title: TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding.
abstract: 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 vivoantitumor 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.
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Penka S
authors.initials: PS
authors.lastname: Petrova
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Natasja Nielsen
authors.initials: NN
authors.lastname: Viller
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Wong
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Xinli
authors.initials: X
authors.lastname: Pang
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Lin
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Dodge
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Vien
authors.initials: V
authors.lastname: Chai
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Vivian
authors.initials: V
authors.lastname: Lee
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Violetta
authors.initials: V
authors.lastname: House
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Noel T
authors.initials: NT
authors.lastname: Vigo
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Debbie
authors.initials: D
authors.lastname: Jin
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Tapfuma
authors.initials: T
authors.lastname: Mutukura
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Marilyse
authors.initials: M
authors.lastname: Charbonneau
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Tran
authors.initials: T
authors.lastname: Truong
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Viau
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Johnson
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Emma
authors.initials: E
authors.lastname: Linderoth
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Sievers
authors.affiliation: 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.
authors.forename: Saman
authors.initials: S
authors.lastname: Maleki Vareki
authors.affiliation: 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.
authors.forename: Rene
authors.initials: R
authors.lastname: Figueredo
authors.affiliation: London Regional Cancer Program, London Health Sciences Centre, Lawson Heath Research Institute, London, Ontario, Canada.
authors.forename: Macarena
authors.initials: M
authors.lastname: Pampillo
authors.affiliation: 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.
authors.forename: James
authors.initials: J
authors.lastname: Koropatnick
authors.affiliation: Princess Margaret Cancer Center, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.affiliation: Princess Margaret Cancer Center, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Nathan
authors.initials: N
authors.lastname: Mbong
authors.affiliation: Princess Margaret Cancer Center, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Liqing
authors.initials: L
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Jean C Y
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Trillium Therapeutics Inc., Mississauga, Ontario, Canada. bob@trilliumtherapeutics.com.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Uger
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics*; D051928:CD47 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000187:drug effects; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D051928:CD47 Antigen; C497894:CD47 protein, human; D007074:Immunoglobulin G; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C501920:SIRPA protein, human; C000626237:TTI-621