Inhibitors of adaptive immune checkpoints have shown promise as cancer treatments. CD47 is an innate immune checkpoint receptor broadly expressed on normal tissues and overexpressed on many tumors. Binding of tumor CD47 to signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells triggers a “don't eat me” signal that inhibits phagocytosis enabling escape of innate immune surveillance. Blocking CD47/SIRPα interaction promotes phagocytosis reducing tumor burden in numerous xenograft and syngeneic animal models. We have developed a next-generation humanized anti-CD47 antibody, AO-176, that not only blocks the CD47/SIRPα interaction to induce tumor cell phagocytosis, but also induces tumor cytotoxicity in hematologic and solid human tumor cell lines, but not normal noncancerous cells, by a cell autonomous mechanism (not ADCC). AO-176 also binds preferentially to tumor versus many normal cell types. In particular, AO-176 binds negligibly to RBCs in contrast to tumor cells, even at high concentrations up to 200 μg/mL and does not agglutinate RBCs up to 1 mg/mL in vitro. These properties are expected not only to decrease the antigen sink, but also to minimize on-target clinical adverse effects observed following treatment with other reported RBC-binding anti-CD47 antibodies. When tested in cynomolgus monkeys, AO-176 was well tolerated with no adverse effects. Finally, we show that AO-176 demonstrates dose-dependent antitumor activity in tumor xenograft models. Taken together, the unique properties and antitumor activity of our next-generation anti-CD47 antibody, AO-176, distinguishes it from other CD47/SIRPα axis targeting agents in clinical development.

中文翻译：

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AO-176 的开发，一种具有新型抗癌特性和可忽略的红细胞结合的下一代人源化抗 CD47 抗体

适应性免疫检查点抑制剂已显示出作为癌症治疗的希望。CD47 是一种先天免疫检查点受体，在正常组织中广泛表达，在许多肿瘤中过度表达。肿瘤 CD47 与巨噬细胞和树突状细胞上的信号调节蛋白 α (SIRPα) 结合会触发“不要吃我”信号，该信号抑制吞噬作用，从而逃避先天免疫监视。在众多异种移植物和同基因动物模型中，阻断 CD47/SIRPα 相互作用可促进吞噬作用减少肿瘤负荷。我们开发了下一代人源化抗 CD47 抗体 AO-176，它不仅阻断 CD47/SIRPα 相互作用以诱导肿瘤细胞吞噬作用，而且在血液和实体人类肿瘤细胞系中诱导肿瘤细胞毒性，但不会对正常非癌性细胞系产生肿瘤细胞毒性。单元，通过单元自治机制（不是 ADCC）。与许多正常细胞类型相比，AO-176 还优先结合肿瘤。特别是，与肿瘤细胞相比，AO-176 与 RBC 的结合可以忽略不计，即使在高达 200 μg/mL 的高浓度下，并且在体外不会凝集高达 1 mg/mL 的 RBC。预计这些特性不仅可以减少抗原汇，而且可以最大限度地减少在用其他报道的 RBC 结合抗 CD47 抗体治疗后观察到的靶向临床不良反应。在食蟹猴中进行测试时，AO-176 耐受性良好，没有不良反应。最后，我们表明 AO-176 在肿瘤异种移植模型中表现出剂量依赖性的抗肿瘤活性。总之，我们的下一代抗 CD47 抗体 AO-176 的独特特性和抗肿瘤活性使其有别于临床开发中的其他 CD47/SIRPα 轴靶向剂。