Antibody Bottle Brush Conjugates (ABCs) Platform
📌 The research introduces Antibody Bottle Brush Conjugates (ABCs) as a novel platform for targeted theranostics, aiming to combine mechanism-of-action and delivery-based therapeutic windows.
🧪 ABCs utilize a bottle brush polymer prodrug design, which features a hydrophilic side chain (blue chains) shielding payloads and linkers, allowing for high drug-to-antibody ratios (DARs) without disrupting antibody function.
🔗 The synthesis involves creating a branched macro monomer via a copper(I)-catalyzed azide-alkyne cycloaddition (Click Chemistry) reaction, followed by polymerization using Grubbs' third-generation catalyst to control the polymer chain length and thus the final DAR.

Therapeutic Window Enhancement
🎯 Traditional drug development seeks to widen the therapeutic window (difference between efficacious and toxic doses), achieved either through mechanism of action (e.g., molecularly targeted therapeutics) or delivery bias (e.g., Antibody Drug Conjugates or ADCs).
⚖️ Current ADCs typically use highly potent payloads (sub-nanomolar potency) and are dosed in a narrow range of 1 to 10 mg/kg because higher doses saturate the tumor periphery without increasing efficacy, and lower doses fail to saturate the periphery.
📈 ABCs overcome payload potency limitations by enabling 10x to 100x higher DARs (e.g., DAR 135 demonstrated), allowing the use of less potent, mechanism-selective drugs that are otherwise unsuitable for standard ADCs.

Preclinical Efficacy and Modularity
🔬 The platform has successfully linked various molecules, including classic chemotherapeutics (Doxorubicin, SN38), PROTACs (ARV771), and imaging agents (Cy5.5 fluorophore), demonstrating high modularity.
📏 The physical properties (size, solubility) of the resulting bottle brush polymers are reproducible and independent of the specific payload or linker used, maintaining an antibody-like size (~10 nm hydrodynamic diameter).
🌟 In murine models, an ABC using the less potent Topoisomerase 2 inhibitor Doxorubicin (DAR 135) achieved 100% survival in xenografts at an antibody dose of 5 mg/kg.

Key Points & Insights
➡️ The core innovation is decoupling payload physical properties from the overall structure's properties using hydrophilic bottle brush side chains, enabling high DARs previously impossible with traditional conjugation methods.
➡️ ABCs allow the use of drugs with mechanisms of action currently underrepresented in ADCs (like Topoisomerase 2 inhibitors), effectively multiplying the two therapeutic windows (mechanism + delivery).
➡️ The system allows for simultaneous conjugation of imaging agents and therapeutic payloads (e.g., SN38 and Cy5.5) to track drug release and nuclear trafficking within cells, providing direct mechanistic evidence.
➡️ Maximum tolerated dose (MTD) guidelines suggest starting ADC payload doses on a payload-mass basis equivalent to the free payload's MTD, which supports using less potent drugs in ABCs if the resulting mass dose remains clinically acceptable.

📸 Video summarized with SummaryTube.com on Dec 16, 2025, 02:57 UTC