7n0a

Structure of Human Leukaemia Inhibitory Factor with Fab MSC1

spinqualitylabelsall models 7n0a, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7n0a is a 3 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 3.1Å Ligands: BMA, GOL, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LIF_HUMAN LIF has the capacity to induce terminal differentiation in leukemic cells. Its activities include the induction of hematopoietic differentiation in normal and myeloid leukemia cells, the induction of neuronal cell differentiation, and the stimulation of acute-phase protein synthesis in hepatocytes. Publication Abstract from PubMed PURPOSE: Leukemia inhibitory factor (LIF) is a multifunctional cytokine with numerous reported roles in cancer and is thought to drive tumor development and progression. Characterization of LIF and clinical-stage LIF inhibitors would increase our understanding of LIF as a therapeutic target. EXPERIMENTAL DESIGN: We first tested the association of LIF expression with transcript signatures representing multiple processes regulating tumor development and progression. Next, we developed MSC-1, a high affinity therapeutic antibody that potently inhibits LIF signaling and tested it immune competent animal models of cancer. RESULTS: LIF was associated with signatures of tumor associated macrophages (TAMs) across 7,769 tumor samples spanning 22 solid tumor indications. In human tumors, LIF receptor (LIFR) was highly expressed within the macrophage compartment and LIF treatment drove macrophages to acquire immunosuppressive capacity. MSC-1 potently inhibited LIF signaling by binding an epitope that overlaps with the gp130 receptor binding site on LIF. MSC-1 showed monotherapy efficacy in vivo and drove TAMs to acquire anti-tumor and pro-inflammatory function in syngeneic colon cancer mouse models. Combining MSC-1 with anti-PD1 lead to strong anti-tumor response and a long-term tumor free survival in a significant proportion of treated mice. CONCLUSION: Overall, our findings highlight LIF as a therapeutic target for cancer immunotherapy. Therapeutic targeting of LIF overcomes macrophage mediated immunosuppression of the local tumor microenvironment.,Hallett R, Bonfill-Teixidor E, Iurlaro R, Arias A, Raman S, Bayliss PE, Egorova O, Neva-Alejo A, McGray AR, Lau E, Bosch A, Beilschmidt M, Maetzel D, Fransson J, Huber-Ruano I, Anido J, Julien JP, Giblin PA, Seoane J Clin Cancer Res. 2022 Nov 28:CCR-21-1888. doi: 10.1158/1078-0432.CCR-21-1888. PMID:36441800 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Antibody 3D structures

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