<br>使用新型双特异性抗体融合蛋白双重阻断 CD47 和 CD24 信号传导可增强巨噬细胞免疫治疗,Molecular Therapy: Oncology

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使用新型双特异性抗体融合蛋白双重阻断 CD47 和 CD24 信号传导可增强巨噬细胞免疫治疗
Molecular Therapy: Oncology ( IF 5.3 ) Pub Date : 2023-11-04 , DOI: 10.1016/j.omto.2023.100747
Yun Yang _{1,

2} , He Wu ₁ , Yan Yang ₁ , Yan Kang ₁ , Runjia He ₁ , Bei Zhou ₁ , Huaizu Guo _{2,

3} , Jing Zhang ₁ , Jianqin Li ₁ , Chunpo Ge ₁ , Tianyun Wang ₁

Affiliation

CD47 及其受体信号调节蛋白 α (SIRPα) 充当显性抗吞噬细胞的“别吃我”信号。最近的研究表明 CD24 是卵巢癌和乳腺癌中巨噬细胞癌症免疫治疗的新靶点。然而，双特异性抗体同时阻断 CD47 和 CD24 是否可能产生潜在的协同作用仍不清楚。在本研究中，我们首次设计并开发了一种用于共靶向CD47和CD24的双特异性抗体融合蛋白PPAB001。数据表明，PPAB001 同时阻断 CD47/SIRPα 和 CD24/Siglec-10 信号传导可有效促进巨噬细胞对肿瘤细胞的吞噬作用。与单一 CD47 或 CD24 靶向药物相比，PPAB001 在抑制小鼠 4T-1 同基因和人 SK-OV-3 异种肿瘤模型中的肿瘤生长方面更有效。从机制上讲，我们发现 PPAB001 治疗显着增加了肿瘤浸润巨噬细胞的比例，并上调了代表性巨噬细胞炎症细胞因子白介素 6 和肿瘤坏死因子 α 的水平。值得注意的是，用 PPAB001 治疗的小鼠肿瘤浸润巨噬细胞中 M1/M2 比率增加表明双重阻断可能促进巨噬细胞从 M2 向 M1 的转变。总而言之，我们的数据支持将 PPAB001 开发为治疗 CD47 和 CD24 双阳性癌症的新型免疫疗法。

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Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy

CD47 and its receptor signal regulatory protein α (SIRPα) act as a dominant antiphagocytic, “don’t eat me” signal. Recent studies reveal CD24 as a novel target for cancer immunotherapy by macrophages in ovarian cancer and breast cancer. However, whether simultaneous blockade of CD47 and CD24 by a bispecific antibody may result in a potential synergy is still unclear. In the present study, we for the first time designed and developed a bispecific antibody fusion protein, PPAB001 for cotargeting CD47 and CD24. Data demonstrate that simultaneous blockade of CD47/SIRPα and CD24/Siglec-10 signaling by PPAB001 potently promoted macrophage phagocytosis of tumor cells. Compared to single CD47 or CD24 targeting agents, PPAB001 was more effective in inhibiting tumor growth in both mouse 4T-1 syngeneic and human SK-OV-3 xenogeneic tumor models. Mechanistically, we found that PPAB001 therapy markedly increased the proportion of tumor-infiltrating macrophages and upregulated interleukin-6 and tumor necrosis factor-α levels that were representative macrophage inflammatory cytokines. Notably, an increased ratio of M1/M2 in tumor-infiltrating macrophages in the mice treated with PPAB001 suggested that the dual blockade may promote the transition of macrophages from M2 to M1. Taken together, our data supported the development of PPAB001 as a novel immunotherapeutic in the treatment of CD47 and CD24 double-positive cancers.

更新日期：2023-11-04

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