From ADCs to ABCs: A New Strategy for High-Capacity Targeted Drug Delivery

Antibody-drug conjugates (ADCs) have emerged as a major advance in cancer therapy. To date, 19 ADC drugs have been approved worldwide, and more than 40 are in pivotal Phase III clinical trials. Despite this progress, ADC technology still faces a key challenge: the limited drug-to-antibody ratio (DAR).

In conventional ADCs, the DAR usually ranges from 2 to 8. Because of this limitation, ADCs must carry highly potent cytotoxic agents—such as microtubule inhibitors or DNA-damaging agents. While effective, these payloads can cause significant side effects and increase the risk of drug resistance. At the same time, many promising drugs with lower toxicity cannot be efficiently incorporated into the ADC framework, restricting the range of therapies that can be developed.

In September 2025, a research team at MIT reported a new drug delivery platform in Nature Biotechnology called Antibody-Bottlebrush Prodrug Conjugates (ABC). Unlike traditional ADCs, this approach addresses the long-standing challenge of limited drug loading with a fundamentally different design concept.

The ABC system links an antibody to a polymer known as a bottlebrush prodrug (BPD) using efficient click chemistry. The BPD has a distinctive structure: its main backbone carries numerous side chains, giving it a brush-like appearance. Each side chain can be equipped with a cleavable linker for drug attachment, while polyethylene glycol (PEG) branches are added to improve water solubility.
ABC

Source: reference [1]

Traditional ADCs lose activity and stability once the DAR exceeds 8. By contrast, the bottlebrush architecture of ABC can raise the DAR as high as 135, enabling the delivery of far more drug molecules at once. This advance not only increases payload capacity but also broadens the choice of therapeutics. In the future, less toxic drugs with favorable safety profiles—not just highly potent cytotoxins—may be integrated into ABC conjugates.

ABC technology also shows strong physicochemical performance. Hydrophobic drug molecules are shielded within a hydrophilic PEG shell, which improves solubility, stability, and prevents aggregation or rapid clearance—issues common in high-DAR ADC systems. Together, these features provide a foundation for longer circulation and enhanced therapeutic potential.

According to published research, the MIT team constructed multiple ABC particles carrying different drugs. Each particle combines an antibody with a BPD. The BPD acts like a flexible “molecular toolbox,” capable of loading widely used chemotherapeutics such as MMAE and SN-38, as well as agents that are difficult to incorporate into conventional ADCs, including doxorubicin (DOX), paclitaxel (PTX), protein degraders like PROTAC ARV771, and even imaging probes such as Cy5.5.

Experimental data showed that ABCs retained HER2 binding comparable to trastuzumab while demonstrating stronger internalization and cytotoxicity in HER2-positive cells.

In terms of pharmacokinetics, ABCs achieved a blood half-life of up to three days—substantially longer than standard ADCs—and displayed higher tumor-specific accumulation.

In mouse tumor models, including BT-474 (HER2 high expression) and HCC-70 (HER2 low expression), ABCs carrying different payloads (MMAE-HER2, SN-38-HER2, DOX-HER2) produced marked tumor suppression. Notably, SN-38-HER2 outperformed the approved drug Enhertu (T-DXd) in the low HER2 model, and DOX-HER2 represented the first successful antibody conjugate for efficient targeted delivery of doxorubicin.

Head-to-head comparisons with marketed ADCs such as Kadcyla (T-DM1) and Enhertu (T-DXd) confirmed that, at equal antibody doses, ABCs generally achieved superior efficacy. The advantage was most pronounced in tumors with low HER2 expression, suggesting the potential to overcome one of the major limitations of current ADC therapies.

The platform also enabled the creation of the world’s first PROTAC-ABC by incorporating the BET degrader ARV771. In vivo studies demonstrated strong antitumor activity with ABC-delivered ARV771 at doses far lower than the free drug. This finding points to a new strategy for delivering PROTACs, a class of therapeutics often limited by poor pharmacokinetics.

Beyond HER2, the modularity of the ABC design was further validated using an anti-MUC1 antibody. The resulting MUC1-ABC achieved effective tumor targeting and suppression in an ovarian cancer model, showing that the platform can be readily adapted to different targets and drug combinations.

Taken together, the ABC platform—with its modular architecture, exceptional drug-loading capacity, and favorable physicochemical properties—addresses the limitations of conventional ADCs in toxicity, DAR constraints, and target range. It not only revitalizes lower-toxicity drugs but also provides a viable delivery strategy for emerging therapeutic classes such as PROTACs, positioning itself as a promising foundation for next-generation targeted cancer therapies.

References:
[1] Bin Liu et al. Antibody-bottlebrush prodrug conjugates for targeted cancer therapy. Nature Biotechnology （2025）, https://www.nature.com/articles/s41587-025-02772-z