ADC Trends

The ADC field has clearly moved from single-antibody, single-cytotoxin design into a "platform proliferation" phase.

Payload Diversification Beyond Cytotoxics

Topoisomerase I inhibitors (the DXd/exatecan class) have overtaken microtubule inhibitors as the dominant next-generation payload, since they allow higher, more stable DAR and strong bystander effect while using moderately (rather than extremely) potent chemistry. Beyond classic cytotoxics, entirely new payload categories are emerging preclinically:

• Immunostimulatory ADCs (ISACs): STING and TLR7/8/9 agonist payloads that activate anti-tumor immunity rather than killing cells directly.

• Degrader-antibody conjugates (DACs): PROTAC- and LYTAC-based payloads for targeted protein degradation — though this modality saw notable 2025 setbacks (ORM-5029 and ABBV-787 discontinued) even as abstract volume grew sharply at AACR 2026.

• Novel mechanistic classes: RNA polymerase II inhibitors (α-amanitin), NAMPT inhibitors, translation inhibitors (omacetaxine), pan-RAS inhibitors, and CHK inhibitors were all newly disclosed at AACR 2026.

• Radionuclides and photosensitizers: for radioimmunotherapy and photoimmunotherapy applications.

Structural Innovation: Bispecific and Multi-Payload Constructs

Bispecific ADCs (BsADCs) are one of the fastest-growing formats, with roughly 211 candidates in development (about 14% of the active ADC pipeline) as of mid-2026, and four candidates (izalontamab brengitecan, JSKN-003, TQB-2102, maridebart cafraglitide) already in Phase III. The rationale is "selectivity squared" — dual-antigen recognition improves tumor selectivity and internalization while reducing antigen-loss resistance. Dual-payload ADCs are growing even faster in relative terms, combining two mechanistically distinct payloads (e.g., topoisomerase inhibitor + MMAE, or exatecan + RNA Pol II inhibitor) in a single construct to hit multiple resistance pathways simultaneously — programs like KH815 and IBI3020 have already reached Phase I.

Linker and DAR Engineering Trends

Hydrophilic linker chemistry (PEG, polysarcosine, phosphoramidate self-immolative platforms) continues to be the key enabler allowing higher, more stable DAR without aggregation — one 2026 phosphoramidate linker platform achieved a highly hydrophilic DAR 8 SN-38 ADC with improved pharmacokinetics over more hydrophobic variants. Interestingly, the field is also exploring the opposite direction: low-DAR, high-potency payload designs (DAR of 2 in some newer programs) as an alternative route to widen the therapeutic window. Traceless cleavable linkers optimized specifically for bystander effect are another active design focus for solid tumors with heterogeneous antigen expression.

Target Expansion and Tumor Microenvironment Modulation

Target selection is broadening well beyond HER2 and CD30 toward TROP2, Nectin-4, B7-H3, CLDN18.2, HER3, CEACAM5, and Claudin targets, alongside novel bispecific target pairs like EGFR×HER3, HER2×HER3, and DLL3×B7-H3. A newer conceptual trend uses ADCs to reprogram the tumor microenvironment rather than just kill tumor cells directly — for example, CCR8-targeting ADCs carrying amanitin payloads that selectively deplete intratumoral regulatory T cells (Tregs) to improve the CD8+/Treg ratio, and phosphonate-based ADCs that activate Vγ9Vδ2 T cells for immune-mediated tumor lysis.

Geographic and Data-Driven Shifts

China has become a major driver of next-generation ADC innovation, now accounting for more than half of global next-generation ADC assets and closing the patent-filing gap with the U.S., while Japan is forecast to potentially surpass the U.S. in new ADC patent publications in 2026. Looking further ahead, reviews describe an emerging "fourth generation" of ADC design defined by mandatory AI/computational integration for multi-parameter developability prediction, routine use of PBPK/QSP modeling to simulate human translational behavior before Phase I, and a shift toward non-cytotoxic, immune-integrated payload strategies.

Summary Table