Author: Valentina Fiori

The global biopharmaceutical community recently convened at the 16th World ADC London, confirming the event as Europe’s premier forum for Antibody-Drug Conjugate (ADC) innovation.

From early-stage discovery to complex commercialization strategies, researchers, industry leaders and regulators gathered with a singular, driving goal: navigating a critical transition into the next era of ADCs.

The dawn of the next-generation ADC market

The global ADC landscape is expanding at an unprecedented rate. By early 2026, the industry celebrated a milestone of 19 formally approved ADCs across major regulatory agencies (FDA, EMA, NMPA).

While traditional oncology ADCs are seeing a striking 28.8% year-over-year growth, the real buzz surrounds next-generation formats. Candidates with multi-specific properties are currently seeing rapid expansion, with an exponential compound annual growth rate (CAGR) of approximately 65%.

To overcome current clinical limitations, the clinical community is moving towards “Next-Gen” architectures. This involves adopting dual-payload constructs, bispecific molecules and non-cytotoxic payloads – such as immunomodulators and targeted enzymes – alongside advanced manufacturing technologies.

Outsmarting tumor resistance

Target antigen biology and acquired molecular resistance – such as HER2 receptor downregulation – remain primary hurdles to clinical success. To counter tumor heterogeneity and robust defense mechanisms, developers are heavily investing in novel payload strategies:

  • Dual-Payload ADCs: By integrating two drugs with synergistic mechanisms (e.g., TOP-1 inhibitors paired with tubulin or PARP inhibitors), therapies can strike tumors from multiple angles. Proprietary platforms for dual-payload assembly took center stage, showcasing advanced linker technologies that allow for the stable, simultaneous attachment of two distinct therapeutic agents.
  • Bispecific and Biparatopic Constructs: Innovation extends to the antibody backbone itself. Biparatopic ADCs are designed to bind two distinct sites on the same antigen, while bispecific ADCs simultaneously target two different receptors, effectively cutting off the tumor’s biological escape routes and increasing tumor specificity.

Beyond traditional cytotoxics: PROTACs, ISACs, and new frontiers

The urgent need for novel mechanisms of action is driving the exploration of unconventional payloads:

  • Degrader Antibody Conjugates (DACs): PROTAC payloads hijack the cell’s natural proteasome system to completely degrade target proteins. Emerging technologies, such as single-domain “shuttles,” now allow these degraders to be transported without the need for complex chemical linkers.
  • Immunostimulating Antibody Conjugates (ISACs): By utilizing TLR and STING agonists, the goal is to transform immunologically “cold” tumors into “hot” ones. Interestingly, for TLR payloads, non-cleavable linkers have proven superior, as the target receptor resides within the exact endolysosomal compartment where the ADC naturally degrades.
  • Novel Toxins and AOCs: Alongside RNA polymerase II inhibitors (like Amanitin, which targets even dormant cells), there is growing interest in Antibody-Oligonucleotide Conjugates (AOCs) for rare genetic diseases. These therapies utilize oligonucleotide payloads to treat severe, rare genetic disorders like muscular dystrophy. The massive hurdle here is “endosomal escape”: currently, less than 1% of the delivered oligonucleotide manages to escape the endosome to reach the cytoplasm.

Redefining conjugation: precision and stability

Chemical instability in historical linker designs often led to the premature release of free payloads into the bloodstream, triggering severe, chemotherapy-like toxicities (such as neutropenia).

To solve this, the field is rapidly abandoning stochastic methods in favor of site-specific conjugation. This shift is essential for producing homogeneous ADCs with a highly standardized drug-to-antibody ratio (DAR).

The workshops marked the entry into a “third generation” of conjugation technologies, which goes beyond the enzymatic methods and engineered cysteines of the second generation. Standout innovations include glycan remodeling, the use of affinity peptides, and “disulfide re-bridging” strategies.

In this latter area, advanced molecules such as pyridazinediones (PDs) not only allow for the stable reconnection of the antibody’s disulfide bonds but also offer an integrated architecture ideal for the simultaneous attachment of dual payloads.

Navigating the analytical and toxicological maze

Despite immense progress, pharmacokinetic realities remain stark: experts noted that a mere fraction – roughly 0.01% – of an injected ADC actually reaches the target tumor tissue. The vast majority is catabolized by healthy tissues, leading to recurrent, dose-limiting toxicities (such as ocular corneal microcysts) that are driven more by the payload than the targeted antigen.

  • Predictive AI: To mitigate these risks, developers are turning to computational modeling. Showcases demonstrated how Model-Informed Drug Development (MIDD) and QSP modeling are helping predict clinical exposure, toxicity, and optimal DAR during preclinical phases, drastically cutting down strategic timelines.
  • Potency Testing: Accurately measuring ADC potency remains complex, requiring separate, rigorous evaluations of antibody binding, lysosomal linker degradation, and payload diffusion.

 

Valentina Fiori holds a PhD in Biochemical and Pharmacological Sciences, and is Biologics R&D Manager at Diatheva, where she leads the development of therapeutic recombinant monoclonal antibodies targeting oncology and infectious diseases. She combines scientific strategy with industrial collaboration, managing complex R&D programs that bridge academic innovation and biopharmaceutical application.