Reference Detail

Ref Type

Journal Article

PMID

(27856600)

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	4	2017 Feb 15	1068-1079	Clin Cancer Res

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
TTI-621	TTI-621	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TTI-621		SIRPalpha-Fc\|TTI621\|TTI 621\|Ontorpacept	CD47 Antibody 30 Immune Checkpoint Inhibitor 147	TTI-621 (Ontorpacept) 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