Antibody–Bottlebrush Conjugates Unlock Diverse Payloads for Targeted Cancer Therapy

Antibody drug conjugates (ADCs), which feature a monoclonal antibody (mAb) for cell targeting linked to a cytotoxic payload for cell killing, are a remarkably effective class of targeted therapeutics. Despite their success, however, ADCs typically rely on highly potent payloads, precluding the use of less potent payloads and a broader range of payload mechanisms of action (MoA).1-4 Moreover, the emerging perspective that passive targeting mechanisms play roles in ADC function in vivo suggests opportunities to engineer new ADCs based on stable prodrug scaffolds with tunable release mechanisms.5,6 Here, inspired by the physics, shape, and chemical versatility of molecular bottlebrush polymers,7-11 we introduce “Antibody–Bottlebrush prodrug Conjugates” (ABCs) as a next-generation targeted cancer therapy platform designed to enable the modular and predictable use of a broad range of payloads with varied potencies and MoAs. ABCs feature an IgG1 mAb covalently conjugated to the terminus of a compact bivalent bottlebrush prodrug (BPD) with payloads bound via cleavable linkers and hydrophilic poly(ethylene glycol) (PEG) branches on each repeat unit. This design enables the synthesis of ABCs with tunable drug-to-antibody ratios (DARs) up to two orders-of-magnitude greater than traditional ADCs without negatively impacting the physical properties of the mAb. The efficiency of ABC manufacturing is highlighted by the synthesis of >10 different variants for distinct targets (HER2 and MUC1) and with payload potencies spanning several orders-of-magnitude, imaging agents for direct ABC visualization, and photocatalysts for proximity-based labeling of the ABC interactome. ABCs display excellent target engagement, cell uptake, and efficacy in antigen expressing tumor-bearing mouse models, suggesting that they may be promising for future clinical translation.