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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 5

Cross-reactivity of humanized 1H9 to SIRPγ.

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Cross-reactivity of humanized 1H9 to SIRPγ.
(A) Binding of anti-SIRPα an...
(A) Binding of anti-SIRPα antibodies 1H9 and Kwar to human SIRPγ was determined by ELISA under increasing concentrations as indicated. Data represent mean ± SD. Each sample was assayed in duplicate (**P value = 0.004). (B) Human T cells from 2 donors and monocyte-derived DCs differentiated from 5 different human allogeneic donors were cocultured at 5:1 ratio in the presence of 10 μg/mL of 1H9, Kwar, nivolumab, or a combination. Proliferated T cells were gated on divided CellTrace Violetlow CD4+ T cells and the fold change in proliferation over T cells and DCs without the addition of an antibody was presented. The indicated P values were determined by multiple 1-way ANOVA. ns, not significant. *P value = 0.030.

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