Mechanisms of monoclonal antibody-drug interactions

The concept of monoclonal antibodies (mAbs) as pharmacotherapeutics was validated in the mid-1980s with the successful clinical development of the fully murine mAb muromonab-CD3 for prevention of acute organ rejection. However, clinical applications of fully murine mAbs are restricted, owing to the high incidence of serious immune-mediated side effects, particularly upon repeated exposure. The rate and severity of immune-mediated toxicities of these agents were significantly attenuated by the development of mouse/human chimeric, fully human, and humanized mAbs. These refinements in molecular structure allowed repeated, long-term administration, where therapeutically warranted, which, in turn, broadened the scope of indications for this class of therapy. Presently, numerous mAbs are approved or are undergoing clinical evaluation for treatment of oncologic and chronic inflammatory diseases. The current experimental development landscape spans respiratory, metabolic, and central nervous system disorders as well as infectious disease. A consequence of the expanding numbers of mAb indications is concomitant administration of these agents with established small molecule pharmacotherapies, which necessitates a comprehensive understanding of mAb-small molecule drug interactions as well as mAb-mAb interactions. Current knowledge indicates that mAbs do not elicit a direct effect on the metabolic/clearance pathways for small molecular therapeutics. However, the immunomodulatory properties of mAbs can indirectly alter clearance of certain small molecule entities through the attenuation of noncatabolic enzymatic pathways.