At the 2025 American Association for Cancer Research (AACR) Annual Meeting, over 250 drug conjugates were unveiled, with antibody-drug conjugates (ADCs) becoming a key highlight in cancer therapy. As biologic missiles that combine targeted delivery with cytotoxic potency, ADCs are showing increasing promise in treating solid tumors.

Figure 1. Drug Conjugates by Therapeutic Class, source: reference [1]

This year’s conference showcased major advances in ADC payload innovations, dual payload strategies, novel targets, and immune-oncology combinations. New technologies like bispecific ADCs (BsADCs), dual payload ADCs, T-cell engaging ADCs (TCE-ADCs), and non-internalizing ADCs are reshaping the landscape of ADC innovation.

Expanding ADC Targets: From Classic to Novel Avenues

The diversification of ADC targets was a significant trend, with 163 different targets reported at AACR 2025. While traditional targets such as HER2, TROP2, CLDN18.2, and Nectin-4 remain popular, emerging targets like CDH17, DLL3, uPARAP, TIGB4, CEACAM5, and GPC3 are gaining traction.

Figure 2. ADC Targets, source: reference [1]

CDH17 as a Promising Example:

Highly expressed in gastrointestinal tumors but with limited expression in normal tissues, CDH17 has emerged as a desirable ADC target. More than 10 companies showcased CDH17-targeting ADCs, including LepuBiopharma's MRG007, LaNova Medicines' LM-350, and TavotekBiotherapeutics' TAVO307.

Next-Generation ADC Modalities Drive Innovation

Bispecific ADCs: Enhancing Therapeutic Strength and Precision

Out of the ADCs presented, 44 were bispecific ADCs, capable of binding two tumor-associated antigens simultaneously, increasing therapeutic efficacy and reducing resistance. EGFR/c-MET was the most common target combo, with six drugs using this pairing.

Hengrui Pharma unveiled two BsADCs—E-cM-Topi (EGFR/c-MET) and EM-TOPi (EGFR/MUC1)—demonstrating target combination innovation. DLL3 also emerged as a popular target, with multiple DLL3-targeted BsADCs in development since 2024. Four of these disclosed preclinical data at AACR 2025.

Innovent also revealed preclinical data for its BsADCs IBI3022 (TROP-2/B7-H4) and IBI3014 (TROP-2/PD-L1). Notably, InnoCare’s DB-1419 shared first-in-human data, showing tumor inhibition and a favorable safety profile, laying a solid foundation for clinical development.

Dual-Payload ADCs: Overcoming Resistance Barriers

Thirteen dual payload ADCs were reported in preclinical stages, with two entering clinical trials in April. These ADCs often combine a topoisomerase I inhibitor with another mechanism to achieve synergistic effects.

KH815 by Kanghong Pharma, currently the world’s most advanced dual-payload ADC, targets TROP2 and combines a Topo I inhibitor with an RNA polymerase II inhibitor, delivering dual DNA and RNA damage. Its unique structure reduces expression of P-gp and HSP70, overcoming resistance to camptothecins. In preclinical models, it showed nanomolar-level cytotoxicity, outperforming drugs like Trodelvy.

Araris Biotech went a step further by launching a triple-payload ADC using AraLinQ™ conjugation technology, showing synergistic effects against Nectin-4.

JSKN021 and JSKN022 by Alphamab Oncology represent the technological peak of dual-target + dual-payload ADCs. JSKN021 targets EGFR/HER3 with T01 and MMAE as payloads, while JSKN022 targets PD-L1 and ITGB6/8, offering new solutions for patients with immunotherapy resistance.

Non-Internalizing ADCs and TCE-ADCs: Broadening Design and Application Boundaries

At AACR 2025, two novel ADC formats emerged, expanding both the structural design space and potential clinical applications of ADCs: non-internalizing ADCs from Yiling Pharmaceutical and T cell-engaging (TCE) ADCs from Leads Biolabs.

Yiling Pharmaceuticals’ YL242 is a non-internalizing ADC that targets free VEGF in the tumor microenvironment (TME). It uses TME-specific enzymes to release its toxin, combining the cytotoxicity of the payload with the anti-angiogenic effect of VEGF antibodies for the treatment of solid tumors.

Leads Biolabs’ LBL-058 is a DLL3/CD3 bispecific ADC that couples TOP1i with a bispecific antibody bridging CD3 on T cells and tumor-specific antigens. This design synergizes T-cell killing with payload cytotoxicity and may overcome resistance associated with single-target DLL3 therapies.

Combination Therapies: ADCs + Immunotherapy for Dual Action

The combination of ADCs with immunotherapy was another highlight. Research shows that ADCs can not only deliver toxins to kill tumor cells directly but also induce immunogenic cell death (ICD) and release tumor antigens, thereby activating the immune system.

By combining with immune checkpoint inhibitors, T-cell co-stimulatory molecules, or bispecific antibodies, ADCs can reshape the TME, overcoming poor immune responses in “cold tumors”.

• • Hengrui’s SHR-A1811 for HER2-mutant NSCLC showed a 74.5% ORR, 11.5 months median PFS, and an 88.2% 12-month OS rate.

• • Junshi Bio’ JS107 combined with toripalimab and chemotherapy for gastric cancer reached an 81% ORR with good safety.

• • CatalYm demonstrated that visugromab (anti-GDF-15 antibody) enhanced ADC efficacy in ovarian and liver cancer models.

• • Furthermore, technologies like Lepu’s GlycoConnect™ and Borui Biopharmaceutical’s CysX™ improved conjugation site precision and drug-to-antibody ratio (DAR) control, enhancing consistency and reducing off-target toxicity.

Conclusion: A Promising Future for ADCs

The 2025 AACR Meeting marked the transition of ADC technology from isolated breakthroughs to systemic innovation. Dual-target and dual-payload designs are expanding therapeutic strategies, while combination therapies and optimized conjugation are enhancing clinical utility.

Moving forward, continuous innovation, balancing speed with safety, and overcoming technical barriers will be key to shaping the future of ADCs. With more clinical data and breakthroughs, ADCs are poised to revolutionize solid tumor treatment and offer more precise, durable survival hopes for patients worldwide.

References:

[1] https://www.linkedin.com/smart-links/AQEKEQYB3k6iIQ/6387e132-004a-41b0-b74c-3d8aeaf090fe