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|Ref Type||Journal Article|
|Authors||Petrova PS, Viller NN, Wong M, Pang X, Lin GH, Dodge K, Chai V, Chen H, Lee V, House V, Vigo NT, Jin D, Mutukura T, Charbonneau M, Truong T, Viau S, Johnson LD, Linderoth E, Sievers EL, Maleki Vareki S, Figueredo R, Pampillo M, Koropatnick J, Trudel S, Mbong N, Jin L, Wang JC, Uger RA|
|Title||TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2017 Feb 15|
|Abstract Text||Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication.Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails.Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo, TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies.Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4); 1068-79. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|TTI-621||SIRPalpha-Fc||CD47 Antibody 13 Immune Checkpoint Inhibitor 94||TTI-621 (SIRPalpha-Fc) is a fusion, consisting of SIRPa fused to the human IgG1 Fc region, that binds to CD47 and blocks inhibitory signaling to macrophages, resulting in increased phagocytosis of tumor cells (PMID: 27856600, PMID: 28286286) may also stimulate cytotoxic T-cells (PMID: 29873856).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||acute myeloid leukemia||not applicable||TTI-621||Preclinical - Pdx||Actionable||In a preclinical study, TTI-621 (SIRPalpha-Fc) decreased tumor burden in acute myeloid leukemia patient-derived xenograft models (PMID: 27856600).||27856600|
|Unknown unknown||hematologic cancer||not applicable||TTI-621||Preclinical - Cell culture||Actionable||In a preclinical study, TTI-621 (SIRPalpha-Fc) increased phagocytosis in 77% (23/30) of the human hematological tumor cell lines tested in culture (PMID: 27856600).||27856600|
|Unknown unknown||Burkitt lymphoma||not applicable||TTI-621||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the mouse surrogate version of TTI-621 (SIRPalpha-Fc) decreased tumor growth in Burkitt lymphoma cell line xenograft models (PMID: 27856600).||27856600|
|Unknown unknown||Advanced Solid Tumor||not applicable||TTI-621||Preclinical - Cell culture||Actionable||In a preclinical study, TTI-621 (SIRPalpha-Fc) increased phagocytosis in 67% (8/12) of the human solid tumor cell lines tested in culture (PMID: 27856600).||27856600|
|Unknown unknown||diffuse large B-cell lymphoma||not applicable||TTI-621||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the mouse surrogate version of TTI-621 (SIRPalpha-Fc) decreased tumor growth in a diffuse large B-cell lymphoma cell line xenograft model (PMID: 27856600).||27856600|