Why ADC Developers Are Exploring New Payloads Beyond Topoisomerase I and Tubulin

Why Is the ADC Industry Seeking Greater Payload Diversity?

Tubulin-disrupting payloads helped establish the clinical viability of ADCs, while topoisomerase I inhibitors have supported a more recent wave of successful development. Both classes remain scientifically and clinically important. Their continued use reflects validated mechanisms, extensive medicinal chemistry experience, and an increasingly sophisticated understanding of how they interact with antibodies, linkers, conjugation methods, and tumor biology.

However, concentration around a limited number of mechanisms creates strategic and biological challenges. Programs aimed at similar targets and indications may struggle to demonstrate meaningful differentiation if they also use closely related payloads. More importantly, tumors can develop resistance at multiple stages of the ADC mechanism, including through changes in antigen expression, internalisation and trafficking, lysosomal processing, drug efflux, payload sensitivity, DNA-damage responses and apoptotic signalling.

Tumor heterogeneity adds another layer of complexity. Antigen abundance, payload sensitivity, proliferative state, and resistance mechanisms can vary within one tumor and between patients. A payload selected largely for potency may therefore be poorly matched to the biological vulnerabilities of the intended indication.

This does not mean replacing established payloads by default. Optimised linker stability and release kinetics, hydrophilicity, site-specific conjugation, drug-to-antibody ratio and bystander activity may improve the performance of established payload mechanisms.. The case for novelty becomes stronger when those engineering improvements cannot overcome a defined biological limitation or provide sufficient clinical differentiation.

Why Is Balancing Payload Potency and Toxicity So Difficult?

An ADC must deliver sufficient active payload to tumour cells despite the relatively limited amount of drug that can be administered systemically. . The payload must therefore produce meaningful activity at low intracellular concentrations, but extreme potency does not automatically create a useful therapy. Payload released prematurely, distributed outside the tumor, or retained in sensitive healthy tissue can narrow the therapeutic window.

Performance depends on more than the payload’s biochemical potency. Molecular size, charge, hydrophobicity, solubility, membrane permeability, susceptibility to efflux, metabolic stability, and the location of release can all affect exposure. The linker must remain sufficiently stable in circulation while releasing an active payload in the intended environment. Drug-to-antibody ratio and conjugation method can influence homogeneity, aggregation, clearance, pharmacokinetics, and the quantity of payload delivered.

The difficulty is compounded by translation. Cell-line potency may not represent activity in heterogeneous human tumors, while xenograft responses may not expose clinically relevant immune, metabolic, or toxicity effects. Species differences can also limit the predictive value of toxicology models.

Payload development consequently requires a system-level assessment. The objective is not to maximize potency in isolation, but to achieve enough tumor-selective exposure, release, and activity to produce durable efficacy at a tolerable dose.

Which Novel ADC Payload Mechanisms Are Emerging?

Several emerging approaches seek to extend ADC activity beyond conventional mitotic disruption or direct DNA damage. Their value will depend on whether targeted delivery can unlock biology that is difficult to exploit with a systemically administered small molecule.

Degrader-antibody conjugates deliver targeted protein degraders or molecular glues rather than conventional cytotoxic agents. The approach combines antibody targeting with selective degradation of a disease-relevant protein inside the cell. The approach could expand the range of addressable biology while potentially improving the exposure profile of degraders whose physicochemical properties limit conventional systemic delivery. However, productive intracellular release, cytosolic access, target engagement, E3-ligase biology, and suitable pharmacodynamic biomarkers remain important development questions.

N-myristoyltransferase inhibitors target protein myristoylation, a lipid modification involved in the localization and function of numerous proteins. Preclinical ADC research has reported tumor regression with targeted NMT inhibitor delivery across multiple xenograft models. This approach has attracted significant industry attention, including Novartis' agreement to acquire Myricx Bio and its NMT inhibitor ADC platform. However, the clinical therapeutic window, biomarker strategy and resistance biology remain to be established.

RNA splicing modulators disrupt spliceosome function and may affect multiple survival pathways simultaneously. This could provide differentiated biology and potential activity against difficult-to-treat tumors. However, evidence remains preclinical, and the safety, dose response, and clinical selectivity of these payloads have yet to be established in patients.

Immunostimulatory antibody conjugates (ISACs)aim to deliver immune agonists such as STING or Toll-like receptor agonists to the tumour microenvironment, with the goal of activating antitumour immunity rather than relying solely on direct tumour-cell killing. The central challenge is achieving sufficient local immune activation while limiting systemic inflammatory toxicity.

Payload approach	Mechanistic rationale	Potential advantage	Main development challenge	Evidence type as of August 2026
Targeted Protein Degraders and molecular-glue conjugates	Removes a selected disease-driving protein	Adds a second layer of molecular selectivity	Cytosolic delivery, target engagement, and design complexity	Published proof of concept and early clinical development
NMT inhibitor payload	Disrupts protein myristoylation and associated oncogenic functions	Provides a differentiated cytotoxic mechanism	Human therapeutic window and biomarker strategy	Preclinical ADC models
RNA splicing modulator	Disrupts spliceosome-dependent survival pathways	May provide activity across multiple resistance pathways	Clinical selectivity and tolerability	IND-enabling and preclinical development
Immuneostimulatory antibody conjugates	Activates innate or adaptive antitumor immunity	May generate activity beyond direct cytotoxicity	Local control of immune activation	Predominantly preclinical and translational evidence

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Can Dual-Payload ADCs Address Resistance and Tumor Heterogeneity?

A dual-payload ADC carries two therapeutic agents on the same antibody. Its rationale is to deliver complementary mechanisms to the same tumor environment, potentially broadening activity across heterogeneous cell populations or reducing the probability that resistance to one mechanism will eliminate the treatment effect.

The concept is compelling, but the combination must be biologically justified. Two payloads should address defined and preferably nonredundant vulnerabilities. Developers must determine whether the mechanisms are additive, synergistic, sequential, or simply competing for limited delivery capacity. Potency matching is particularly important because one payload can dominate activity at concentrations where the second contributes little.

Payload ratio, total drug-to-antibody ratio, linker chemistry, release kinetics, membrane permeability, and intracellular localization must also be coordinated. Raising the total payload load can alter hydrophobicity, stability, pharmacokinetics, aggregation, and manufacturability. Separately optimized release may be necessary if the two mechanisms require different intracellular timing or compartments.

Preclinical studies have reported enhanced antitumour activity for several dual-payload designs, including combinations intended to address tumour heterogeneity, payload resistance or DNA-damage response mechanisms. More recently, dual-payload ADCs have begun entering clinical development, including constructs combining a topoisomerase I inhibitor with an ATR inhibitor.

These findings provide a mechanistic rationale for combining payloads, but preclinical results do not establish universal clinical benefit. Dual-payload ADCs have started moving into oncology clinical trials, while many programs remain at the preclinical stage.

Clinical success will depend on demonstrating that improved depth or durability of response outweighs overlapping toxicity, analytical complexity, manufacturing burden, and development cost.

What Will Determine the Clinical Success of Next-Generation ADC Payloads?

A viable payload strategy must pass five connected development gates:

• Biological rationale: Is the mechanism relevant to the indication, tumor state, and expected resistance landscape?
• Mechanistic differentiation: Does it address a limitation that established payloads or better ADC engineering cannot adequately solve?
• Therapeutic window: Can sufficient active payload reach the tumor without creating unacceptable systemic or on-target toxicity?
• Translational strategy: Are there relevant models, biomarkers, pharmacodynamic measurements, and exposure-response relationships that can inform human dose selection and development decisions?
• Developability: Can the payload-linker system be synthesized, conjugated, characterized, manufactured, stored, and scaled reproducibly?

This framework helps prevent potency from becoming the sole proxy for payload quality.

No single function can answer all five questions. Chemistry and medicinal chemistry must work with biology, engineering, pharmacology, toxicology, translational science, manufacturing, and clinical development. A novel mechanism that performs exceptionally in a cell assay may still fail because it cannot be released effectively, tolerated at an active exposure, translated through suitable models, or manufactured consistently.

Moving Payload Innovation Toward Clinical Impact

Greater payload diversity is being explored because resistance, tumor heterogeneity, safety limitations, and pipeline competition cannot always be resolved through target selection alone. Established topoisomerase I and tubulin payloads will remain important, particularly where smarter linker, conjugation, and antibody design can improve their performance.

Novel mechanisms and dual-payload ADCs create additional options, but novelty is not evidence of clinical value. Success will depend on biological rationale, therapeutic window, translational predictability, and developability, supported by coordinated decisions across scientific and development functions.

Explore the Future of ADC Payload Development

The 3rd ADC Payload Summit is the only industry-focused summit dedicated specifically to ADC payload discovery and development. Join leaders across payload chemistry, medicinal chemistry, biology, engineering, translational science, toxicology, and ADC R&D to evaluate novel mechanisms, dual-payload strategies, resistance, therapeutic-window optimization, and clinical translation.

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