Localized CD47 blockade enhances immunotherapy for murine melanoma.

Autor:	Ingram JR; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115., Blomberg OS; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142., Sockolosky JT; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305., Ali L; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115., Schmidt FI; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142., Pishesha N; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142., Espinosa C; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142., Dougan SK; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115., Garcia KC; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305.; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305., Ploegh HL; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142; hidde.ploegh@childrens.harvard.edu mldougan@partners.org., Dougan M; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142; hidde.ploegh@childrens.harvard.edu mldougan@partners.org.; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Sep 19; Vol. 114 (38), pp. 10184-10189. Date of Electronic Publication: 2017 Sep 05.
DOI:	10.1073/pnas.1710776114
Abstrakt:	CD47 is an antiphagocytic ligand broadly expressed on normal and malignant tissues that delivers an inhibitory signal through the receptor signal regulatory protein alpha (SIRPα). Inhibitors of the CD47-SIRPα interaction improve antitumor antibody responses by enhancing antibody-dependent cellular phagocytosis (ADCP) in xenograft models. Endogenous expression of CD47 on a variety of cell types, including erythrocytes, creates a formidable antigen sink that may limit the efficacy of CD47-targeting therapies. We generated a nanobody, A4, that blocks the CD47-SIRPα interaction. A4 synergizes with anti-PD-L1, but not anti-CTLA4, therapy in the syngeneic B16F10 melanoma model. Neither increased dosing nor half-life extension by fusion of A4 to IgG2a Fc (A4Fc) overcame the issue of an antigen sink or, in the case of A4Fc, systemic toxicity. Generation of a B16F10 cell line that secretes the A4 nanobody showed that an enhanced response to several immune therapies requires near-complete blockade of CD47 in the tumor microenvironment. Thus, strategies to localize CD47 blockade to tumors may be particularly valuable for immune therapy. Competing Interests: Conflict of interest statement: K.C.G. is a cofounder of Alexo, a biotechnology company focused on the clinical translation of anti-human CD47 antagonists.
Databáze:	MEDLINE
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