SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models.,Acta Pharmacologica Sinica

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SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-01-14 , DOI: 10.1038/s41401-018-0198-0
Chang-Yong Yang _{1,

2,

3} , Lei Wang ₄ , Xing Sun ₃ , Mi Tang ₃ , Hai-Tian Quan ₄ , Lian-Shan Zhang ₃ , Li-Guang Lou ₄ , Shao-Hua Gou _{1,

2}

Affiliation

Emerging evidence demonstrates that a c-Met antibody-drug conjugate (ADC) has superior efficacy and safety profiles compared with those of currently available small molecules or antibody inhibitors for the treatment of c-Met-overexpressing cancers. Here we described both the in vitro and in vivo efficacies of SHR-A1403, a novel c-Met ADC composed of a humanized IgG2 monoclonal antibody against c-Met conjugated to a novel cytotoxic microtubule inhibitor. SHR-A1403 showed high affinity to c-Met proteins derived from human or monkey and potent inhibitory effects in cancer cell lines with high c-Met protein expression. In mice bearing tumors derived from cancer cell lines or patient HCC tissues with confirmed c-Met overexpression, SHR-A1403 showed excellent anti-tumor efficacy. Antibody binding with c-Met contributed to SHR-A1403 endocytosis; the subsequent translocation to lysosomes and cytotoxicity of the released toxin are speculated to be predominant mechanisms underlying the anti-tumor activity of SHR-A1403. In conclusion, SHR-A1403 showed significant anti-tumor activity in cancer cell lines, xenograft mouse models and an HCC PDX model, which all have high c-Met levels. These data provide references for SHR-A1403 as a potential therapy for the treatment of cancers with c-Met overexpression.

中文翻译：

SHR-A1403 是一种新型 c-Met 抗体药物偶联物，在 c-Met 过表达模型中发挥令人鼓舞的抗肿瘤活性。

新的证据表明，与目前用于治疗 c-Met 过表达癌症的小分子或抗体抑制剂相比，c-Met 抗体药物偶联物 (ADC) 具有优越的功效和安全性。在这里，我们描述了 SHR-A1403 的体外和体内功效，SHR-A1403 是一种新型 c-Met ADC，由与新型细胞毒性微管抑制剂缀合的抗 c-Met 人源化 IgG2 单克隆抗体组成。SHR-A1403 对源自人或猴的 c-Met 蛋白表现出高亲和力，并对 c-Met 蛋白高表达的癌细胞系具有有效的抑制作用。在携带来自癌细胞系或已证实 c-Met 过度表达的患者 HCC 组织的肿瘤的小鼠中，SHR-A1403 显示出优异的抗肿瘤功效。抗体与 c-Met 结合有助于 SHR-A1403 内吞作用；随后向溶酶体的易位和释放毒素的细胞毒性被推测是 SHR-A1403 抗肿瘤活性的主要机制。总之，SHR-A1403 在癌细胞系、异种移植小鼠模型和 HCC PDX 模型中显示出显着的抗肿瘤活性，这些模型都具有高 c-Met 水平。这些数据为SHR-A1403作为治疗c-Met过表达癌症的潜在疗法提供了参考。

更新日期：2019-05-16

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