Tailored immunoconjugate therapy depending on a quantity of tumor stroma

Abstract

The purpose of this study was to clarify the appropriate combination of targeting antibody and conjugate-design of anti-tumor immunoconjugate depending on a quantity of tumor stroma. Most human solid tumors including pancreatic cancer (PC) forming hypovascular and stroma-rich tumor hinders the penetration of monoclonal antibodies (mAbs) into the cells, and that leads to failure of the conventional cell-targeting immunoconjugate strategy. To overcome this drawback, SN-38 as topoisomerase 1 inhibitor was conjugated to a mAb to collagen 4, a plentiful component of the tumor stroma via ester-bond. The immunoconjugate, which was able to release SN-38 in physiological condition outside the cells, was effective to stroma-rich PC-tumor. On the other hand, anti-CD 20 mAb-PEG-SN-38 via carbamate-bond as conventional immunoconjugate, enabled SN-38 to be released by a carboxylesterase inside of the tumor cell following the internalization, showed strong anti-tumor activity against malignant lymphoma as hypervascular and stroma-poor tumor. The conjugate-design, in parallel with the choice of targeting antibodies, should be selected to maximize the therapeutic effect in each individual tumor having a distinct stromal structure. © 2012 Japanese Cancer Association.