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Targeting macrophage checkpoint inhibitor SIRPα for anticancer therapy
Jie Liu, … , Irving L. Weissman, Jens-Peter Volkmer
Jie Liu, … , Irving L. Weissman, Jens-Peter Volkmer
Published May 19, 2020
Citation Information: JCI Insight. 2020;5(12):e134728. https://doi.org/10.1172/jci.insight.134728.
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Research Article Immunology Therapeutics

Targeting macrophage checkpoint inhibitor SIRPα for anticancer therapy

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Abstract

The CD47/signal regulatory protein α (Cd47/SIRPα)interaction provides a macrophage immune checkpoint pathway that plays a critical role in cancer immune evasion across multiple cancers. Here, we report the engineering of a humanized anti-SIRPα monoclonal antibody (1H9) for antibody target cancer therapy. 1H9 has broad activity across a wide range of SIRPα variants. Binding of 1H9 to SIRPα blocks its interaction with CD47, thereby promoting macrophage-mediated phagocytosis of cancer cells. Preclinical studies in vitro and in vivo demonstrate that 1H9 synergizes with other therapeutic antibodies to promote phagocytosis of tumor cells and inhibit tumor growth in both syngeneic and xenograft tumor models, leading to survival benefit. Thus, 1H9 can potentially act as a universal agent to enhance therapeutic efficacy when used in combination with most tumor-targeting antibodies. We report a comparison of anti-SIRPα and anti-CD47 antibodies in CD47/SIRPα double-humanized mice and found that 1H9 exhibits a substantially reduced antigen sink effect due to the limited tissue distribution of SIRPα expression. Toxicokinetic studies in nonhuman primates show that 1H9 is well tolerated, with no treatment-related adverse effects noted. These data highlight the clinical potential of 1H9 as a pan-therapeutic with the desired properties when used in combination with tumor-targeting antibodies.

Authors

Jie Liu, Seethu Xavy, Shirley Mihardja, Sharline Chen, Kavitha Sompalli, Dongdong Feng, Timothy Choi, Balaji Agoram, Ravindra Majeti, Irving L. Weissman, Jens-Peter Volkmer

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Figure 4

Humanized 1H9 binds to different SIRPα variants and synergizes with cetuximab to promote phagocytosis across donors expressing different SIRPα variants.

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Humanized 1H9 binds to different SIRPα variants and synergizes with cetu...
(A) ELISA binding of 1H9 to human SIRPα-V1, SIRPα-V2, and an irrelevant Fc fusion proteins under increasing concentrations as indicated. Each sample was assayed in triplicate. Data represent mean ± SD. (B) Monocytes derived from 3 human donors, which express SIRPα as V1/V1, V2/V2, and V1/V5 variants, were incubated with 1 μg/mL AF488-labeled CD47-Fc fusion protein in the absence or presence of increasing concentrations of humanized 1H9. Binding of CD47 on the cells was measured and analyzed by flow cytometry. Binding was calculated and normalized on the mean fluorescence intensity of CD47/SIRPα binding in the absence of 1H9 as 100%. (C) HT-29 tumor cells were labeled with CFSE and incubated with human monocyte–derived macrophages, which express SIRPα as V1/V1 (n = 10), V2/V2 (n = 2), and V1/V5 (n = 1) variants, in the presence of 10 μg/mL humanized 1H9 or 0.1 μg/mL cetuximab, either alone or in combination. Fold increase of phagocytosis was calculated by phagocytosis induced by the combination treatment over phagocytosis induced by cetuximab alone.

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