Vijayan Dipti, Barkauskas Deborah S, Stannard Kimberley, Sult Erin, Buonpane Rebecca, Takeda Kazuyoshi, Teng Michele W L, Sachsenmeier Kris, Hay Carl, Smyth Mark J
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
MedImmune, LLC., Gaithersburg, MD, USA.
Oncoimmunology. 2017 Apr 5;6(5):e1312044. doi: 10.1080/2162402X.2017.1312044. eCollection 2017.
The emerging role for CD73 in driving cancer growth and metastasis has presented opportunities to develop anti-CD73 monoclonal antibodies (mAbs) in the treatment of human cancers. Blockade of CD73 by antagonistic CD73 mAbs ameliorates tumor growth and metastasis via the inhibition of enzymatic and non-enzymatic CD73 pathways. In this study, we investigated whether Fc-receptor cross-linking represented a non-redundant mechanism by which anti-CD73 mAbs exert potent suppression of solid tumors and metastases. We engineered four anti-CD73 mAbs, each different in their ability to modulate CD73 enzymatic function and bind Fc receptors. mAbs recognizing a similar epitope of CD73 (CD73-04, TY/23 and 2C5) displayed the greatest antitumor activity. Importantly, we observed that the optimal control of metastasis by anti-CD73 mAbs involved primarily Fc receptor engagement, while suppression of solid tumors required both, enzyme inhibition and activation of Fc receptors. Engagement of Fc-receptors was also essential for optimal anti-metastatic effect in combination with either A2AR inhibitor or anti-PD-1 mAb treatment. The control of experimental metastases relied on the activation of host NK cells and IFNγ, while NK cells, CD8 T cells and IFNγ were needed for effective antitumor effect in the spontaneous metastases model. These observations advance our understanding of the enzymatic and non-enzymatic functions of anti-CD73 mAbs in solid tumors and metastases. Altogether, these findings will greatly assist in the design of anti-CD73 mAbs to be used as either single agents or in combination with other immunotherapeutic molecules or targeted therapies.
CD73在驱动癌症生长和转移方面的新作用为开发抗CD73单克隆抗体（mAb）用于治疗人类癌症提供了机会。通过拮抗性CD73 mAb阻断CD73可通过抑制酶促和非酶促CD73途径改善肿瘤生长和转移。在本研究中，我们调查了Fc受体交联是否代表抗CD73 mAb对实体瘤和转移灶发挥有效抑制作用的一种非冗余机制。我们构建了四种抗CD73 mAb，它们在调节CD73酶功能和结合Fc受体的能力上各不相同。识别CD73相似表位的mAb（CD73-04、TY/23和2C5）表现出最大的抗肿瘤活性。重要的是，我们观察到抗CD73 mAb对转移的最佳控制主要涉及Fc受体的参与，而对实体瘤的抑制则需要酶抑制和Fc受体的激活。Fc受体的参与对于与A2AR抑制剂或抗PD-1 mAb联合治疗时的最佳抗转移效果也至关重要。实验性转移的控制依赖于宿主NK细胞和IFNγ的激活，而在自发性转移模型中，有效抗肿瘤作用则需要NK细胞、CD8 T细胞和IFNγ。这些观察结果加深了我们对抗CD73 mAb在实体瘤和转移灶中的酶促和非酶促功能的理解。总之，这些发现将极大地有助于设计抗CD73 mAb，其可作为单一药物或与其他免疫治疗分子或靶向疗法联合使用。
