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 The 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 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.

中文翻译：

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用于曲妥珠单抗耐药乳腺癌免疫治疗的人 CD47/HER2 双特异性抗体的开发和评估

曲妥珠单抗耐药乳腺癌（BC）的治疗在临床环境中仍然是一个挑战。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。在这里，我们开发了一种针对曲妥珠单抗耐药 BC 的新型抗 CD47/HER2 双特异性抗体 (BsAb)，命名为 IMM2902。 IMM2902 对曲妥珠单抗敏感和曲妥珠单抗耐药的 BC 细胞均表现出高结合亲和力、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。实验数据表明，IMM2902 比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来源的异种移植 (PDX) 小鼠模型和脐带血 (CB) 人源化 HCC1954 小鼠中，其抑制肿瘤生长的效果优于各自的对照模型。通过空间转录组测定、多重免疫荧光 (mIFC) 和测定，我们的研究结果证明 IMM2902 有效刺激巨噬细胞产生 CXC 基序趋化因子配体 (CXCL) 9 和 CXCL10，从而促进 T 细胞和 NK 细胞募集到肿瘤部位。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。总的来说，我们的结果强调了一种治疗 HER2 BC 的新方法，这种方法表现出显着的抗肿瘤功效，且不会在曲妥珠单抗耐药的 BC 细胞中引起脱靶毒性。