Rethinking ADC Payloads From Cytotoxics to Targeted Small Molecules

By: Dr. Allan Jordan, VP of Oncology Drug Discovery, Sygnature Discovery and Dr. Josh Greally, Scientific Business Development Manager and ADC Lead, Sygnature Discovery

The antibody-drug conjugate (ADC) field has endeavored to overcome the challenge of payload cytotoxicity, utilizing the ADC modality to deliver highly potent molecules to tumour sites while aiming to achieve remarkable efficiency and limited toxicity. Yet, clinical success rates remain constrained by the bottleneck of chronic cumulative, dose-limiting toxicity.

Many patients abandon ADC therapies not because their cancer progresses, but because they cannot tolerate the associated toxicities. Across several approved therapies, adverse events force between 15% and 20% of patients, or over 50% in some cohorts, to abandon treatment early.¹ This highlights that aiming for tolerability does not always result in liveability. For a patient enduring recurrent cytopenias, ocular toxicity or severe gastrointestinal distress, the value of a targeted therapy matters little if the treatment still erodes day-to-day quality of life.

This reality exposes a glaring vulnerability in current development pipelines: the industry relies heavily on a restricted pool of established cytotoxic classes. Topoisomerase I (Topo1) inhibitors clearly illustrate this problem. Although these payloads dominate clinical portfolios and drive massive commercial excitement, they also rank among the most toxic approved agents, routinely causing severe dose-limiting adverse events like neutropenia and interstitial lung disease.² When developers rotate this same limited payload class across different targets, it offers diminishing clinical returns. It forces patients to endure identical systemic consequences even when their disease biology suggests a different intervention.

As a result, the current payload discussion is now moving beyond the question of whether a warhead is potent enough in isolation to whether small molecules can be designed or adapted for conjugation in ways that improve both efficacy and tolerability. The next major leap in ADC performance requires a fundamental shift in how the industry selects and engineers the active drug, reducing reliance on generic cytotoxics and committing to rationally designing targeted small molecules specifically for conjugation.

Why the Parcel Matters as Much as the Delivery Vehicle

The historical bias in ADC development overwhelmingly favors the targeting antibody. Developers treated the therapeutic complex like a highly engineered delivery van. They spent decades optimizing the biological vehicle to ensure it arrived at the exact correct address on the tumor cell surface. This focus on the delivery mechanism has often left the payload as a secondary concern. The industry operated on the assumption that as long as the biological vehicle reached its destination, any highly potent cytotoxic agent packed inside would automatically secure a clinical response.

“The antibody is just the delivery van. It is the thing that delivers the payload to the tumour. The true value, and the true opportunity, lies in the parcel inside.”
— Dr. Allan Jordan, VP of Oncology Drug Discovery, Sygnature Discovery

Although the antibody comprises the vast majority of the construct’s molecular weight, relatively small changes in linker placement, conjugation chemistry and payload architecture can materially alter the behavior of the whole ADC. Those changes can influence hydrophilicity, stability and overall developability. They can also affect the drug-antibody ratio in ways that shape tissue permeability and cell uptake, which means payload design cannot be treated just as a late-stage addition to an otherwise defined antibody strategy.

This matters because antibody precision alone does not neutralize the liabilities of a broadly toxic payload. It changes where exposure begins, but it does not fully determine what happens after payload release or the occurrence of premature leakage into circulation. A more credible route beyond legacy cytotoxics is to move the payload strategy much closer to the center of ADC design and judge it as part of an integrated system rather than as a secondary component.

What Selectivity Squared Really Means

Most traditional payloads kill any dividing cell they enter, but building selectivity into both the payload and the antibody of the ADC provides an alternative solution. This dual-specificity approach, which we colloquially call “selectivity squared,” is where the antibody provides one layer of selectivity through targeted delivery, while the payload provides a second layer through its own biological preference for a disease-relevant pathway.

That second layer matters because antibody selectivity does not fully determine what happens once the payload is released. If the released species still carries broad systemic toxicity, better targeting may narrow exposure without fully changing the underlying tolerability problem. By contrast, a payload aimed at a specific disease mechanism offers a more coherent way to widen the therapeutic window, as the prematurely released payload remains largely inert unless the healthy cell also possesses the exact aberrant signalling pathway or genetic vulnerability the small molecule requires to act.

“We must match the targeting selectivity of the antibody with the mechanistic and biological selectivity of the payload.”
— Dr. Josh Greally, ADC Lead, Sygnature Discovery

That does not make selectivity automatic, nor does it mean every targeted mechanism will translate cleanly in an ADC format. Aligning antigen biology with payload biology gives teams a better chance of separating tumor effect from systemic burden. This is why the next phase of ADC differentiation is likely to depend less on reusing familiar warheads and more on building target-payload logic into the design from the outset. Developers can harness this dual specificity to attack complex heterogeneous tumors with an improved safety profile. This may allow clinicians to escalate administered doses to ensure adequate tumor penetration, potentially avoiding the dose-limiting systemic toxicities associated with conventional agents.

Bringing Fallen Angel Compounds a Second Life

The shift toward targeted payloads provides an exciting opportunity for drug developers to rescue abandoned assets. Biopharma archives hold thousands of highly effective small molecules that demonstrated excellent target engagement in early development but failed to progress in the clinic as standalone therapies. These “fallen angel” compounds were often shelved because they could not survive the demands of systemic administration.

In some cases, the problem was never the mechanism itself, but the exposure pattern needed to make a free small molecule work. Antibody delivery changes that equation by altering where exposure begins and how the active species reaches tumor tissue. In that setting, a molecule may still be unsuitable as a standalone therapy while remaining entirely rational as a conjugated payload.

A fallen angel is worth revisiting only when transformation into an ADC addresses the right part of the failure profile. The point is not to rescue discarded compounds for their own sake, but to ask whether antibody delivery can make a previously unworkable profile newly tractable by localizing activity and reducing the liabilities that limited free-drug use.

The Rules of Anti-Traditional Medicinal Chemistry

Traditional drug discovery relies on established frameworks like Lipinski’s rule of five to ensure small molecules survive systemic circulation. Chemists routinely spend years optimizing compounds to resist metabolic degradation, avoid rapid clearance and maintain therapeutic blood levels. Designing a targeted small molecule for an ADC requires the exact opposite approach, forcing developers to practice “anti-traditional medicinal chemistry,” where an effective payload must inherently fail as a standalone systemic drug.

If a highly potent payload detaches from its linker in peripheral blood, it immediately poses a toxicity risk to healthy tissue. To mitigate this danger, chemists must engineer metabolic soft spots directly into the molecular structure of the active agent. These intentional vulnerabilities promote rapid degradation the moment the free drug encounters plasma enzymes or hepatic clearance mechanisms. The large molecule delivery vector acts as a protective shield during transit, rendering the circulatory stability of the free small molecule largely unnecessary and potentially dangerous. The antibody provides the long half-life required for tumor localization, while the payload requires an exceptionally short systemic half-life.

High systemic clearance transforms a premature release event from a clinical emergency into a silent biological exhaust pathway. When a targeted payload carrying engineered soft spots leaks into circulation, the body breaks it down and excretes the inactive metabolites before they can engage off-target receptors. Engineered instability confines the active drug’s half-life almost exclusively to the intracellular environment of the tumor cell.

Where Chemistry Becomes Make-Or-Break

The process of attaching a linker to a highly optimized small molecule fundamentally alters its chemical identity. Repurposing a fallen angel payload requires significant synthetic expertise because the parent molecule was rarely intended for conjugation. It is also unlikely to have been developed with the intention of encompassing the molecular properties required for use as an ADC payload.

The requirement for chemical precision extends to emerging dual-payload strategies. Conjugating two distinct mechanisms of action to a single antibody - such as combining a Topo1 inhibitor with a DNA repair blocker - offers a compelling, additive approach to overcoming tumor resistance. However, it further increases the chemical complexity by demanding a precise balance of the stoichiometry, release kinetics and aggregation risks of two entirely different small molecules within one biologic. By integrating these chemical considerations with the overarching biological strategy early in development, teams can effectively minimize downstream translational risk and prevent unforced errors in the clinic.

How Linker Analysis and Payload Validation Answer Key Development Questions

Evaluating a targeted small molecule for conjugation demands a thorough reassessment of the screening cascade. Rigorous, highly specific screening cascades are necessary to validate the mechanistic viability of a novel concept long before initiating in vivo studies.

The testing sequence needs to mirror the physical journey of the conjugate. Feasibility is confirmed first, ensuring the novel chemical entity can be conjugated to the antibody without aggregating or losing target affinity. Assessment then shifts focus to cellular mechanics, using techniques such as live-cell imaging and pH-sensitive assays to map receptor internalization dynamics that support intracellular payload delivery and verify that the complex reaches the correct lysosomal or endosomal compartment.

Confirming conjugation feasibility and epitope binding data alone cannot determine whether the payload will release efficiently once internalized. Release from the linker and lysosomal escape dictate the final therapeutic outcome, requiring liquid chromatography-mass spectrometry (LC-MS) readouts to investigate linker cleavage kinetics. The active species relies on successfully exiting the vesicle to reach its intended intracellular target. These analytical methods add the most value when they answer defined pharmacokinetic (PK) and development questions: Does the chosen linker selectively release the payload where needed, and remain stable where not? Does the linker cleave at the intended physiological pH? Does the active species successfully escape the endosome to reach the intracellular target?

Why the Next Payload Shift Is an Interdisciplinary One

The structural complexity of next-generation ADCs demands a new operational model. Historically, biologics teams and small molecule chemists operated in isolated silos. That fragmented approach hinders the development of targeted therapeutics like ADC payloads because the optimization of the active drug and the linker - the elements that differentiate an ADC from a standard antibody - are fundamentally small molecule challenges, but the mechanistic understanding of those changes is a biological one.

Success requires integrating deep medicinal chemistry expertise directly into the biological design process from the earliest stages of ADC discovery. The practical solution lies in implementing continuous Design-Make-Test-Analyze (DMTA) cycles tailored specifically for payload, linker and conjugation optimization. This borderless workflow accelerates drug discovery by evaluating physical feasibility, intracellular trafficking, linker cleavage kinetics and payload release in a continuous loop. Iterative testing allows teams to balance raw potency against systemic stability and overall developability long before initiating expensive in vivo studies.

Moving the industry beyond traditional cytotoxics relies heavily on this interdisciplinary integration. Eradicating the current clinical tolerability bottleneck requires developers to treat the payload as an engineered, selectively active component rather than a generic cytotoxic agent. By bridging the gap between large and small molecule sciences, the ADC field can move toward a future where targeted therapeutics offer unprecedented precision, delivering treatments that patients can safely tolerate every day.

References

1. Nguyen, T. D., Bordeau, B. M., & Balthasar, J. P. (2023). Mechanisms of ADC Toxicity and Strategies to Increase ADC Tolerability. Cancers, 15(3), 713. https://doi.org/10.3390/cancers15030713
2. Fu, Zheng, et al. “Antibody drug conjugate: The biological missile for targeted cancer therapy.” Signal Transduction and Targeted Therapy. Vol.7 (2022): 93. Web.

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