At the recently concluded 2025 American Association for Cancer Research (AACR) annual meeting, the development progress of Antibody-Drug Conjugates (ADCs) became a focal point in the global oncology treatment field. As "biological missiles" with both targeting and cytotoxic abilities, ADCs have further unleashed their potential in the treatment of solid tumors. This year's meeting not only continued exploring optimizations for traditional targets but also showcased breakthrough progress in areas like dual-targets, dual payloads, combination therapies, and technological innovations. Notably, Chinese pharmaceutical companies have demonstrated strong R&D vitality.

Target Innovation: From Single Point to Multi-dimensional Precision Breakthrough

CDH17

The rise of CDH17 (Cadherin-17) has opened up new possibilities for gastrointestinal cancer treatment. This target is highly expressed in gastric and colorectal cancers (50%-90%), yet almost "invisible" in normal tissues, making it a hot choice for ADC development.

• LBL-054 (VielaBio): A humanized CDH17 IgG1 monoclonal antibody conjugated with the topoisomerase inhibitor Exatecan through a hydrophilic cleavable linker (DAR=6). Preclinical data showed that LBL-054 is highly stable in plasma and exhibits strong tumor regression ability in xenograft models, with a significant bystander effect, supporting its clinical development.
• HDM2017 (Huadong Medicine): Using a CPT derivative as the toxin, EC50 as low as 0.1-1.0nM, achieving 71-97% and 71-90% tumor growth inhibition (TGI) in colorectal cancer (CRC) and gastric cancer (GC) models respectively. Its efficient internalization (43-75%) and targeted specificity lay the foundation for clinical translation.
• Dual-target ADC VBC108 (Orange Sail Pharma): The world's first CDH17/CLDN18.2 dual-target ADC, which overcomes the treatment bottleneck of gastrointestinal cancers through a synergistic targeting mechanism. Preclinical data shows it can simultaneously activate dual-target pathways, reduce off-target toxicity, and enhance efficacy. It has entered rapid clinical development.
• Other candidate drugs:
  • SCR-A008 (Xian Sheng Pharma): Uses a novel topoisomerase inhibitor CPT116 (DAR=8), showing potential "best treatment drug" characteristics in solid tumor models.
  • YL217 (Yilian Biotech): Developed based on the TMALIN? platform, utilizing tumor microenvironment activation to release toxins, and has FDA IND approval.
  • BSI-721 (Bionovo): MMAE-conjugated ADC, which significantly inhibits tumor growth in low CDH17-expressing pancreatic cancer models, showing broad-spectrum potential.

MSLN (Mesothelin)

MSLN is overexpressed in high-mortality tumors such as ovarian and pancreatic cancer, making it a classic target for ADC development. This meeting presented two differentiated MSLN ADCs:

• PF-08052666 (Pfizer/Nonagene): Uses a novel topoisomerase inhibitor SGD-12280 and high DAR design, overcoming the limitations of traditional DM4 toxins. In ovarian cancer, lung cancer, and colorectal cancer models, its efficacy significantly exceeds the benchmark ADC and can maintain cytotoxicity in the presence of soluble MSLN. It is currently in Phase I clinical trials (NCT06466187).
• RC88 (Rongchang Biotech): Uses Thiel-bridge conjugation technology to combine MMAE with the MSLN antibody, with unique binding kinetics to different regions of MSLN (especially the C-terminal). It has received FDA fast-track status for platinum-resistant ovarian cancer and is undergoing Phase I/II trials (NCT04175847), showing potential in both monotherapy and combination therapy.

PSMA (Prostate-Specific Membrane Antigen)

PSMA is a core target for prostate cancer treatment. GenSci143, developed by Kinase Pharmaceuticals, is a dual-target ADC that simultaneously targets B7-H3 and PSMA. In metastatic castration-resistant prostate cancer (mCRPC) models, it showed superior efficacy compared to DS-7300 and ARX517, with significantly enhanced plasma stability. Pharmacokinetic data from crab-eating monkeys support its clinical translation potential.

Technological Leap: Synergistic Effects of Dual Payloads and Dual Targets

The rise of dual payload ADCs was a major highlight at this year's meeting. KH815 by Kanghong Pharmaceutical, as the first dual-payload ADC to enter clinical trials, targets TROP-2 and combines topoisomerase inhibitors with RNA polymerase 2 inhibitors, achieving synergistic cytotoxicity through carboxyl and glycoside conjugation techniques. Preclinical data showed a high dose tolerance of up to 40mg/kg/dose, potentially providing new options for TROP-2 positive tumors.

Araris Biotech has further broken through by launching a three-payload ADC, utilizing de-glycosylated IgG combined with transglutaminase technology (AraLinQ?), showing multi-toxin synergistic effects when targeting Nectin-4, overcoming the sensitivity limitations of traditional ADCs. Corning Jerry's JSKN021 and JSKN022 represent the technical peak of dual-target, dual-payload ADCs:

• JSKN021 targets EGFR/HER3 and precisely conjugates topoisomerase I inhibitor T01 and microtubule inhibitor MMAE using glycosylation-specific conjugation techniques, showing significantly better efficacy in various tumor models compared to single-payload ADCs.
• JSKN022 integrates PD-L1 with ITGB6/8 dual targets, utilizing the immune modulation mechanism of Envafolimab, providing a new solution for PD-1/PD-L1 resistant patients.

Dual-Antibody ADC Development

R&D in dual-antibody ADCs is also diversified. Yilian Biotech's dual-toxin platform combines topoisomerase 1 inhibitors and microtubule inhibitors, aiming to overcome resistance through multi-mechanism synergy. Orange Sail Pharma's CDH17/CLDN18.2 dual-antibody ADC improves tumor cell recognition accuracy by targeting antigens with complementary spatial distributions. Their Nectin4/TROP2 dual-antibody ADC was previously selected as an AACR Late-Breaking Abstract, showcasing the foresight of the strategy.

Clinical Translation: Is Monotherapy or Combination More Advantageous?

Sheng Rui Pharmaceutical's SHR-A1811 for HER2-mutant non-small cell lung cancer (NSCLC) showed Phase II data with an ORR of 74.5%, a median PFS of 11.5 months, and a 12-month OS rate of 88.2%, making it a potential first-line treatment for this indication. Junshi Biosciences' JS107 (CLDN18.2 ADC), in combination with Toripalimab and chemotherapy, achieved an ORR of 81%, marking the first clinical benefit of CLDN18.2 ADC combined with immunotherapy and showing controllable safety. Additionally, the monotherapy of JS107 for CLDN18.2 high-expressing gastric cancer showed an ORR of 34.8% and a median PFS of 4.11 months, demonstrating its potential in different treatment scenarios.

Innovation in combination strategies goes beyond drug combinations. CatalYm's research shows that GDF-15 neutralizing antibody Visugromab can reverse tumor microenvironment immune suppression, enhancing ADC efficacy. The synergistic effect was verified in ovarian cancer and liver cancer models. Lepu Biotech's GlycoConnect? and Borui Biotech's CysX? technologies optimize conjugation sites and DAR values, enhancing ADC homogeneity and stability, reducing off-target toxicity.

Future Challenges: How to Break Through Technical Bottlenecks?

Chinese pharmaceutical companies' performance at this year's AACR was remarkable: 46 out of 97 ADCs in development worldwide are from Chinese enterprises, with global leadership in target layout density for CDH17, CLDN18.2, and others. However, hidden concerns lurk behind this prosperity: 8 out of the 11 CDH17 ADCs adopt similar Exatecan toxin + cleavable linker designs, with a clear lack of differentiated innovation. While dual-target ADCs from Orange Sail Pharma and dual-payload technologies from Corning Jerry are refreshing, clinical translation still faces three major challenges: stability of manufacturing processes, controllability of toxic side effects, and cost-effectiveness in commercialization.

In the global competition, Lepu Biotech's GlycoConnect technology achieves uniform conjugation through glycosylation sites, controlling batch-to-batch differences within 5%. Borui Biotech's CysX technology optimizes the DAR value with inter-chain disulfide bonds, improving toxin release accuracy by 40%. But will these technological breakthroughs translate into clinical advantages? As giants like Pfizer and AstraZeneca accelerate their dual-antibody ADC developments, can Chinese companies' technical reserves keep up with the next round of positioning wars?

Conclusion

The 2025 AACR conference marks a leap in the ADC field, from single-target breakthroughs to systematic innovation. Dual-target and dual-payload designs expand treatment dimensions, and combination strategies and technological innovations enhance clinical benefits. Chinese pharmaceutical companies, with localized target selection and differentiated technological platforms, are gradually transitioning from participants to rule-makers. However, how to maintain continuous innovation ability and balance R&D speed with safety in the fierce competition will be the core issue in the next stage. With more clinical data accumulation and technological barriers being overcome, ADCs are expected to reshape the treatment landscape of solid tumors and provide more precise and lasting survival hopes for global patients.