(512d) Antibody Bottlebrush Conjugates (ABCs): A New Strategy for Targeted Cancer Therapy

Antibody drug conjugates (ADCs), which are composed of a monoclonal antibody for cell targeting linked to a cytotoxic payload, have emerged as a promising class of targeted chemotherapeutics. Despite their success in the clinic, ADCs suffer key drawbacks. For instance, the number and type of payload molecules conjugated to each ADC is limited due to the restricted number of conjugation sites as well as the deterioration of physical properties as the number of conjugated payloads increases. Moreover, extensive optimization of each drug payload and linker chemistry needs to be done to achieve a maximal therapeutic index for each ADC. Finally, though antibodies offer exquisite targeting potential, still <1% of injected ADC accumulates in the target tissue, leading to major off-site toxicities that cannot be overcome with traditional designs. To overcome these challenges, we have developed a fundamentally new antibody-targeted prodrug platform, which we refer to as “antibody bottlebrush conjugates” or “ABCs”. ABCs feature an antibody conjugated to bottlebrush polymers of similar size and shape. The latter carry inactivated “prodrugs” attached at each repeat unit along a polymer backbone along with hydrophilic polymer chains that shield the prodrugs from premature activation and release. The high density of PEGylation can significantly increase the pharmacokinetics of the ABCs. The linker used to attach each prodrug can be tuned to control the drug release rate and achieve activation preferentially in cancer cells. Importantly, these linkers are independent of the conjugation site to the antibody, allowing for a broad range of linker structures to be optimized without affecting the ABC properties. Finally, due to the unique structure of the bottlebrush prodrug, it is possible to include a very large number of drugs (>100) on each ABC, thus overcoming the need for highly toxic agents and opening the door to the use of a broader palette of drugs. Further, different drugs and antibodies can be easily mixed-and-matched, providing for modular development of novel ABCs with predictable properties.