一种新型条件活性生物抗 EpCAM x 抗 CD3 双特异性抗体,具有用于癌症免疫疗法的协同肿瘤选择性。

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-03-06 DOI:10.1080/19420862.2024.2322562
Gerhard Frey, Ana Paula G Cugnetti, Haizhen Liu, Charles Xing, Christina Wheeler, Hwai Wen Chang, William J Boyle, Jay M Short
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引用次数: 0

摘要

上皮细胞粘附分子(EpCAM)是一种跨膜糖蛋白,在癌症生物学中发挥着多种作用。EpCAM 在大多数实体瘤中都有表达,因此是一个极具吸引力的治疗靶点。然而,由于 EpCAM 在正常上皮组织中也高度表达,因此靶向 EpCAM 的研究一直具有挑战性。由于严重的细胞因子释放效应,以及严重的靶上、瘤外药物相关毒性,开发 EpCAM 特异性 T 细胞吸引剂的最初尝试并不成功。我们开发了新型条件活性生物(CAB)双特异性抗体,能在酸性肿瘤微环境中与 EpCAM 和 CD3 结合。在健康组织中,EpCAM 和 CD3 的结合会因一种新型的双 CAB 选择而大大降低,在这种选择中,每个结合域都会因被称为蛋白质相关化学开关(PaCS)的生理化学物质的存在而被独立阻断。CAB 抗 EpCAM T 细胞吞噬因子显示了预期的双特异性结合特性,并通过在肿瘤微环境中招募 T 细胞,介导了对 EpCAM 阳性癌细胞株的强效裂解。异种移植研究表明,CAB 双特异性抗体的疗效与非 CAB 抗 EpCAM 双特异性抗体相似,但它们在非人灵长类动物体内的毒性明显降低,表明治疗指数空前扩大了 100 倍以上。这些临床前研究结果表明,双 CAB 双特异性抗体既可能是一种强大而安全的治疗平台,也可能是一种针对表达 EpCAM 的肿瘤患者的 T 细胞诱导疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy.

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays several roles in cancer biology. EpCAM is an attractive therapeutic target because of its expression in most solid tumors. However, targeting EpCAM has been challenging because it is also highly expressed in normal epithelial tissues. Initial attempts to develop EpCAM-specific T-cell engagers were unsuccessful due to severe cytokine release effects, as well as serious on-target, off-tumor drug-related toxicities. We developed novel, conditionally active biological (CAB) bispecific antibodies that bind to both EpCAM and CD3 in an acidic tumor microenvironment. In healthy tissues, binding to EpCAM and CD3 is greatly reduced by a novel, dual CAB selection, where each binding domain is independently blocked by the presence of physiological chemicals known as Protein-associated Chemical Switches (PaCS). The CAB anti-EpCAM T-cell engagers displayed the anticipated bispecific binding properties and mediated the potent lysis of EpCAM-positive cancer cell lines through the recruitment of T cells in the tumor microenvironment. Xenograft studies showed that the efficacy of CAB bispecific antibodies is similar to that of a non-CAB anti-EpCAM bispecific antibody, but they have markedly reduced toxicity in non-human primates, indicating an unprecedentedly widened therapeutic index of over 100-fold. These preclinical results indicate that the dual CAB bispecific antibody is potentially both a powerful and safe therapeutic platform and a promising T cell-engaging treatment for patients with EpCAM-expressing tumors.

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来源期刊
mAbs
mAbs 工程技术-仪器仪表
CiteScore
10.70
自引率
11.30%
发文量
77
审稿时长
6-12 weeks
期刊介绍: mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.
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