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Siglec-7 糖免疫结合单克隆抗体或 NK 细胞结合生物制剂可诱导针对卵巢癌的强大抗肿瘤免疫。

Siglec-7 glyco-immune binding mAbs or NK cell engager biologics induce potent antitumor immunity against ovarian cancers.

机构信息

Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

出版信息

Sci Adv. 2023 Nov 3;9(44):eadh4379. doi: 10.1126/sciadv.adh4379. Epub 2023 Nov 1.

DOI:10.1126/sciadv.adh4379
PMID:37910620
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10619929/
Abstract

Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value. We focused on Siglec-7 as a surface antigen for engaging this population. Human antibodies against Siglec-7 were developed and characterized. Coculture of OC cells with PBMCs/NKs and Siglec-7 binding antibodies showed NK-mediated killing of OC lines. Anti-Siglec-7 mAb (DB7.2) enhanced survival in OC-challenged mice. In addition, the combination of DB7.2 and anti-PD-1 demonstrated further improved OC killing in vitro. To use Siglec-7 engagement as an OC-specific strategy, we engineered an NK cell engager (NKCE) to simultaneously engage NK cells through Siglec-7, and OC targets through FSHR. The NKCE demonstrated robust in vitro killing of FSHR OC, controlled tumors, and improved survival in OC-challenged mice. These studies support additional investigation of the Siglec-7 targeting approaches as important tools for OC and other recalcitrant cancers.

摘要

卵巢癌 (OC) 是一种致命的妇科恶性肿瘤，对 CPI 的反应有限。因此，利用 NK 细胞等其他免疫途径可能具有重要价值。我们专注于 Siglec-7 作为结合这一群体的表面抗原。我们开发并鉴定了针对 Siglec-7 的人源化抗体。OC 细胞与 PBMC/NK 细胞共培养，以及 Siglec-7 结合抗体共孵育，结果显示 NK 介导了 OC 细胞系的杀伤作用。抗 Siglec-7 mAb (DB7.2) 增强了 OC 荷瘤小鼠的生存能力。此外，DB7.2 与抗 PD-1 的联合使用在体外进一步提高了 OC 的杀伤作用。为了将 Siglec-7 结合作为 OC 特异性策略，我们设计了一种 NK 细胞激活剂 (NKCE)，通过 Siglec-7 同时结合 NK 细胞，并通过 FSHR 结合 OC 靶点。NKCE 表现出对 FSHR OC 的强大体外杀伤作用，控制了肿瘤，并提高了 OC 荷瘤小鼠的生存率。这些研究支持进一步研究 Siglec-7 靶向方法，作为 OC 和其他难治性癌症的重要工具。

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