Background
Human cadherin-6 (CDH6) is a type II cadherin, containing 5 extracellular domains and a large cytoplasmic domain for the interaction with catenin molecules.1 CDH6 protein localizes to the basolateral membrane of epithelial cells and mediates calcium-dependent cell–cell adhesion.2 Increased CDH6 expression has been identified in several cancer types, including serous-type ovarian cancer, renal cell carcinoma, and thyroid cancer.3Antibody drug conjugation (ADC) targeting CDH6 has been reported with promising clinical efficacy in treating ovarian cancer. CD3 T cell engaging bispecific antibodies (TCE) have demonstrated promising therapeutic efficacy in the treatment of hematological malignancies, whereas suboptimal efficacy in the treatment of solid tumors and the risk of inducing cytokine release syndrome (CRS) continue to be major challenges. Here we reported a novel ‘2+1’ CDH6 &x2179; CD3 bispecific T cell engager (TCE), ATG-106, which exerted potent anti-tumor efficiency in vitro and in vivo, with reduced risk of CRS.
Methods
ATG-106 was developed by introducing a novel conformational epitope-targeted anti-CD3 single chain fragment variable (scFv) antibody to the hinge region of a novel humanized CDH6 monoclonal antibody. The CD3 binding site is concealed by the anti-CDH6 Fab arm before binding to CDH6, due to the steric hindrance. It was assessed in a series of in vitro studies including binding affinity, cell based CD3 signal pathway activation, and T cell dependent cytotoxicity (TDCC). The in vivo efficacy of ATG-106 was evaluated in human PBMC reestablished OVCAR-3 xenograft model.
Results
ATG-106 bound to a CDH6-positive cell line, OVCAR-3, with a sub-nanomolar grade EC50. It showed limited binding capability to CD3+ cells before CDH6 crosslinking. ATG-106 strongly activated CD3+T cells in the presence of CDH6-positive target cells which lead to a potent T cell dependent cytotoxicity with single-digit pM IC50 values. ATG-106 also demonstrated promising in vivo anti-tumor activity in OVCAR-3 xenograft models. Twice a week dosing of ATG-106 showed significant tumor growth inhibition (TGI). The mean TGI values for 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg dosing of ATG-106 were 132.53%, 140.34%, and 140.23%, respectively. All the mice in ATG-106 treatment groups exhibited tumor shrinkage, with complete remission observed in 0.3 mg/kg (3 out of 6 mice) and 1 mg/kg (3 out of 6 mice) treatment groups (figure 1).
Conclusions
ATG-106 demonstrated powerful T cell dependent cytotoxicity and in vivo anti-tumor efficacy against ovarian cancer preclinically, which warrants further clinical evaluation.
Abstract 1069 Figure 1
ATG-106, a novel ‘2+1’ format CDH6-targeted T-cell Engager (TCE), shows potent T cell dependent cytotoxicity and in vivo anti-tumor efficacy in human PBMC reestablished ovarian cancer cell derived xenograft model. Growth curves of OVCAR-3 ovarian tumors treated with IgG control or ATG-106 twice a week for 5 doses, as indicated by red arrows. 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg ATG-106 produced significant anti-tumor efficacy with mean TGI values of 132.53%, 140.34%, and 140.23%, respectively. Complete tumor remission was observed in 0.3 mg/kg (3 out of 6 mice) and 1 mg/kg (3 out of 6 mice) treatment groups
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