Technologies

Researchers from Cornell University, Beth Israel Deaconess Medical Center and Pfizer Inc.'s Centers for Therapeutic Innovation (CTI) have invented a technology for the opportunity to develop a potential medicine with a novel mechanism for the treatment of solid tumors. The asset is 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.

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 (Alajati et al., 2015; He et al., 2016a; Ikeda et al., 2009). An anti-CDCP1-ADC may have activity as a single agent or in combination with current standard of care with the potential to improve efficacy and minimize overlapping toxicities.

Sequential screening of a complex phage library led to the isolation of a fully human antibody that binds human, cynomolgous 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. PDX models were established by direct implantation of freshly resected human tumor samples in immunocompromised mice and propagated by passaging xenograft fragments into additional animals. Because they are not cultured in vitro, PDX models frequently preserve the genotype and recapitulate the architecture and, importantly, the drug sensitivity of the original human tumor from which they were derived (Tentler et al., 2012). 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 (Scherl-Mostageer et al., 2001; Hooper et al., 2003). Chronic inhibition/absence of CDCP1 seems to be of little to no consequence as knockout mice lacking it have no reported pathologies (Spassov et al., 2012). This suggests that targeting CDCP1 in diseases such as cancer should pose relatively limited safety risks.

Competitive Landscape:

CDCP1 represents a promising target that has been largely unexplored. Based on publicly available information, there are 5 other assets in preclinical or discovery stages that specifically target CDCP1, with two being ADCs from Alexion Pharma and Bluefin Biomedicine (founded 2016). There has been no development reported on the preclinical asset from Alexion since 2008 and no reports of clinical activity with the Bluefin Biomedicine asset. Hence, the CDCP1-ADC described here may be considered a leader in this class. There are more than a dozen ADCs in various stages of the development cycle for solid tumors. Kadcyla™, targeting Her2 positive breast cancer, is the only ADC currently approved for solid tumors.