7um3

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Crystal structure of a Fab in complex with a peptide derived from the LAG-3 D1 domain loop insertion

Structural highlights

7um3 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3983Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LAG3_HUMAN Lymphocyte activation gene 3 protein: Inhibitory receptor on antigen activated T-cells (PubMed:20421648, PubMed:7805750, PubMed:8647185). Delivers inhibitory signals upon binding to ligands, such as FGL1 (By similarity). FGL1 constitutes a major ligand of LAG3 and is responsible for LAG3 T-cell inhibitory function (By similarity). Following TCR engagement, LAG3 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity). May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1, possibly by acting as a coreceptor for PDCD1/PD-1 (By similarity). Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells (PubMed:20421648, PubMed:7805750, PubMed:8647185). Also mediates immune tolerance: constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function (By similarity). Also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation (By similarity). Binds MHC class II (MHC-II); the precise role of MHC-II-binding is however unclear (PubMed:8647185).[UniProtKB:Q61790][1] [2] [3] May function as a ligand for MHC class II (MHC-II) on antigen-presenting cells (APC), promoting APC activation/maturation and driving Th1 immune response.[UniProtKB:Q61790]

Publication Abstract from PubMed

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 antitumor 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 II/III trial showing that relatlimab combined with nivolumab is a well-tolerated regimen that demonstrates superior progression-free survival compared with nivolumab monotherapy in patients with unresectable or metastatic melanoma.

Preclinical Characterization of Relatlimab, a Human LAG-3-Blocking Antibody, Alone or in Combination with Nivolumab.,Thudium K, Selby M, Zorn JA, Rak G, Wang XT, Bunch RT, Hogan JM, Strop P, Korman AJ Cancer Immunol Res. 2022 Oct 4;10(10):1175-1189. doi: , 10.1158/2326-6066.CIR-22-0057. PMID:35981087[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
9 reviews cite this structure
LAG-3 : recent developments in combinational therapies in cancer.
Chavanton et al. (2024)
8 more
10 other articles
No citations found

See Also

References

  1. ↑ Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, Parmiani G, Belli F, Rivoltini L, Castelli C. LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol. 2010 Jun 1;184(11):6545-51. doi: 10.4049/jimmunol.0903879. Epub 2010, Apr 26. PMID:20421648 doi:http://dx.doi.org/10.4049/jimmunol.0903879
  2. ↑ Huard B, Tournier M, Hercend T, Triebel F, Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur J Immunol. 1994 Dec;24(12):3216-21. doi: 10.1002/eji.1830241246. PMID:7805750 doi:http://dx.doi.org/10.1002/eji.1830241246
  3. ↑ Huard B, Prigent P, Pages F, Bruniquel D, Triebel F. T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding. Eur J Immunol. 1996 May;26(5):1180-6. doi: 10.1002/eji.1830260533. PMID:8647185 doi:http://dx.doi.org/10.1002/eji.1830260533
  4. ↑ Thudium K, Selby M, Zorn JA, Rak G, Wang XT, Bunch RT, Hogan JM, Strop P, Korman AJ. Preclinical Characterization of Relatlimab, a Human LAG-3-Blocking Antibody, Alone or in Combination with Nivolumab. Cancer Immunol Res. 2022 Aug 18. pii: 707916. doi: 10.1158/2326-6066.CIR-22-0057. PMID:35981087 doi:http://dx.doi.org/10.1158/2326-6066.CIR-22-0057

Contents


PDB ID 7um3

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OCA

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