vivo IFN-γ signaling suppression; and (2) the pseudohypoxic HIF-1α program drives upregulation of IDO1 (indoleamine 2,3-dioxygenase 1), the rate-limiting enzyme in the tryptophan→kynurenine degradation pathway, with aberrant kynurenine pathway activity confirmed in metastatic SDHB-driven PPGL by multi-omics (PMID 42230482). Together these mechanisms create a profoundly T-cell-hostile TME in SDH-deficient tumors.
Upstream event:
SDH loss → intracellular and extracellular succinate accumulation; HIF-1α stabilization (pseudohypoxia)
Downstream effects:
Extracellular succinate accumulation in the SDH-deficient tumor microenvironment (TME) directly suppresses T-cell function and can promote T-cell exhaustion, which is hypothesised (not shown in the cited work) to drive upregulation of inhibitory checkpoint receptors including LAG-3 (Lymphocyte Activation Gene 3) on tumor-infiltrating CD8⁺ T cells. LAG-3 binds MHC-II on antigen-presenting cells with higher affinity than CD4, and ligation of LAG-3 on exhausted TILs delivers a co-inhibitory signal that arrests T-cell effector programs. Relatlimab, an FDA-approved anti-LAG-3 monoclonal antibody (Opdualag, with nivolumab), targets this exhaustion-driven checkpoint.
Upstream event:
SDH loss → succinate accumulation → T-cell functional suppression and exhaustion in immunosuppressive TME (Gudgeon et al. Cell Rep 2022, PMID 35977513; Pfefer T et al., Immunol Lett 2026 review, PMID 41724335) → (inferred, untested) LAG-3 upregulation on exhausted TILs
Downstream effects:
LAG3
Lymphocyte Activation Gene 3 Protein
LAG-3 (Lymphocyte Activation Gene 3; UniProt P18627) is a type I transmembrane protein structurally homologous to CD4, expressed predominantly on activated and exhausted CD8⁺ cytotoxic T cells, CD4⁺ helper T cells, NK cells, and plasmacytoid dendritic cells. Its extracellular domain binds MHC class II molecules (on antigen-presenting cells and tumor cells expressing MHC-II) with approximately 100-fold higher affinity than CD4, delivering a potent co-inhibitory signal that suppresses T-cell proliferation, cytokine production, and cytolytic function. LAG-3 is a hallmark marker of the T-cell exhaustion program: co-expression of LAG-3 with PD-1 and TIM-3 defines the most functionally impaired tumor-infiltrating lymphocyte (TIL) subset. Relevance to SDH-deficient tumors — succinate-driven exhaustion axis: Gudgeon et al. (Cell Rep 2022, PMID 35977513) demonstrated that extracellular succinate directly suppresses CD8⁺ T-cell cytolytic function in vitro and in the TME, establishing succinate as an immunosuppressive oncometabolite in addition to its epigenetic (TET/KDM4 inhibition) roles. Pfefer T et al. (Immunol Lett 2026 review, PMID 41724335) extended this mechanism, reporting that succinate promotes T-cell exhaustion in the tumor microenvironment — a process generally linked to co-inhibitory checkpoint receptor expression (LAG-3 upregulation here is inferred, not shown by the cited work). In SDH-deficient tumors, constitutive succinate overproduction from the blocked ETC complex II creates a persistent, high-succinate TME, potentially sustaining chronic T-cell exhaustion and LAG-3 upregulation. Relatlimab (BMS-986016) is a fully human IgG4 anti-LAG-3 monoclonal antibody developed by Bristol-Myers Squibb. It blocks LAG-3/MHC-II interactions, relieving the co-inhibitory brake on exhausted TILs. Opdualag (relatlimab 160 mg + nivolumab 480 mg, fixed-dose combination) was FDA-approved in March 2022 for unresectable or metastatic melanoma based on the RELATIVITY-047 trial (NCT03470922), becoming the first LAG-3 checkpoint inhibitor to receive regulatory approval. The RELATIVITY-047 data (Tawbi HA et al., NEJM 2022) demonstrated a significant progression-free survival benefit of dual LAG-3 + PD-1 blockade over PD-1 monotherapy, establishing that LAG-3 is a clinically validated non-redundant checkpoint target alongside PD-1.
UniProt: P18627
Tumor Type Applicability
Approved Indications
- Unresectable or metastatic melanoma (FDA approved March 2022, as Opdualag [relatlimab 160 mg + nivolumab 480 mg]; NCT03470922)
Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.
Coming in Phase 3
For research exploration only — not medical advice. Consult your doctor before acting on any information.
Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.