Overcoming Resistance: How WuXi Biology Enables Next-Generation ADC Discovery

As drug resistance increasingly threatens the durability of antibody-drug conjugate (ADC) therapies, WuXi Biology, a segment of WuXi AppTec, is addressing this key hurdle through its ADC resistance model platform, which features a diverse panel of resistant cell lines. These capabilities enable clients to unravel resistance pathways, optimize next-generation ADC candidates, and ultimately deliver greater benefit to cancer patients worldwide.

ADC Development Momentum and the Growing Challenge of Resistance

Antibody-drug conjugates represent one of the most dynamic frontiers in oncology drug development. Often described as “magic bullets” for their ability to combine precise targeting with potent cytotoxicity, ADCs have evolved significantly over the past two decades. To date, at least 16 ADCs have received global approval, addressing both hematological malignancies and solid tumors such as breast and lung cancers, thereby expanding treatment options for patients.

For patients with triple-negative breast cancer (TNBC), recent progress has brought renewed hope. Since the second quarter of this year, two ADC therapies, Datroway (datopotamab deruxtecan) and Trodelvy (sacituzumab govitecan), have received FDA approval for adults with unresectable or metastatic TNBC who are ineligible for PD-1/PD-L1 inhibitor therapy.

The recent approvals for ADC drugs in TNBC reflect the accelerating translation of this therapeutic modality. By conjugating a targeting antibody to a cytotoxic payload through a linker, ADCs harness the antibody’s binding specificity to deliver the payload directly into tumor cells.

Behind the wave of ADC approvals lies continued innovation in linkers, payloads, and conjugation methods. For example, the development of ADCs was once constrained by unstable linkers that caused premature payload release and excessive toxicity, or by suboptimal drug-to-antibody ratios (DAR) that limited efficacy. Next-generation ADCs, powered by novel payloads, optimized DAR, and the “bystander effect”, have delivered transformative efficacy across a range of refractory tumor types.

Meanwhile, drug resistance has emerged as a major bottleneck limiting the long-term effectiveness of ADCs. Once resistance develops, disease recurrence often follows, diminishing the prospect of a durable survival benefit.

ADC resistance mechanisms span the entire drug action pathway: tumor cells may downregulate target expression or mutate target structure to prevent drug binding; altered expression of specific membrane proteins can reduce drug internalization; once inside the cell, changes in the lysosomal environment may inhibit payload release, while overexpression of efflux pumps actively expels the payload. In addition, intracellular mutations can impair payload activity. Adding to this complexity, tumor heterogeneity frequently gives rise to multiple coexisting resistance mechanisms, making ADC design and validation increasingly demanding.

Uncovering Novel Resistance Mechanisms to Guide ADC Design

Beyond well-characterized resistance pathways, exploring previously unrecognized resistance mechanisms is critical for developing more effective therapies. Recently, WuXi Biology identified a novel resistance mechanism from the perspective of cellular metabolism.

By gradually increasing the ADC concentration, the team established a cell line with acquired ADC resistance from a HER2-overexpressing gastric cancer cell line.

Intriguingly, HER2 expression and ADC binding remained unchanged in these resistant cells, indicating that resistance was not caused by the ADC failing to recognize or bind tumor cells. Instead, the drug entered cells but was rendered ineffective through an unknown mechanism.

Further analysis revealed that a group of drug-metabolizing enzymes was upregulated in resistant cells. Among these, AKR1C was identified as the key driver of drug inactivation. AKR1C expression was significantly elevated in resistant tumor cells. These enzymes can modulate ADC metabolism, thereby impacting the payload’s tumor-killing efficacy.

This finding points to a new strategy to overcome resistance. Further tests showed that reducing AKR1C expression via siRNA or target-specific inhibitors restored ADC sensitivity in resistant cells. In preclinical models, combining an AKR1C inhibitor with the ADC effectively suppressed the growth of resistant tumors, indicating that this combination strategy can reverse drug resistance.

Elucidation of the AKR1C-mediated resistance mechanism has also informed clients’ ADC design and validation strategies. As one client noted in their research, based on the mechanism discovered by WuXi Biology, they have modified their payload to develop a new ADC candidate, which showed robust resistance evasion and durable tumor growth inhibition in early testing.

An Integrated Resistance Platform Supporting ADC Discovery

This breakthrough was made possible by the ADC resistance model platform established by WuXi Biology.

WuXi Biology has developed capabilities spanning the full spectrum of resistance mechanisms through multiple strategies: ADC-induced resistance, payload-induced resistance, and engineered cell lines. Among these, ADC-induced resistance models are generated by exposing tumor cells to intact ADCs over time to recapitulate natural resistance evolution. Payload-induced resistance models, in contrast, involve continuous exposure to free ADC payloads to simulate payload-specific resistance pathways.

Based on these strategies, more than 30 resistant cell models have been created, covering major ADC targets, and the team has collaborated with more than 100 clients worldwide. This platform is extensively utilized for investigating resistance mechanisms and assessing the efficacy of next-generation ADCs, helping clients tackle the challenge of drug resistance.

The ADC resistance model platform is now an integral part of WuXi Biology’s oncology resistance landscape.

Across drug modalities ranging from ADCs to novel small-molecule targeted drugs, chemotherapy drugs, and protein degraders, WuXi Biology has established a comprehensive platform featuring a resistance model library with over 250 models covering more than 40 key targets and over 15 cancer types. The platform enables systematic elucidation of resistance mechanisms and supports the evaluation of next-generation drug activity as well as synergistic combination strategies. 

Looking ahead, sustained platform innovation and close collaboration with global clients will help drive novel therapies that offer longer-lasting hope and improved outcomes for cancer patients worldwide.

Key Takeaways

• WuXi Biology, a segment of WuXi AppTec, has built an integrated ADC discovery platform covering antibody generation, payload evaluation, conjugation, and comprehensive in vitro and in vivo testing, offering clients an integrated discovery solution.
• WuXi Biology addresses ADC resistance challenges for global innovators by developing its ADC resistance model platform, which includes more than 30 resistant cell models covering major ADC targets.
• In a case study, WuXi Biology has identified a novel AKR1C-mediated ADC resistance mechanism leveraging its ADC resistance model platform, supporting clients in the discovery of novel ADC candidates.
• By enabling the discovery of effective, resistance-evading ADCs, WuXi Biology accelerates delivery of meaningful benefits to cancer patients worldwide.