Despite some impressive clinical results with immune checkpoint inhibitors, the majority of patients with cancer do not respond to these agents, in part due to immunosuppressive mechanisms in the tumor microenvironment. High levels of adenosine in tumors can suppress immune cell function, and strategies to target the pathway involved in its production have emerged. CD73 is a key enzyme involved in adenosine production. This led us to identify a novel humanized antagonistic CD73 antibody, mAb19, with distinct binding properties. mAb19 potently inhibits the enzymatic activity of CD73 in vitro , resulting in an inhibition of adenosine formation and enhanced T-cell activation. We then investigated the therapeutic potential of combining CD73 antagonism with other immune modulatory and chemotherapeutic agents. Combination of mAb19 with a PD-1 inhibitor increased T-cell activation in vitro . Interestingly, this effect could be further enhanced with an agonist of the adenosine receptor ADORA3. Adenosine levels were found to be elevated upon doxorubicin treatment in vivo , which could be blocked by CD73 inhibition. Combining CD73 antagonism with doxorubicin resulted in superior responses in vivo . Furthermore, a retrospective analysis of rectal cancer patient samples demonstrated an upregulation of the adenosine pathway upon chemoradiation, providing further rationale for combining CD73 inhibition with chemotherapeutic agents. This study demonstrates the ability of a novel CD73 antibody to enhance T-cell function through the potent suppression of adenosine levels. In addition, the data highlight combination opportunities with standard of care therapies as well as with an ADORA3 receptor agonist to treat patients with solid tumors. This article is featured in Highlights of This Issue, [p. 2095][1] [1]: /lookup/volpage/20/2095?iss=11

中文翻译：

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一种用于抑制免疫抑制腺苷通路的新型拮抗性 CD73 抗体

尽管免疫检查点抑制剂取得了一些令人印象深刻的临床结果，但大多数癌症患者对这些药物没有反应，部分原因是肿瘤微环境中的免疫抑制机制。肿瘤中高水平的腺苷可以抑制免疫细胞功能，并且已经出现了针对参与其产生的途径的策略。CD73 是参与腺苷生成的关键酶。这使我们确定了一种具有独特结合特性的新型人源化拮抗性 CD73 抗体 mAb19。mAb19 在体外有效抑制 CD73 的酶活性，从而抑制腺苷形成并增强 T 细胞活化。然后我们研究了将 CD73 拮抗作用与其他免疫调节剂和化学治疗剂相结合的治疗潜力。mAb19 与 PD-1 抑制剂的组合在体外增加了 T 细胞活化。有趣的是，腺苷受体 ADORA3 的激动剂可以进一步增强这种效果。发现体内阿霉素处理后腺苷水平升高，这可以通过 CD73 抑制来阻断。将 CD73 拮抗作用与多柔比星相结合可在体内产生更好的反应。此外，对直肠癌患者样本的回顾性分析表明，放化疗后腺苷通路上调，为将 CD73 抑制与化疗药物相结合提供了进一步的理论依据。这项研究证明了一种新型 CD73 抗体能够通过有效抑制腺苷水平来增强 T 细胞功能。此外，数据强调了与标准护理疗法以及与 ADORA3 受体激动剂联合治疗实体瘤患者的机会。这篇文章刊登在本期要闻中，[p。2095][1] [1]: /lookup/volpage/20/2095?iss=11