Journal Article
. 2017 Sep; 114(38):10184-10189.
doi: 10.1073/pnas.1710776114.

Localized CD47 blockade enhances immunotherapy for murine melanoma

Jessica R Ingram 1 Olga S Blomberg 1 Jonathan T Sockolosky 2 Lestat Ali 3 Florian I Schmidt 1 Novalia Pishesha 1 Camilo Espinosa 1 Stephanie K Dougan 3 K Christopher Garcia 2 Hidde L Ploegh 4 Michael Dougan 4 
  • PMID: 28874561
  •     24 References
  •     46 citations


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.

Keywords: T cell; cancer; immunotherapy; macrophage; protein engineering.

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