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

IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Bioengineering & Translational Medicine Pub Date : 2024-03-11 DOI:10.1002/btm2.10651
Limei Shen, Alison M. Schaefer, Karthik Tiruthani, Whitney Wolf, Samuel K. Lai
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引用次数: 0

摘要

理想的肿瘤特异性免疫调节疗法应该既能优先靶向肿瘤,又能减少肿瘤内的免疫抑制环境。在这一指导原则的指引下,我们开始探索设计 Siglec-15(S15)靶向双特异性抗体(bsAb),以加强对三阴性乳腺癌(TNBC)的治疗。S15 似乎只在巨噬细胞和多种肿瘤细胞(包括人类和小鼠 4T1 TNBC)上表达。TGF-β 是一种生长激素,经常与肿瘤侵袭性增加有关,包括在 TNBC 中。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,我们设计了一种同时靶向 Siglec15 和 TGF-β 的双特异性抗体(bsAb)。在移植了正位 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,不仅与对照组单克隆抗体(mAb)相比效果更好,而且明显优于单独针对 S15 的 mAb、单独针对 TGF-β 的 mAb 以及抗 S15 和抗 TGF-β mAb 的鸡尾酒。与所有其他治疗组不同的是,在研究结束时,我们没有在使用S15/TGF-β bsAb治疗的小鼠身上发现肝脏和肺部转移。观察到的 S15/TGF-β bsAb 抗肿瘤反应的增强与肿瘤中较少的免疫抑制环境有关。这些结果表明,S15 靶向 bsAb 是治疗 TNBC 以及其他可能的 S15 阳性实体瘤的一种很有前景的治疗策略。
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Siglec15/TGF-β bispecific antibody mediates synergistic anti-tumor response against 4T1 triple negative breast cancer in mice

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.

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来源期刊
Bioengineering & Translational Medicine
Bioengineering & Translational Medicine Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
8.40
自引率
4.10%
发文量
150
审稿时长
12 weeks
期刊介绍: Bioengineering & Translational Medicine, an official, peer-reviewed online open-access journal of the American Institute of Chemical Engineers (AIChE) and the Society for Biological Engineering (SBE), focuses on how chemical and biological engineering approaches drive innovative technologies and solutions that impact clinical practice and commercial healthcare products.
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