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.
Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10184-10189. doi: 10.1073/pnas.1710776114. Epub 2017 Sep 5.
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.
CD47 是一种广泛表达于正常和恶性组织的抗吞噬配体，通过受体信号调节蛋白α（SIRPα）传递抑制信号。CD47-SIRPα 相互作用的抑制剂通过增强异种移植模型中的抗体依赖性细胞吞噬作用（ADCP）来改善抗肿瘤抗体反应。包括红细胞在内的多种细胞类型的内源性 CD47 表达会形成一个强大的抗原消耗池，可能会限制 CD47 靶向治疗的疗效。我们生成了一种能够阻断 CD47-SIRPα 相互作用的纳米抗体 A4。A4 与抗 PD-L1 协同作用，但与抗 CTLA4 治疗无协同作用，在同基因 B16F10 黑色素瘤模型中协同作用。增加剂量或通过将 A4 融合到 IgG2a Fc（A4Fc）来延长半衰期都不能克服抗原消耗池的问题，在 A4Fc 的情况下，还会出现全身毒性问题。生成一种分泌 A4 纳米抗体的 B16F10 细胞系表明，要增强对几种免疫疗法的反应，需要在肿瘤微环境中近乎完全阻断 CD47。因此，将 CD47 阻断定位到肿瘤的策略对于免疫治疗可能特别有价值。
