TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding.

Autor:	Petrova PS; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Viller NN; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Wong M; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Pang X; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Lin GH; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Dodge K; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Chai V; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Chen H; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Lee V; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., House V; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Vigo NT; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Jin D; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Mutukura T; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Charbonneau M; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Truong T; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Viau S; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Johnson LD; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Linderoth E; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Sievers EL; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Maleki Vareki S; London Regional Cancer Program, London Health Sciences Centre, Lawson Heath Research Institute, London, Ontario, Canada.; Department of Oncology, University of Western Ontario, London, Ontario, Canada., Figueredo R; London Regional Cancer Program, London Health Sciences Centre, Lawson Heath Research Institute, London, Ontario, Canada.; Department of Oncology, University of Western Ontario, London, Ontario, Canada., Pampillo M; London Regional Cancer Program, London Health Sciences Centre, Lawson Heath Research Institute, London, Ontario, Canada., Koropatnick J; London Regional Cancer Program, London Health Sciences Centre, Lawson Heath Research Institute, London, Ontario, Canada.; Department of Oncology, University of Western Ontario, London, Ontario, Canada., Trudel S; Princess Margaret Cancer Center, University Health Network (UHN), Toronto, Ontario, Canada., Mbong N; Princess Margaret Cancer Center, University Health Network (UHN), Toronto, Ontario, Canada., Jin L; Princess Margaret Cancer Center, University Health Network (UHN), Toronto, Ontario, Canada., Wang JC; Princess Margaret Cancer Center, University Health Network (UHN), Toronto, Ontario, Canada.; Division of Medical Oncology and Hematology, Department of Medicine, UHN, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada., Uger RA; Trillium Therapeutics Inc., Mississauga, Ontario, Canada. bob@trilliumtherapeutics.com.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Feb 15; Vol. 23 (4), pp. 1068-1079. Date of Electronic Publication: 2016 Nov 17.
DOI:	10.1158/1078-0432.CCR-16-1700
Abstrakt:	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 . (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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