Bispecific and Biparatopic Antibody Drug Conjugates

The conceptual framework for antibody drug conjugates (ADC’s) emerged contemporaneously with the discovery of antibodies, with Paul Ehrlich proposing in the early 1900’s the concept of a “magic bullet”, an ideal therapeutic that would specifically target a disease-causing agent without causing harm to the body. This concept still underpins the overarching goal of biopharmaceutical development today: to produce drugs that have a broad therapeutic index by effectively targeting the disease while causing minimal damage to normal tissue. Although the concept of ADC’s is simple, achieving the ideal combination of properties has proven challenging, as reflected by the limited number of ADC’s that have demonstrated success in the clinic to date. Recent years have witnessed a burgeoning field, with the number of clinical stage ADC’s more than doubling in just the last two years to more than 70 candidates currently in clinical development. Despite the successes to date and the prospect of new ADC’s reaching patients in the coming years, many challenges remain and there is substantial room for improvement, most notably in improving the therapeutic index. The key challenge in developing an ADC is balancing its efficacy and safety. This review will focus on ways to capitalize on bispecific antibody technology to improve the therapeutic index of ADC’s, in pursuit of the magic bullet ideal. The nature of bispecific antibodies allows for fine tuning of the interactions between each target to impact the overall properties of the molecule. Here, we discuss some of the cutting edge bispecific antibody strategies that are currently under investigation to address both the efficacy and safety aspects of ADC’s.