Seagen Inc, Bothell, Washington, USA
Seagen Inc, Bothell, Washington, USA.
J Immunother Cancer. 2023 Oct;11(10). doi: 10.1136/jitc-2023-007572.
SGN-B7H4V is a novel investigational vedotin antibody-drug conjugate (ADC) comprising a B7-H4-directed human monoclonal antibody conjugated to the cytotoxic payload monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine citrulline (mc-vc) linker. This vedotin linker-payload system has been clinically validated in multiple Food and Drug Administration approved agents including brentuximab vedotin, enfortumab vedotin, and tisotumab vedotin. B7-H4 is an immune checkpoint ligand with elevated expression on a variety of solid tumors, including breast, ovarian, and endometrial tumors, and limited normal tissue expression. SGN-B7H4V is designed to induce direct cytotoxicity against target cells by binding to B7-H4 on the surface of target cells and releasing the cytotoxic payload MMAE upon internalization of the B7-H4/ADC complex.
B7-H4 expression was characterized by immunohistochemistry across multiple solid tumor types. The ability of SGN-B7H4V to kill B7-H4-expressing tumor cells in vitro and in vivo in a variety of xenograft tumor models was also evaluated. Finally, the antitumor activity of SGN-B7H4V as monotherapy and in combination with an anti-programmed cell death-1 (PD-1) agent was evaluated using an immunocompetent murine B7-H4-expressing Renca tumor model.
Immunohistochemistry confirmed B7-H4 expression across multiple solid tumors, with the highest prevalence in breast, endometrial, and ovarian tumors. In vitro, SGN-B7H4V killed B7-H4-expressing tumor cells by MMAE-mediated direct cytotoxicity and antibody-mediated effector functions including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. In vivo, SGN-B7H4V demonstrated strong antitumor activity in multiple xenograft models of breast and ovarian cancer, including xenograft tumors with heterogeneous B7-H4 expression, consistent with the ability of vedotin ADCs to elicit a bystander effect. In an immunocompetent murine B7-H4-expressing tumor model, SGN-B7H4V drove robust antitumor activity as a monotherapy that was enhanced when combined with an anti-PD-1 agent.
The immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors. SGN-B7H4V demonstrates robust antitumor activity in preclinical models through multiple potential mechanisms. Altogether, these preclinical data support the evaluation of SGN-B7H4V as a monotherapy in the ongoing phase 1 study of SGN-B7H4V in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies.
SGN-B7H4V 是一种新型的研究用抗体药物偶联物（ADC），由一种针对 B7-H4 的人源单克隆抗体与细胞毒性有效载荷单甲基澳瑞他汀 E（MMAE）通过蛋白酶可切割的马来酰亚胺基己酰缬氨酸瓜氨酸（mc-vc）接头连接而成。这种连接物-有效载荷系统已在多个经美国食品药品监督管理局批准的药物中得到临床验证，包括 Brentuximab vedotin、Enfortumab vedotin 和Tisotumab vedotin。B7-H4 是一种免疫检查点配体，在多种实体瘤中表达上调，包括乳腺癌、卵巢癌和子宫内膜癌，并且在正常组织中的表达有限。SGN-B7H4V 通过与靶细胞表面的 B7-H4 结合，并在 B7-H4/ADC 复合物内化后释放细胞毒性有效载荷 MMAE，从而诱导对靶细胞的直接细胞毒性。
通过免疫组织化学在多种实体瘤类型中对 B7-H4 表达进行了表征。还评估了 SGN-B7H4V 在多种异种移植肿瘤模型中体外和体内杀死 B7-H4 表达的肿瘤细胞的能力。最后，使用免疫活性的表达 B7-H4 的 Renca 肿瘤模型评估了 SGN-B7H4V 作为单药治疗和与抗程序性细胞死亡-1（PD-1）药物联合治疗的抗肿瘤活性。
免疫组织化学证实了 B7-H4 在多种实体瘤中的表达，在乳腺癌、子宫内膜癌和卵巢癌中表达最为普遍。在体外，SGN-B7H4V 通过 MMAE 介导的直接细胞毒性和抗体介导的效应功能（包括抗体依赖性细胞毒性和抗体依赖性细胞吞噬作用）杀死 B7-H4 表达的肿瘤细胞。在体内，SGN-B7H4V 在多种乳腺癌和卵巢癌的异种移植模型中表现出强大的抗肿瘤活性，包括 B7-H4 表达异质性的异种移植肿瘤，这与 vedotin ADC 能够引发旁观者效应一致。在免疫活性的表达 B7-H4 的小鼠肿瘤模型中，SGN-B7H4V 作为单药治疗具有强大的抗肿瘤活性，与抗 PD-1 药物联合使用时增强。
免疫检查点配体 B7-H4 是一种在多种实体瘤中表达的有前途的分子靶标。SGN-B7H4V 通过多种潜在机制在临床前模型中表现出强大的抗肿瘤活性。总的来说，这些临床前数据支持在晚期实体瘤中进行的 SGN-B7H4V 单药治疗的正在进行的 1 期研究（NCT05194072）以及与免疫疗法的潜在未来临床联合应用中评估 SGN-B7H4V。
