The following insights are drawn from a World ADC London panel discussion on “What’s the New Path to the Next Generation of ADCs?” featuring Mohit Trikha, Bob Lutz, Ya-Chi Chen and Josh Greally, moderated by Allan Jordan. These drug discovery experts gathered to debate a question determining the future of ADCs: How can these therapies deliver meaningful efficacy while remaining tolerable enough for patients to live with day-to-day?
Plotting a kinder therapeutic destination
When planning a long journey in a navigation app, you enter the final destination first and let the system calculate the best route backward. In antibody-drug conjugate (ADC) development, the field has historically operated in reverse. Developers focus intensely on the immediate scientific step, optimizing the antibody or identifying a stable linker, with the assumption that these technical wins will eventually lead to a better therapeutic endpoint.
At the recent World ADC event in London, a starkly different narrative anchored the panel discussion. The conversation moved beyond platform performance metrics toward a more practical question: Can patients realistically live with these therapies? Addressing the primary bottleneck in ADC development is no longer potency, but tolerability. Every technical element of development must now be engineered backward from the ultimate destination, which is the patient’s daily quality of life.
A “manageable grade 3” adverse event on a clinical trial report often translates to something very different in real life. This physical toll has a very real impact on quality of life, meaning a patient cannot attend a family event, go to work or play with their grandchildren. Mohit Trikha, President and COO at Kivu Bioscience, emphasized that the industry must look beyond just new mechanisms of action and focus heavily on new mechanisms of tolerability. He argued that patients do not care about the underlying biological mechanism of interstitial lung disease or the pharmacokinetic profile of their treatment. Many patients abandon therapy not because their cancer has progressed, but because they are entirely exhausted by the adverse events they live with daily.
"A patient does not care whether they are experiencing neutropenia or interstitial lung disease. What matters to them is dealing with cytopenias, vomiting or diarrhea every day." — Mohit Trikha, President and COO at Kivu Bioscience
This reality exposes a glaring paradox in modern oncology. Bob Lutz, Chief Scientific Officer at Iksuda Therapies, reinforced this observation. He noted that Topoisomerase 1 (Topo1) inhibitors generate considerable enthusiasm within the development community, yet these molecules also rank among the most clinically toxic payloads in approved ADCs and frequently drive patients to halt therapy. Developers relying on a highly limited class of known payloads limit clinical benefit and accelerate cancer resistance. The industry must focus on entirely new mechanisms of tolerability to truly advance patient care.
“The challenge shouldn’t be just something that works, but something that works in a way that is kinder to our patients.” — Dr. Bob Lutz, Chief Scientific Officer, Iksuda Therapies
Rethinking selective payload delivery
The industry has not taken full advantage of cancer biology to design drugs that specifically hit what is wrong with cancer cells. The first generation of ADCs relied on a highly restricted class of payloads, such as microtubule polymerization inhibitors and Topo1 inhibitors. Swapping between these limited payloads offers minimal clinical benefit and inevitably leads to the emergence of tumor resistance.
If patient quality of life is the destination, the method of getting there requires a rethink of ADC architecture. This shift was immediately evident during a live audience poll preceding the panel, where the majority of respondents voted that “more selective payloads” will define the next generation of therapeutics.
This shift in focus corrects a historical imbalance. Allan Jordan, Vice President of Oncology Drug Discovery at Sygnature Discovery, likened traditional ADC design to an online shopping delivery. For years, the industry obsessed over the delivery van (the antibody), ensuring it arrived at the correct address. However, the van is merely the vehicle; it’s the parcel (payload) that matters. The true value and the true risk lie within the parcel.
Rescuing the “fallen angels:” Repurposing failed small molecules
This change in approach opens the door to “fallen angel” payloads, in which developers can leverage the precise targeting of antibodies to rescue small-molecule therapies. These forgotten assets often possess the exact properties needed for a highly effective targeted payload. They typically share several distinct characteristics:
Failure as systemic treatments due to systemic on-target toxicity or poor pharmacokinetic parameters
Lacking the long half-lives and broad tissue penetration required for oral small molecules
Attaching these failed systemic drugs to an antibody delivers them directly to the tumor. This approach bypasses their traditional delivery challenges and avoids the associated toxicities that made these molecules unfeasible.
To build safer therapeutics, developers are moving toward what Jordan and Greally describe as “selectivity squared.” This approach combines the targeting precision of the antibody with a payload that is intrinsically selective for a specific tumor biology, rather than relying on a broad-spectrum cytotoxin. The move away from toxic payloads comes down to a fundamental understanding of the biology and its subsequent application. Future therapeutics must match the targeting selectivity of the antibody with the mechanistic selectivity of the payload.
“The fallen angel payloads, all the forgotten assets that had systemic toxicity or poor tissue penetration, may be positioned beautifully to be ADC payloads.” — Dr. Allan Jordan, Vice President of Oncology Drug Discovery, Sygnature Discovery
Linkers and dual-payload precision
Linker stability is deeply entwined with this delivery. First-generation ADCs suffered from stable linkers associated with interstitial lung disease or unstable linkers that caused toxicity due to premature payload release. Ya-Chi Chen, Chief Scientific Officer at OBI Pharma, noted that current dosing schedules, typically Q2W (every two weeks) or Q3W (every three weeks), are strictly limited by this premature release, as the resulting hematological toxicity requires at least two weeks for the patient’s body to recover.
Developers need to address these structural flaws directly to improve the patient experience. The next generation of therapeutics relies on advanced chemistry to dictate exactly when and where the active drugs take effect. This structural evolution requires innovation across two specific areas of the conjugate.
Controlling payload release
New linker designs aim to control payload release directly within the tumor, extending the payload’s half-life at the specific site of action. Advancements in site-specific conjugation now provide the homogeneous drug-antibody ratio (DAR) required to stabilize these pharmacokinetic profiles. Innovative linker designs also actively modulate the payload’s solubility to prevent aggregation, which is essential for achieving higher DAR.
Overcoming tumor resistance
This precision also extends to dual-payload and bispecific approaches. Bispecific ADCs actively enhance internalization and payload delivery, a strategy that is especially useful for treating tumors with heterogeneous antigen expression. Pairing a Topo1 inhibitor that damages DNA with a second payload that blocks the DNA repair pathway amplifies the therapeutic effect and prevents tumor resistance. Alternatively, combining MMAE with a Topo1 inhibitor allows simultaneous targeting of two distinct checkpoints of the cell cycle.
“If we rely on a single target or a single mechanism of action, the cancer will find a way to adapt. Cancers do this very well. By having a dual payload with multiple mechanisms, that adaptation can be prevented.” — Dr. Ya-Chi Chen, Chief Scientific Officer, OBI Pharma
Engineering fast-clearance therapeutics: “Anti-traditional medicinal chemistry”
Implementing these new components exposes a significant knowledge gap in the pipeline. Repurposing payloads requires a counterintuitive approach to drug design. Josh Greally, ADC Lead at Sygnature Discovery, described this required shift as “almost anti-traditional medicinal chemistry.”
Instead of engineering a small molecule to remain stable in the bloodstream, ADC payloads should be engineered to degrade quickly after detaching from the antibody. At this point, the specific mechanism of action will be executed within the tumor microenvironment and free drug that remains will cause systemic toxicities. Payloads designed with metabolic “soft spots” may be the way to improve patient quality of life when using next-generation ADCs. Medicinal chemists rely on established guidelines, such as Lipinski’s rules, to predict a small molecule’s success. Greally pointed out that no such strict rulebook exists for ADC payloads.
“In small molecule development, we have Lipinski’s rules to give us parameters for what makes a good small molecule therapy. When we look at it from a payload perspective, we don’t have that guideline [...] the way in which those payloads interact is completely different.” — Dr. Josh Greally, ADC Lead, Sygnature Discovery
Developers must interrogate antibody-antigen engagement, internalization, linker cleavage and endosomal escape in depth. When evaluating fallen angel assets for ADC potential, discovery teams should use conjugation feasibility and intracellular trafficking assays to identify the most promising candidates. Otherwise, developers can end up selecting for the wrong attributes while assuming the antibody will solve the delivery problem by default.
Internalization and the DAR debate
The panel challenged two defaults that still shape early ADC decisions. Teams often treat target expression as the main gate, and teams often treat a fixed DAR as the starting point.
Mohit Trikha argued that internalization can be a better predictor of delivery. Fast trafficking can make lower surface copy numbers workable, because payload success depends on what happens after binding and not just how much target is there.
The relationship between DAR and clinical dose is undergoing a similar recalibration. Historically, developers aimed to maximize DAR to deliver as much payload as possible to the tumor. The panel argued that developers must instead ask what is right given delivery mechanics, pointing toward an industry-wide move to the lowest DAR that remains efficacious.
“Developers often go in with a prerequisite DAR, but we need to ask if that is the correct approach based on delivery mechanics.” — Dr. Josh Greally, ADC Lead at Sygnature Discovery
Lowering the DAR yields a cleaner safety profile, which allows clinicians to safely administer a higher overall antibody dose. Commercial dosing levels already show that higher antibody dosing can be feasible, for example, Elahere at about 6 mg/kg and Enhertu at 5.4 mg/kg. Lutz expanded on this by noting that higher antibody doses improve payload delivery to the tumor in a positive, nonlinear way. Better stratification lets teams choose cleaner constructs with fewer avoidable liabilities, and that supports longer time on treatment.
Breaking down silos to engineer kinder, more effective therapeutics
As developers master these rules, the application of ADCs is extending far beyond traditional oncology. There is growing interest in applying ADC technology to immunology and neuroscience, alongside the rise of degrader-antibody conjugates (DACs).
Solving these multifaceted challenges requires dismantling the silos that traditionally separate biologics and medicinal chemistry. Greally observed that the ADC space now acts as the direct interface between these disciplines, bringing antibody engineers and chemists together into cohesive teams.
Rather than relying on isolated breakthroughs, successful next-generation ADCs require a highly integrated approach that treats the payload, linker and antibody as a unified system. Developers can map a new route forward by starting with the patient’s daily reality as the endpoint. This mindset delivers highly selective therapeutics capable of turning cancer into a chronic, manageable disease. Allan Jordan summarized this necessary evolution:
“We can no longer afford to design molecules in a vacuum. The future of oncology requires developers to engineer therapeutics backward from the patient experience to deliver treatments that are both effective and genuinely kind.” — Dr. Allan Jordan, Vice President of Oncology Drug Discovery, Sygnature Discovery
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