Maplirpacept: a CD47 decoy receptor with minimal red blood cell binding and robust anti-tumor efficacy
IntroductionCD47 is highly expressed on cancer cells and triggers an anti-phagocytic “don’t eat me” signal when bound by the inhibitory signal regulatory protein α (SIRPα) expressed on macrophages. While CD47 blockade can mitigate tumor growth, many CD47 blockers also bind to red blood cells (RBCs),...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1518787/full |
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| author | Mithunah Krishnamoorthy Mithunah Krishnamoorthy Ruth Seelige Christopher R. Brown Nancy Chau Natasja Nielsen Viller Lisa D. S. Johnson Emma Linderoth Jean C. Y. Wang Jean C. Y. Wang Jean C. Y. Wang Christopher P. Dillon Keith Abayasiriwardana Clare Lees Mark Wong Megan M. Kaneda Robert A. Uger Gloria H. Y. Lin Gloria H. Y. Lin |
| author_facet | Mithunah Krishnamoorthy Mithunah Krishnamoorthy Ruth Seelige Christopher R. Brown Nancy Chau Natasja Nielsen Viller Lisa D. S. Johnson Emma Linderoth Jean C. Y. Wang Jean C. Y. Wang Jean C. Y. Wang Christopher P. Dillon Keith Abayasiriwardana Clare Lees Mark Wong Megan M. Kaneda Robert A. Uger Gloria H. Y. Lin Gloria H. Y. Lin |
| author_sort | Mithunah Krishnamoorthy |
| collection | DOAJ |
| description | IntroductionCD47 is highly expressed on cancer cells and triggers an anti-phagocytic “don’t eat me” signal when bound by the inhibitory signal regulatory protein α (SIRPα) expressed on macrophages. While CD47 blockade can mitigate tumor growth, many CD47 blockers also bind to red blood cells (RBCs), leading to anemia. Maplirpacept (TTI-622, PF-07901801) is a CD47 blocking fusion protein consisting of a human SIRPα fused to an IgG4 Fc region and designed to limit binding to RBCs.MethodsTo determine maplirpacept binding to RBCs and interference with blood tests, human blood samples were used. The ability of maplirpacept to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy as a monotherapy and in combination with other therapeutic agents was evaluated in xenograft models.ResultsIn the current study, we demonstrate that maplirpacept has limited binding to RBCs while driving enhanced macrophage-mediated phagocytosis of hematological tumor cells in vitro and reducing tumor burden in human xenograft models. Moreover, phagocytosis of neoplastic cells can be enhanced when maplirpacept is combined with other therapeutic agents, including antibodies or chemotherapeutic agents.ConclusionThese preclinical results establish maplirpacept as an effective CD47 blocker that mitigates the potential for anemia in patients. |
| format | Article |
| id | doaj-art-4e038d160182470aa267098c5beecdaa |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-4e038d160182470aa267098c5beecdaa2025-08-20T03:11:22ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15187871518787Maplirpacept: a CD47 decoy receptor with minimal red blood cell binding and robust anti-tumor efficacyMithunah Krishnamoorthy0Mithunah Krishnamoorthy1Ruth Seelige2Christopher R. Brown3Nancy Chau4Natasja Nielsen Viller5Lisa D. S. Johnson6Emma Linderoth7Jean C. Y. Wang8Jean C. Y. Wang9Jean C. Y. Wang10Christopher P. Dillon11Keith Abayasiriwardana12Clare Lees13Mark Wong14Megan M. Kaneda15Robert A. Uger16Gloria H. Y. Lin17Gloria H. Y. Lin18Pfizer Oncology, Pfizer Inc., La Jolla, CA, United StatesResearch and Development, Trillium Therapeutics Inc., Mississauga, ON, CanadaPfizer Oncology, Pfizer Inc., La Jolla, CA, United StatesPfizer Oncology, Pfizer Inc., La Jolla, CA, United StatesPfizer Oncology, Pfizer Inc., La Jolla, CA, United StatesResearch and Development, Trillium Therapeutics Inc., Mississauga, ON, CanadaResearch and Development, Trillium Therapeutics Inc., Mississauga, ON, CanadaResearch and Development, Trillium Therapeutics Inc., Mississauga, ON, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaDivision of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, CanadaDepartment of Medicine, University of Toronto, Toronto, ON, CanadaPfizer Oncology, Pfizer Inc., La Jolla, CA, United StatesPfizer Oncology, Pfizer Inc., La Jolla, CA, United StatesPfizer Oncology, Pfizer Inc., La Jolla, CA, United StatesResearch and Development, Trillium Therapeutics Inc., Mississauga, ON, CanadaPfizer Oncology, Pfizer Inc., La Jolla, CA, United StatesResearch and Development, Trillium Therapeutics Inc., Mississauga, ON, CanadaPfizer Oncology, Pfizer Inc., La Jolla, CA, United StatesResearch and Development, Trillium Therapeutics Inc., Mississauga, ON, CanadaIntroductionCD47 is highly expressed on cancer cells and triggers an anti-phagocytic “don’t eat me” signal when bound by the inhibitory signal regulatory protein α (SIRPα) expressed on macrophages. While CD47 blockade can mitigate tumor growth, many CD47 blockers also bind to red blood cells (RBCs), leading to anemia. Maplirpacept (TTI-622, PF-07901801) is a CD47 blocking fusion protein consisting of a human SIRPα fused to an IgG4 Fc region and designed to limit binding to RBCs.MethodsTo determine maplirpacept binding to RBCs and interference with blood tests, human blood samples were used. The ability of maplirpacept to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy as a monotherapy and in combination with other therapeutic agents was evaluated in xenograft models.ResultsIn the current study, we demonstrate that maplirpacept has limited binding to RBCs while driving enhanced macrophage-mediated phagocytosis of hematological tumor cells in vitro and reducing tumor burden in human xenograft models. Moreover, phagocytosis of neoplastic cells can be enhanced when maplirpacept is combined with other therapeutic agents, including antibodies or chemotherapeutic agents.ConclusionThese preclinical results establish maplirpacept as an effective CD47 blocker that mitigates the potential for anemia in patients.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1518787/fullCD47phagocytosisred blood cellshematological malignancesSIRP alpha |
| spellingShingle | Mithunah Krishnamoorthy Mithunah Krishnamoorthy Ruth Seelige Christopher R. Brown Nancy Chau Natasja Nielsen Viller Lisa D. S. Johnson Emma Linderoth Jean C. Y. Wang Jean C. Y. Wang Jean C. Y. Wang Christopher P. Dillon Keith Abayasiriwardana Clare Lees Mark Wong Megan M. Kaneda Robert A. Uger Gloria H. Y. Lin Gloria H. Y. Lin Maplirpacept: a CD47 decoy receptor with minimal red blood cell binding and robust anti-tumor efficacy Frontiers in Immunology CD47 phagocytosis red blood cells hematological malignances SIRP alpha |
| title | Maplirpacept: a CD47 decoy receptor with minimal red blood cell binding and robust anti-tumor efficacy |
| title_full | Maplirpacept: a CD47 decoy receptor with minimal red blood cell binding and robust anti-tumor efficacy |
| title_fullStr | Maplirpacept: a CD47 decoy receptor with minimal red blood cell binding and robust anti-tumor efficacy |
| title_full_unstemmed | Maplirpacept: a CD47 decoy receptor with minimal red blood cell binding and robust anti-tumor efficacy |
| title_short | Maplirpacept: a CD47 decoy receptor with minimal red blood cell binding and robust anti-tumor efficacy |
| title_sort | maplirpacept a cd47 decoy receptor with minimal red blood cell binding and robust anti tumor efficacy |
| topic | CD47 phagocytosis red blood cells hematological malignances SIRP alpha |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1518787/full |
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