Abstract C121: Development of CRB-701 (SYS6002): A novel site-specific, Nectin-4 targeting ADC

Abstract

Abstract CRB-701 (SYS6002) is a clinical stage, next generation ADC targeting Nectin-4 wherein two monomethyl auristatin E (MMAE) moieties are site-specifically conjugated to a novel Nectin-4 targeting IgG1 antibody via a cleavable linker. Nectin proteins are cell adhesion molecules belonging to the immunoglobulin (Ig) superfamily that participate in cell-to-cell interactions and form adhesion junctions between cells. Nectin-4 is widely expressed in epithelial cancers including bladder, breast, lung, colorectal, pancreatic, and ovarian. By contrast the expression level of Nectin-4 is very low in healthy adult human tissues. Due to this differential expression, Nectin-4 has emerged as a robust tumor associated antigen (TAA) that has been clinically validated in urothelial carcinoma by Enfortumab Vedotin (EV). While approved, EV carries associated toxicity concerns including skin rash, peripheral neuropathy and ocular toxicities that can lead to EV discontinuations and lasting adverse effects. CRB-701 (SYS6002) has demonstrated high affinity Nectin-4 binding (~2ng/ml) across species and has selectivity for Nectin-4 among the Nectin family of proteins (>5000 ng/ml). The antibody retains potent in vitro activity against FcgRI and C1q (<10nM) conferring antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) activity in vitro. Compared to EV, CRB-701 (SYS6002) reduces free MMAE exposure by 4.8-9.7-fold when adjusted to ADC exposure (AUC) and there is a 2.2-7.4-fold reduction in MMAE in circulation based on Cmax in rats and non-human primates. Collectively these data reflect lower free MMAE in plasma, reducing the risk of MMAE-induced toxicities observed with EV in the clinic. This improved PK and safety profile coincides with a longer half-life of the ADC in plasma potentially reducing the frequency of administration to achieve efficacy. The internalization rate of CRB-701 (SYS6002) was 2-fold faster than EV when assessed in nectin-4 expressing cells. These data may explain the statistically significant reduction in tumor growth observed in a BL0597 patient derived xenograft model (PDX) of bladder cancer with low Nectin-4 protein expression by IHC (H score =50) when compared to EV at the same dose and frequency. Collectively these data suggest that CRB-701 (SYS6002) could demonstrate an improved therapeutic index and PK profile relative to EV and as such could achieve higher tolerated concentrations at lower dose frequency. The stability of the site-specific linker and the reduction in the drug-antibody ratio (DAR) could lead to a differentiated profile clinically that enables higher doses, longer treatment duration and a greater potential in drug combinations in nectin-4 positive tumors. CRB-701 (SYS6002) is currently being explored clinically in a phase 1 dose escalation with an anticipated completion date mid-2024. Citation Format: Rachael Brake, Zhaopeng Sun, Mo Dan, Lu Lv, Congcong Niu, Yang Zhang, Mingyue Shen, XiXin Hu, Xiwu Hui, Andrew Kolodziej. Development of CRB-701 (SYS6002): A novel site-specific, Nectin-4 targeting ADC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C121.