Antibody-Drug Conjugates: A Review on the Epitome of Targeted Anti- Cancer Therapy.

Abstract

Cancer is one of the deadly diseases which is characterized by unchecked cell division or abnormal cell growth due to the incapability of cell cycle arrest. As the treatment for this is to kill the cancerous cells, the main challenge for scientists is to direct the cell killing to cancerous cells while leaving the normal cells unharmed. Antibody-Drug Conjugates (ADC) are one such targeted anti-cancer therapy. It is an effective drug delivery system that utilizes the targeting action of antibody along with cell death by potent cytotoxic agent, linked up with one another by a linker molecule and thus helps to reduce toxicity to non-target cells, ensure broad therapeutic window and overcome multi-drug resistance. Multiple parameters like total antibody (conjugated and unconjugated antibody), conjugated antibody, conjugated drug, unconjugated antibody and unconjugated (free) drug are needed to be analyzed to find out the behavior as well as safety and efficacy of ADCs. With 2 FDA approved drugs (Kadcylca and Adcetris) and more than 40 drugs undergoing clinical trial, this field has gained pace in recent years. Some challenges still persist in this field like reducing immunogenic response to antibodies, ensuring the ADC homogeneity and antibody-drug ratio, selection of appropriate targets, successful conjugation of drug to antibody, securing the stability of linkers in systemic circulation as well as improvement of oral bioavailability. With the advent of stable linkers, cytotoxic drugs having higher potency and better conjugation capability with the linker and antibodies having high specificity, these ADCs can overcome the limitations of cancer treatment. This review focuses on the criteria for proper construction of ADC, conjugation techniques, the target choices, the underlying mechanism of action and pharmacokinetic considerations associated with ADC.