Evaluation of Non-covalent Antibody Drug Complexes (ADCx) for Targeted Drug Delivery

This project proposes the development of a non-covalent antibody-based drug delivery strategy. The strategy, abbreviated ADCx for Antibody Drug Complex, consists of an anti-drug antibody that is bound to a drug ex vivo and targeted to a cell type of interest through a secondary affinity ligand. ADCx is designed to bypass the linker payload conjugation step that is necessary for antibody-drug conjugates (ADCs). Despite the tremendous interest in ADC technology, ADCs evaluated in clinical trials have a consistent difficulty: a narrow therapeutic window. The clinical trial failure rate of ADCs is 89% and the most common reason for failure is poor efficacy at the maximum tolerated dose. For approved ADCs, most patients experience adverse events that can cause dose delays, dose reductions, and patient withdrawal from therapy. ADC toxicities result from off-site payload delivery, which is primarily due to challenges associated with the linker payload. As a result, substantial research and development efforts have been dedicated to identifying better linkers, payloads, and conjugation sites. Linker payload optimization has proven difficult, and introducing one solution can create a new problem. This proposal tests the hypothesis that avoiding the linker payload with ADCx is the best way to achieve safe and effective antibody drug therapies. Our laboratory has developed a lead anti-MMAE anti-HER2 ADCx that has been optimized using pharmacokinetic model informed antibody engineering. The anti-HER2 anti-MMAE ADCx will be directly compared to trastuzumab-vc-MMAE ADC in a series of pharmacokinetic, efficacy, and tolerability studies in mice. Subsequently, we will determine critical antibody and drug attributes to maximize ADCx tolerability and efficacy. Like ADCs, the ADCx concept may be used to treat many conditions. In some cases, we anticipate that ADCx can deliver payloads unsuitable for ADC conjugation due to a lack of reactive sites or stability when exposed on the ADC surface. Therefore, we will discover additional anti-drug antibodies against other payloads for application with ADCx. Priority will be given to drugs that have multiple treatment indications, facilitating a modular approach in which the secondary targeting ligand can be easily replaced to develop a panel of targeted ADCx. Optimization efforts will be conducted on lead anti-drug antibodies to ensure good developability characteristics. Collectively, these efforts will lay the groundwork to establish ADCx as a versatile drug delivery strategy.