An Anti-CD147 Antibody-Drug Conjugate Mehozumab-DM1 is Efficacious Against Hepatocellular Carcinoma in Cynomolgus...

Effective treatment strategies are urgently needed for hepatocellular carcinoma (HCC) patients due to frequent therapeutic resistance and recurrence. Antibody-drug conjugate (ADC) is a specific antibody-drug conjugated with small molecular compounds, which has potent killing activity against cancer cells. However, few ADC candidates for HCC are undergoing clinical evaluation. CD147 is a tumor-associated antigen that is highly expressed on the surface of tumor cells. Here CD147 is found significantly upregulated in tumor tissues of HCC. Mehozumab-DM1, a humanized anti-CD147 monoclonal antibody conjugated with Mertansine (DM1) is developed. Mehozumab-DM1 is effectively internalized by cancer cells and demonstrated potent antitumor efficacy in HCC cells. In vivo evaluation of Mehozumab-DM1 is conducted in a CRISPR-mediated PTEN and TP53 mutation cynomolgus monkey liver cancer model, which is poorly responsive to sorafenib treatment. Mehozumab-DM1 demonstrated potent tumor inhibitory efficacy at doses of 0.2 and 1.0 mg kg^-1 treatment groups in cynomolgus monkey. No treatment-related adverse reactions or body weight loss are observed. Interestingly, Mehozumab-DM1 treatment induced RIPK-dependent tumor cell necroptosis through inhibiting IκB kinase/NF-κB pathway. In conclusion, Mehozumab-DM1 potently inhibits hepatoma through effective internalization to release payload and inducing cell necroptosis to enhance the bystander effect, which is a promising treatment for refractory HCC.