Antibodies targeting immune checkpoints are emerging as potent and viable cancer therapies, but not all patients respond to these as single agents. Concurrently targeting additional immunosuppressive pathways is a promising approach to enhance immune checkpoint blockade, and bifunctional molecules designed to target two pathways simultaneously may provide a strategic advantage over the combination of two single agents. M7824 (MSB0011359C) is a bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the extracellular domain of human transforming growth factor–β (TGF-β) receptor II, which functions as a “trap” for all three TGF-β isoforms. We demonstrate that M7824 efficiently, specifically, and simultaneously binds PD-L1 and TGF-β. In syngeneic mouse models, M7824 suppressed tumor growth and metastasis more effectively than treatment with either an anti–PD-L1 antibody or TGF-β trap alone; furthermore, M7824 extended survival and conferred long-term protective antitumor immunity. Mechanistically, the dual anti-immunosuppressive function of M7824 resulted in activation of both the innate and adaptive immune systems, which contributed to M7824’s antitumor activity. Finally, M7824 was an effective combination partner for radiotherapy or chemotherapy in mouse models. Collectively, our preclinical data demonstrate that simultaneous blockade of the PD-L1 and TGF-β pathways by M7824 elicits potent and superior antitumor activity relative to monotherapies.

针对免疫检查点的抗体正在作为有效且可行的癌症治疗方法出现，但并非所有患者都以单一药物对其产生反应。同时靶向其他免疫抑制途径是增强免疫检查点阻断的一种有前途的方法，设计成同时靶向两种途径的双功能分子可能比两种单一药物的组合具有战略优势。M7824（MSB0011359C）是一种双功能融合蛋白，由针对程序性死亡配体1（PD-L1）的单克隆抗体组成，融合至人类转化生长因子-β（TGF-β）受体II的胞外域，起着“陷阱”的作用。对于所有三种TGF-β同工型。我们证明，M7824有效，特别是同时绑定PD-L1和TGF-β。在同系小鼠模型中，M7824比单独使用抗PD-L1抗体或单独的TGF-β捕集阱治疗更有效地抑制了肿瘤的生长和转移。此外，M7824延长了生存期并赋予了长期的保护性抗肿瘤免疫力。从机制上讲，M7824的双重抗免疫抑制功能可激活先天免疫系统和适应性免疫系统，从而增强M7824的抗肿瘤活性。最后，M7824是小鼠模型中放射疗法或化学疗法的有效组合伙伴。总的来说，我们的临床前数据表明，相对于单一疗法，M7824同时阻断PD-L1和TGF-β途径可引发有效且优越的抗肿瘤活性。M7824延长了生存期，并赋予了长期的保护性抗肿瘤免疫力。从机制上讲，M7824的双重抗免疫抑制功能可激活先天免疫系统和适应性免疫系统，从而增强M7824的抗肿瘤活性。最后，M7824是小鼠模型中放射疗法或化学疗法的有效组合伙伴。总的来说，我们的临床前数据表明，相对于单一疗法，M7824同时阻断PD-L1和TGF-β途径可引发有效且优越的抗肿瘤活性。M7824延长了生存期，并赋予了长期的保护性抗肿瘤免疫力。从机制上讲，M7824的双重抗免疫抑制功能可激活先天免疫系统和适应性免疫系统，从而增强M7824的抗肿瘤活性。最后，M7824是小鼠模型中放射疗法或化学疗法的有效组合伙伴。总的来说，我们的临床前数据表明，相对于单一疗法，M7824同时阻断PD-L1和TGF-β途径可引发有效且优越的抗肿瘤活性。M7824是小鼠模型中放射疗法或化学疗法的有效组合伙伴。总的来说，我们的临床前数据表明，相对于单一疗法，M7824同时阻断PD-L1和TGF-β途径可引发有效且优越的抗肿瘤活性。M7824是小鼠模型中放射疗法或化学疗法的有效组合伙伴。总的来说，我们的临床前数据表明，相对于单一疗法，M7824同时阻断PD-L1和TGF-β途径可引发有效且优越的抗肿瘤活性。