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Anti-CDCP1 Antibody-Drug Conjugate for the Treatment of Solid Tumors
Weill Cornell Medicine
Antibody Conjugated
Oncology
Pre-Clinical
Researchers from Cornell University, Beth Israel Deaconess Medical Center and Pfizer Inc.’s Centers for Therapeutic Innovation (CTI) have invented a fully humanized antibody against CUB Domain Containing Protein-1 (CDCP1) conjugated to a proprietary cytotoxic linker-payload, being developed for the treatment of solid tumors over-expressing CDCP1.
Background
Unmet Needs
Novel therapeutics for the treatment of solid tumors that complement the current standard of care (SOC) by targeting distinct mechanisms of action (MOAs) such as CDCP1
Product Description
The asset is an antibody drug conjugate (ADC) that specifically targets CDCP1, a single pass transmembrane domain protein, over-expressed in numerous cancers including those of the lung, ovary, and breast. Sequential screening of a complex phage library led to the isolation of a fully human antibody that binds human, cynomolgus monkey, and mouse CDCP1. Multiple rounds of engineering produced a final antibody with good target binding affinity and manufacturability characteristics. This antibody was specifically conjugated to a proprietary linker-payload, resulting in a CDCP1-targeting ADC.
The CDCP1-ADC was evaluated in numerous non-clinical patient derived xenograft (PDX) cancer models. Among the models in which the CDCP1-ADC was examined were: non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, breast cancer, and ovarian cancer. In total, more than 40 independent PDX models were examined. Using RECIST criteria, we recorded a complete response in 20%, a partial response in 43%, and stable disease in 18% of the models tested, resulting in an objective response rate of 63%. Of these, non-small cell lung, head and neck, ovarian, and breast cancers were the most responsive while small cell lung and bladder cancers were generally resistant to treatment.
Non-clinical in vivo PK parameters of the CDCP1-ADC were in line with other assets of this class. Non- GLP compliant toxicology studies showed the ADC to be generally well-tolerated with no deaths observed even at the highest doses. These studies allowed the prediction of clinical dosing that is in line with, or superior to, other assets in the class. The CDCP1 protein is normally expressed at low levels in healthy epithelial tissues, most prominently in lung and colon. Chronic inhibition/absence of CDCP1 seems to be of little to no consequence as knockout mice lacking it have no reported pathologies. This suggests that targeting CDCP1 in diseases such as cancer should pose relatively limited safety risks.
Lewis C. Cantley
PCT-US2019-060276 (2019.11.07)
Patent Family: US, EP, JP, CN, MX, CA, AU
• "The SRC-associated protein CUB Domain-Containing Protein-1 regulates adhesion and motility". Benes, C. H. et al. Oncogene 2011, 31(5), 653–663
• "Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients". Emerling, B. M. et al. Proceedings of the National Academy of Sciences of the United States of America 2013, 110(9), 3483–3488
