An ideal tumor‐specific immunomodulatory therapy should both preferentially target the tumor, while simultaneously reduce the immunosuppressive environment within the tumor. This guiding principle led us to explore engineering Siglec‐15 (S15) targeted bispecific antibody (bsAb) to enhance therapy against triple negative breast cancer (TNBC). S15 appears to be exclusively expressed on macrophages and diverse tumor cells, including human and mouse 4T1 TNBC. TGF‐β is a growth hormone frequently associated with increased tumor invasiveness, including in TNBC. Here, to overcome the immune‐suppressive environment within TNBC tumors to enable more effective cancer therapy, we engineered a bispecific antibody (bsAb) targeting both Siglec15 and TGF‐β. In mice engrafted with orthotopic 4T1 tumors, S15/TGF‐β bsAb treatment was highly effective in suppressing tumor growth, not only compared to control monoclonal antibody (mAb) but also markedly more effective than mAbs against S15 alone, against TGF‐β alone, as well as a cocktail of both anti‐S15 and anti‐TGF‐β mAbs. We did not detect liver and lung metastasis in mice treated with S15/TGF‐β bsAb, unlike all other treatment groups at the end of the study. The enhanced anti‐tumor response observed with S15/TGF‐β bsAb correlated with a less immunosuppressive environment in the tumor. These results underscore S15‐targeted bsAb as a promising therapeutic strategy for TNBC, and possibly other S15 positive solid tumors.

中文翻译：

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Siglec15/TGF-β双特异性抗体介导小鼠体内针对4T1三阴性乳腺癌的协同抗肿瘤反应

理想的肿瘤特异性免疫调节疗法应优先靶向肿瘤，同时减少肿瘤内的免疫抑制环境。这一指导原则引导我们探索设计 Siglec-15 (S15) 靶向双特异性抗体 (bsAb)，以增强对三阴性乳腺癌 (TNBC) 的治疗。S15 似乎只在巨噬细胞和多种肿瘤细胞上表达，包括人和小鼠 4T1 TNBC。TGF-β 是一种生长激素，经常与肿瘤侵袭性增加相关，包括 TNBC。在这里，为了克服 TNBC 肿瘤内的免疫抑制环境以实现更有效的癌症治疗，我们设计了一种针对 Siglec15 和 TGF-β 的双特异性抗体 (bsAb)。在移植了原位 4T1 肿瘤的小鼠中，S15/TGF-β bsAb 治疗在抑制肿瘤生长方面非常有效，不仅与对照单克隆抗体 (mAb) 相比，而且比单独针对 S15、单独针对 TGF-β 的 mAb 显着更有效。以及抗 S15 和抗 TGF-β 单克隆抗体的混合物。与研究结束时的所有其他治疗组不同，我们在接受 S15/TGF-β bsAb 治疗的小鼠中没有检测到肝和肺转移。使用 S15/TGF-β bsAb 观察到的增强的抗肿瘤反应与肿瘤中较少的免疫抑制环境相关。这些结果强调 S15 靶向 bsAb 作为 TNBC 以及可能其他 S15 阳性实体瘤的有前途的治疗策略。