Immune checkpoint blockade (ICB) with anti-CD47 antibodies (aCD47) is a promising therapeutic approach that has the potential to revolutionize the treatment of acute myeloid leukemia (AML). However, the low immune response rate and high systemic hematotoxicity remain substantial barriers to its success in clinical AML treatment. A synthetic protein nanogel formulation of aCD47 and resiquimod (R848) (termed CR-TNG) is developed that targets TIM-3 on the surface of leukemia cells. Upon intravenous injection, the CR-TNG efficiently conjugates onto the blood-circulating leukemia cells and migrates toward the bone marrow (BM) by exploiting the natural BM homing capability of leukemia cells. CR-TNG releases aCD47 and R848 in a bone marrow hypoxic microenvironment, which significantly induces immunosuppression and enhances the anti-leukemia immune response by activating macrophage “eat me” signaling and priming myeloid macrophages in the BM niche. These findings provide a leukemia cell-hitchhiking drug delivery strategy that addresses both systemic hematotoxicity and low immune response rate in AML.

中文翻译：

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白血病细胞搭便车缺氧反应性纳米凝胶改善急性髓性白血病的免疫治疗


使用抗 CD47 抗体 （aCD47） 的免疫检查点阻断 （ICB） 是一种很有前途的治疗方法，有可能彻底改变急性髓性白血病 （AML） 的治疗。然而，低免疫反应率和高全身性血液毒性仍然是其在临床 AML 治疗中取得成功的重大障碍。开发了一种 aCD47 和瑞喹莫特 （R848） 的合成蛋白纳米凝胶制剂（称为 CR-TNG），靶向白血病细胞表面的 TIM-3。静脉注射后，CR-TNG 有效地结合到血液循环白血病细胞上，并通过利用白血病细胞的天然 BM 归巢能力迁移到骨髓 （BM）。CR-TNG 在骨髓缺氧微环境中释放 aCD47 和 R848，通过激活巨噬细胞“吃我”信号传导和启动 BM 生态位中的髓系巨噬细胞，显着诱导免疫抑制并增强抗白血病免疫反应。这些发现提供了一种白血病细胞搭便车药物递送策略，可同时解决 AML 中的全身性血液毒性和低免疫反应率。