Cancer stromal targeting (CAST) therapy and tailored antibody drug conjugate therapy depending on the nature of tumor stroma

Abstract

In spite of recent success of monoclonal antibody (mAb) drug conjugate (ADC) therapy in patients with hypervascular and special tumors recognized by a particular mAb, there are several issues to be solved for ADC counted as universal therapy for any types of cancer. Especially most human solid tumors possess abundant stroma that hinders the distribution of ADC. To overcome these drawbacks, we developed a unique strategy that the cancer stromal targeting (CAST) therapy by cytotoxic immunoconjugate bound to the collagen IV or fibrin network in the tumor stroma from which the payload is released gradually and distributed throughout the tumor, resulting in the arrest of tumor growth due to induced damage to tumor cells and tumor vessels. In addition to the CAST therapy, we clarified the appropriate combination of targeting antibody and conjugate design of antitumor immunoconjugate depending on a quantity of tumor stroma. Hence, we selected two types of conjugate linker, ester bond and carbamate bond. It was found that combination of stromal targeting mAb and a linker composed of ester bond to release drug outside the cells was effective against the stroma-rich cancer. Conversely, cancer cell targeting via carbamate bond to release drug inside the cells was effective against stroma-poor cancer. It seemed that outcome of ADC therapy against each individual tumor having distinct stromal structure was dependent on the selection of conjugation design, as well as targeting mAb.