Abstract
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.
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Author contributions
SHG and LGL conceived the project and planned the experiments. CYY and LW designed and participated in all the experiments and wrote the paper. HTQ participated in in vitro experiments. XS and MT analyzed the results. SHG, LGL and LSZ reviewed and edited the manuscript. All authors contributed to and approved the final manuscript.
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Yang, Cy., Wang, L., Sun, X. et al. SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models. Acta Pharmacol Sin 40, 971–979 (2019). https://doi.org/10.1038/s41401-018-0198-0
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DOI: https://doi.org/10.1038/s41401-018-0198-0
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