Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivo.

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-10-09 DOI:10.1080/19420862.2024.2412881
Zheng Wang, Yu Liu, Yunxia Xu, Lin Lu, Zhen Zhu, Baojie Lv, Xin Fang, Yao Tang, Jinhua Wang, Yu Cheng, Ying Hu, Junwen Lou, Peican Wu, Chendan Liu, Yanjun Liu, Xin Zeng, Qing Xu
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引用次数: 0

Abstract

Currently approved human epidermal growth factor receptor 2 (HER2)-targeted antibody therapies are largely derived from trastuzumab, including trastuzumab-chemotherapy combinations, fixed-dose trastuzumab-pertuzumab combinations, and trastuzumab antibody-drug conjugates. To expand the options, bispecific antibodies, which may better utilize the benefits of combination therapy, are being developed. Among them, biparatopic antibodies (bpAbs) have shown improved efficacy compared to monoclonal antibody (mAb) combinations in HER2-positive patients. BpAbs bind two independent epitopes on the same antigen, which allows fine-tuning of mechanisms of action, including enhancement of on-target specificity and induction of strong antigen clustering due to the unique binding mode. To fully utilize the potential of bpAbs for anti-HER2 drug development, it is crucial to consider formats that offer stability and high-yield production, along with a functional balance between the two epitopes. In this study, we rationally designed a bpAb, KJ015, that shares a common light chain with two Fab arms and exhibits functionally balanced high affinity for two HER2 non-overlapping epitopes. KJ015 demonstrated high-expression titers over 7 g/L and stable physicochemical properties at elevated concentrations, facilitating subcutaneous administration with hyaluronidase. Moreover, KJ015 maintained comparable antibody-dependent cytotoxicity, phagocytosis, and complement-dependent cytotoxicity with trastuzumab plus pertuzumab. It exhibited enhanced synergy when administered subcutaneously with hyaluronidase and anti-PD-1 mAb in a mouse tumor model, suggesting promising clinical prospects for this combination.

抗 HER2 双抗体 KJ015 具有接近原生的结构、功能平衡的高亲和力以及与体内抗 PD-1 治疗的协同效应。
目前获批的人类表皮生长因子受体 2(HER2)靶向抗体疗法主要来自曲妥珠单抗,包括曲妥珠单抗-化疗联合疗法、固定剂量曲妥珠单抗-保妥珠单抗联合疗法以及曲妥珠单抗抗体-药物共轭物。为了扩大选择范围,目前正在开发双特异性抗体,以更好地利用联合疗法的优势。其中,双特异性抗体(bpAbs)在 HER2 阳性患者中的疗效比单克隆抗体(mAb)联合疗法更好。bpAbs 与同一抗原上的两个独立表位结合,可对作用机制进行微调,包括增强靶向特异性,以及因其独特的结合模式而诱导抗原强聚集。要充分发挥 bpAbs 在抗 HER2 药物开发中的潜力,关键是要考虑能提供稳定性和高产率生产的形式,以及两个表位之间的功能平衡。在这项研究中,我们合理地设计了一种 bpAb KJ015,它与两条 Fab 臂共用一条轻链,对两个不重叠的 HER2 表位表现出功能平衡的高亲和力。KJ015 的高表达滴度超过 7 g/L,在高浓度下具有稳定的理化特性,便于与透明质酸酶一起皮下注射。此外,KJ015 还具有与曲妥珠单抗加百妥珠单抗相当的抗体依赖性细胞毒性、吞噬作用和补体依赖性细胞毒性。在小鼠肿瘤模型中,当KJ015与透明质酸酶和抗PD-1 mAb一起皮下注射时,它显示出更强的协同作用,这表明这种组合具有广阔的临床前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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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