Codrituzumab

Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis. The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients with chronic obstructive pulmonary disease (COPD). Here, we investigated the co-receptors to fully decipher the complex machinery of airway HH pathway activation in health and COPD. The core elements and co-receptors of HH signalling were investigated in lung cell populations using single-cell RNAseq analysis. The transcript levels of the principal co-receptor GPC3 were investigated on public RNAseq datasets and by RT-qPCR. The localisation of GPC3 was evaluated through immunofluorescent stainings on isolated bronchial AEC and tissues from non-COPD and COPD patients. GPC3 pharmacological modulation was achieved with Codrituzumab during AEC differentiation. We demonstrated that the core elements were not abundant in pulmonary cell populations. Focusing on co-receptors, GPC3 was the most expressed transcript in tracheobronchial epithelial cells. The decrease in GPC3 transcript levels correlated with the severity of airway obstrution in COPD patients. Finally, interfering with GPC3 signalling during AEC differentiation induced downregulation of the HH pathway attested by a decrease of Gli2 leading to reduced ciliogenesis and altered mucin production. GPC3 appears as a crucial co-receptor for the HH pathway in the respiratory context. The modulation of GPC3 may represent a novel experimental strategy to tune HH signalling in therapeutic perspectives.

Hepatocellular carcinoma (HCC) remains one of the most common and highly fatal malignancies in humans worldwide with increasing prevalence and limited therapeutic options. For many decades, many researchers have attempted to find effective curative methods for HCC and great strides have been made. GPC3 is overexpressed in HCC, but not in normal liver, making it a rational immunotherapeutic target for HCC. GC33, a humanized mAb directed against GPC3, is a safe and well-tolerated therapy choice for patients with HCC, which tested in a phase I trial in advanced HCC patients. Phase II trials of GC33 to evaluate its efficacy and safety in advanced or metastatic HCC, showed no significant differences in overall survival and progression-free survival compared with the placebo. Retrospective analysis indicates that high drug exposure and high CD16 expression may contribute to the clinical efficacy of GC33. Chugai Pharmaceutical has restarted its Phase I trial of GC33, continuing to explore its clinical value targeting GPC3 in solid tumors. To enhance the antitumor potency of GC33, we designed a GPC3/CD16A bispecific antibody (QDEB). In this study, we obtained QDEB at high purity and assessed its effectiveness in the therapy of HCC compared with GC33. In vitro cytotoxicity assays and in vivo experiments demonstrated that QDEB could enhance anti-tumor efficacy compared with GC33. CD16A activation and increased cytokines release were associated with higher anti-tumor activity. In conclusion, this bispecific antibody may possibly help develop new therapeutic strategies for HCC and develop new treatment options in the future.