New Directions Towards the Development of Protein Drug Conjugates for the Treatment of Cancer

Abstract

The innovative development and success of monoclonal antibodies (mAbs) was essential in the race to defeat the growing cancer disease burden. And subsequently the development of Antibody drug conjugates has revolutionized cancer therapeutics. These target specific missiles have many appealing advantageous features that has earned the intrigue of researchers around the world. It has paved the way for emerging conjugation strategies over the years. The discovery of new tools and technology has been driven at an accelerated pace to overcome the various limitations that impede and complicate the efficacy of antibody drug conjugates for the treatment of cancer.

This thesis illustrates the multiple resistance mechanisms that cancer cells use to evade treatment and explores the strategies to overcome these limitations using various innovative ground-breaking approaches to outmaneuver these resistance mechanisms.

There are various strategies currently in the workings among researchers worldwide that use various tools and technologies capable of guaranteeing homogeneity, stability, and control of the conjugation sites on the antibody that are imperative in the successful pharmacokinetics and pharmacodynamics of the antibody drug conjugate. To amplify this notion, we experimentally developed an antibody drug conjugate using an alternative approach that took advantage of the available conjugation sites on the antibody to successfully develop a dual payload conjugate. Astonishingly the characterization and cytotoxic results showed promising results and amplified that this hypothesis is worth exploring.

This notion paves the way to target two mechanisms including inhibiting microtubule polymerization and damaging DNA by conjugating two different potent cytotoxic agents that can target both the above-mentioned mechanisms at the same time to result in complete cell death and apoptosis. These ideas are delineated in the following chapters in this thesis.