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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 6

In vivo therapeutic activity of combination treatment with humanized 1H9.

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In vivo therapeutic activity of combination treatment with humanized 1H9...
(A) B16F10 (2.5e5) cells were engrafted subcutaneously into CD47/SIRPα double-humanized mice (n = 7 for PBS, 6 for anti–PD-L1, and 8 for the 1H9 and MIAP410 alone and in the combination groups). Twelve days after engraftment, treatment was initiated with PBS, 10 mg/kg of 1H9, anti–PD-L1 antibody, or MIAP410, or a combination of 1H9 and anti–PD-L1 antibody 3 times a week until the termination of the study. Caliper measurements were obtained 3 times per week during treatment and until the termination of the study to assess tumor burden and/or tumor recurrence. (B) Kaplan-Meier plot of overall survival of B16F10-engrafted cohorts. (C) Raji cells were engrafted subcutaneously into SIRPα-humanized immunodeficient mice (n = 5 for each group). Ten days after engraftment, treatment was initiated with PBS, 10 mg/kg of 1H9, or rituximab, or a combination of 1H9 and rituximab 3 times a week until the termination of the study. Total flux measurements were obtained once per week during treatment and until the termination of the study to assess tumor burden and/or tumor recurrence. Statistics: repeated 1-way ANOVA with Holm-Šidák correction.

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