Abstract 1819: CBP-1008 shows excellent efficacy and desirable drug safety profile in preclinical models

Abstract

Abstract Folate Receptor Alpha (FRα) is the high affinity folate transporter which is highly expressed in ovarian, lung and breast cancer. Transient Receptor Potential Vanilloid 6(TRPV6), a calcium channel characterized by its high calcium selectivity. It plays an important role in calcium absorption in small intestine and calcium uptake in other epithelial tissues. TRPV6 is also upregulated in breast, ovarian and prostate cancer. CBP-1008, A first-in-class drug conjugate which targets both FRα and TRPV6 with low molecular-weight ligands has been developed. CBP-1008 binds to FRα with high affinity and TRPV6 with low affinity. In presence of TRPV6, CBP-1008 shows faster FRα-mediated internalization and cytotoxicity than it does in absence of TRPV6. Systemic clearance CBP-1008 is observed within 6 hrs. However, the drug retained and accumulated in tumors with a half-life over 48 hrs. As a result, CBP-1008 shows excellent efficacy on tumors with target expression and the response is durable. MTD of CBP-1008 reaches 4 mg/kg in mice, 2 mg/kg in rat and 1 mg/kg in monkey. During the development of molecularly-targeted therapeutics, biomarker assays which can stratify patients and enrich those who respond well to the therapy, play a very critical role. We generated an anti-TRPV6 antibody and developed a first-in-class IHC-based TRPV6 assay. This assay along with an FRα IHC assay have been validated per CAP/CLIA guidelines for patient selection in our clinical trials. Intended indications including ovarian cancer, endometrial cancer, breast, NSCLC and pancreatic cancer. We have evaluated a panel of ovarian PDX models for their biomarker expression and response to CBP-1008 to determine their correlation. It is found that FRα+/TRPV6+ tumor responds better than tumors which have at least one marker negative. Within the FRα+/TRPV6+ tumors, tumor growth inhibition well correlates with IHC score of FRα (R2=0.89). It is indicated that clinical trials in selected indications using biomarkers assay to screening patients will expedite the clinical development of CBP-1008. Initial clinical response has been observed in our Phase I trial. Citation Format: Wei Tan, Wei Wang, Tingting Bu, Xuelian Liu, Yan Teng, Baohua Huang. CBP-1008 shows excellent efficacy and desirable drug safety profile in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1819.