Preclinical studies of ADC therapy for solid tumors

Abstract

Antibody engineering technologies that allow genetic modification of murine antibodies to produce chimeric mouse-human antibodies, or humanized antibodies, have led to the development of new therapeutic regimens using monoclonal antibodies (mAbs) for treatment of solid tumors. In some therapeutic designs, the antibody is itself the therapeutic agent, whereas in others it is the vehicle by which a cytotoxic agent is concentrated upon the tumor cells. The second approach diminishes the clearance of the therapeutic agent from the body and has yielded very promising results encouraging further study. Successful antibody drug conjugates (ADCs) have three important components; the antibodies, the linkers, and the payloads, which are chemotherapeutic drugs. The antibody is selected to bind to a specific component of the tumor tissue and fix the conjugate to it, thereby concentrating the effect of the drug. The linkers are categorized into cleavable and non-cleavable linkers and serve to bind the drug payload to the antibody. Using this strategy the payloads can achieve 100-1000 fold higher cytotoxic potency than conventional anti-cancer agents because comparable therapeutic effects can be achieved when the number of payloads conjugated to each antibody molecule is as few as 10 drug molecules. However, in some circumstances the efficacy of the ADC technique can be diminished by the composition of intercellular stroma of tumor, which can impede access of the ADC to the target tumor cells after extravasation from the leaky tumor vasculature. There are six major issues to optimize in the treatment of solid tumors with ADCs, which are: extravasation of the conjugate from tumor vessels, traversing cancer stroma barrier, attaching to the antibody binding site, internalization into cancer cells, the drug releasing, and direct cytotoxic effectthe bystander killing effect on cells adjacent to the site of release of the cytotoxic agent.The ADCs which achieve these aims can significantly improve treatment outcomes for patients with solid tumors.