Development and evaluation of a human CD47/HER2 bispecific antibody for Trastuzumab-resistant breast cancer immunotherapy

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-02-13 DOI:10.1016/j.drup.2024.101068
Binglei Zhang , Jianxiang Shi , Xiaojing Shi , Xiaolu Xu , Le Gao , Song Li , Mengmeng Liu , Mengya Gao , Shuiling Jin , Jian Zhou , Dandan Fan , Fang Wang , Zhenyu Ji , Zhilei Bian , Yongping Song , Wenzhi Tian , Yichao Zheng , Linping Xu , Wei Li
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Abstract

The treatment for trastuzumab-resistant breast cancer (BC) remains a challenge in clinical settings. It was known that CD47 is preferentially upregulated in HER2+ BC cells, which is correlated with drug resistance to trastuzumab. Here, we developed a novel anti-CD47/HER2 bispecific antibody (BsAb) against trastuzumab-resistant BC, named IMM2902. IMM2902 demonstrated high binding affinity, blocking activity, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and internalization degradation effects against both trastuzumab-sensitive and trastuzumab-resistant BC cells in vitro. The in vivo experimental data indicated that IMM2902 was more effective than their respective controls in inhibiting tumor growth in a trastuzumab-sensitive BT474 mouse model, a trastuzumab-resistant HCC1954 mouse model, two trastuzumab-resistant patient-derived xenograft (PDX) mouse models and a cord blood (CB)-humanized HCC1954 mouse model. Through spatial transcriptome assays, multiplex immunofluorescence (mIFC) and in vitro assays, our findings provided evidence that IMM2902 effectively stimulates macrophages to generate C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, thereby facilitating the recruitment of T cells and NK cells to the tumor site. Moreover, IMM2902 demonstrated a high safety profile regarding anemia and non-specific cytokines release. Collectively, our results highlighted a novel therapeutic approach for the treatment of HER2+ BCs and this approach exhibits significant anti-tumor efficacy without causing off-target toxicity in trastuzumab-resistant BC cells.

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开发和评估用于抗曲妥珠单抗乳腺癌免疫疗法的人类 CD47/HER2 双特异性抗体
曲妥珠单抗耐药乳腺癌(BC)的治疗在临床上仍是一项挑战。众所周知,CD47在HER2+ BC细胞中优先上调,这与曲妥珠单抗的耐药性相关。在此,我们开发了一种新型抗CD47/HER2双特异性抗体(BsAb),用于抗曲妥珠单抗耐药的BC细胞,命名为IMM2902。IMM2902在体外对曲妥珠单抗敏感和曲妥珠单抗耐药的BC细胞均表现出很高的结合亲和力、阻断活性、抗体依赖性细胞毒性(ADCC)、抗体依赖性细胞吞噬作用(ADCP)和内化降解作用。体内实验数据表明,在曲妥珠单抗敏感的BT474小鼠模型、曲妥珠单抗耐药的HCC1954小鼠模型、两种曲妥珠单抗耐药的患者异种移植(PDX)小鼠模型和脐带血(CB)人源化HCC1954小鼠模型中,IMM2902抑制肿瘤生长的效果优于各自的对照组。通过空间转录组检测、多重免疫荧光(mIFC)和体外检测,我们的研究结果证明,IMM2902 能有效刺激巨噬细胞生成 C-X-C motif 趋化因子配体(CXCL)9 和 CXCL10,从而促进 T 细胞和 NK 细胞招募到肿瘤部位。此外,IMM2902 在贫血和非特异性细胞因子释放方面表现出较高的安全性。总之,我们的研究结果凸显了一种治疗 HER2+ BCs 的新型疗法,这种疗法对曲妥珠单抗耐药的 BC 细胞具有显著的抗肿瘤疗效,且不会引起脱靶毒性。
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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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