Our Learnings from World ADC London: Designing the Next Generation of Smarter, Safer ADCs

At this year’s World ADC London, Sygnature Discovery hosted a panel discussion exploring a topic that continues to reshape oncology drug development: what will define the next generation of antibody–drug conjugates (ADCs)?

The conversation brought together voices from across the ADC ecosystem, including:

• Dr. Allan Jordan (Moderator), Vice President, Oncology Drug Discovery, Sygnature Discovery
• Dr. Josh Greally, ADC lead and Scientific Business development manager, Sygnature Discovery
• Dr. Mohit Trikha, President & COO, Kivu Bioscience
• Dr. Bob Lutz, Chief Scientific Officer, Iksuda Therapies
• Dr. Ya‑Chi Chen, Chief Scientific Officer, OBI Pharma

Before the discussion began, we ran a live poll to get a real‑time pulse from the room.

From 46 respondents, the top areas believed to define next‑generation ADCs were:

• More selective payloads
• Linker chemistry and stability
• Conjugation strategies
• Bispecific approaches

These priorities shaped what became an insightful, technical, and refreshingly honest discussion. Below, we share our key learnings, combining Sygnature’s perspective with expert viewpoints from our panel.

Tolerability is becoming the critical differentiator in ADC development

One of the strongest themes from the panel was the growing importance of tolerability. Potency isn’t the bottleneck anymore; chronic toxicity often is. But the panel also noted that we have new ways to overcome these challenges. As Allan Jordan noted:

“We talk of selectivity squared… having the selectivity of the antibody but also the selectivity of the payload and moving away from those toxic payloads. I think a lot of this comes down to a fundamental understanding of the biology.”

Mohit Trikha reinforced this transformation, from the day-to-day patient perspective:

“A patient doesn’t really care whether they’re having neutropenia or interstitial lung disease. What matters to them is, hey, I’ve got to deal with cytopenias… I don’t know what ocular tox is. Patients are worried about the GI tox, vomiting or diarrhoea.”

This points to a clear opportunity: ADCs will win when their efficacy more significantly outweigh the dose limiting factors, enabling a netter therapeutics wind and more consistent dosing for patients.

Explore how medicinal chemistry influences modern ADC design in our blog: https://www.sygnaturediscovery.com/blog/evolving-role-of-med-chem-in-adc-development/.

Linkers and conjugation chemistry are now strategic design levers

Our panelists agreed that linker and conjugation innovations will help shape the next evolution of ADC performance toward these goals.

Ya‑Chi Chen summarized it well:

“The first generation (of ADCs) had stable linkers, which may have been associated with toxicity, or unstable linkers, which caused toxicity due to premature release of the payload.”

For Sygnature, this resonates strongly with what our integrated ADC discovery team observes in client programs: site‑specific conjugation, tumor‑responsive linkers, and solubility‑tuned ADCs consistently produce more predictable PK/PD behavior.

But improved ADCs will not come just form improved chemistry – our understanding of biological mechanism also needs to become part of the critical path toward better therapeutics.  As Josh Greally added:

“When we look at the payloads, we don’t yet have guidelines to understand what makes a good payload… We also have to understand antibody–antigen engagement, internalization, linker cleavage, and then endosomal escape. I don’t think we fully understand the payload biochemical properties required for the desired outcome.”

Bispecific and dual‑payload ADCs offer real value when guided by biology

The panel explored the promise and pitfalls of newer ADC formats.

When bispecific ADCs can be viable:

• A greater level of payload delivery is required (or gating)
• More selective delivery is required using heterogenous antigen fingerprints (and gating)

Dual‑payload ADCs can also help overcome resistance and engineer synergistic mechanisms.

Ya-Chi Chen highlighted some common pairings:

“We see Topo‑I payloads damaging the DNA and dual payloads also blocking the DNA repair pathway. We also see MMAE plus Topo‑I targeting two checkpoints of the cell cycle to prevent escape.”

But the panel was also clear that complexity isn’t inherently an advantage and leads to challenges in deconvoluting the path to clinic.

As Mohit Trikha cautioned:

“If we get the dual payload ratio wrong, for example 4:2 versus 2:4, you only get one shot at it. You don’t know from a tox perspective which component will dominate.”

Sygnature’s perspective:

These technologies can be transformative, but biological rationale must lead the ADC design choices, not the reverse. And we need to be holistic in our thinking as we evaluate these agents to determine their clinical suitability. The application of dual payloads is primarily employed to overcome resistance mechanisms, yet it doesn’t address the payload toxicity issues, we believe payloads selection for dual payload strategies need to be carefully thought through to ensure that it doesn’t just double the toxicity of the ADC.

Internalization may be a stronger predictor of ADC success than expression

One of the most compelling insights came from a debate about patient selection. Historically, ADCs have relied on antigen expression as the key determinant for clinical success. But internalization is emerging as a much stronger predictor.

As Mohit Trikha reflected:

“It’s not about expression, it’s about internalization. Precious things can come in small packages.”

This is a pivotal shift for ADC developers.

It suggests that early internalization and trafficking assays should become core components of target identification and validation, this should also be a key parameter that is assessed throughout the ADC development process.

The field is re‑thinking DAR, dose and delivery as an integrated system

The relationship between dose, drug-antibody ratio (DAR) and delivery came up repeatedly.

ADCs have historically escalated DAR to increase potency. But lower DAR variants often deliver cleaner safety profiles, allowing higher antibody doses that can improve overall tumor exposure more efficiently than simply adding more payload.

As Josh Greally explained:

“We need to understand exactly what the payload mechanisms are. We often go in with a prerequisite DAR, but we need to ask if that’s the right approach based on delivery. Because specific parameters have worked well for one molecule doesn’t mean it works for all, we need to optimise for each ADC, the correct DAR will be influenced by multiple aspects such as: indication, payload, linker, conjugation and antibody”

Bob Lutz added:

“I think as we go along we’ll be able to reduce the DAR more and more as we select patients better. That translates to improved safety. I do think we’re going to be moving in all cases to the lowest DAR that works.”

This mindset aligns with the shift toward precision tuning, rather than “maximum payload loading.”

“Fallen‑angel” payloads may be the most under‑used innovation opportunity

A particularly exciting conversation centred around payloads that once failed as systemic drugs, often because they were:

• Dose limiting toxicity
• Too short‑lived
• Poorly distributed
• Prone to off‑target effects

As Allan Jordan explained:

“The fallen‑angel payloads… all the forgotten assets that had systemic toxicity or poor tissue penetration… they are positioned beautifully to be ADC payloads.”

Sygnature has increasingly supported partners in rapidly evaluating archived small molecules for ADC potential, using conjugation feasibility and intracellular trafficking assays to identify promising candidates.

This is a high‑value opportunity for biotechs looking to expand their pipelines quickly and efficiently.

To see how the field is exploring unconventional payloads, mechanisms and delivery strategies, read our blog: https://www.sygnaturediscovery.com/blog/exploring-new-paths-in-adc-development/.

Looking ahead: ADCs are becoming more precise, not just more potent

Our panel at World ADC made one thing clear: the future of ADCs lies in a more integrated approach, with multidisciplinary teams working closely together with a patient centred approach. Success will come from:

• Designing for tolerability as much as for potency
• Engineering linkers and conjugation strategies that enhance selective delivery
• Choosing formats (bispecifics, dual payloads) based on biological need
• Measuring internalization, not relying solely on expression
• Tuning DAR and dose as a coupled system
• Revisiting “fallen‑angel” payloads with fresh eyes

These insights reflect the direction of our own work at Sygnature Discovery, where interdisciplinary teams collaborate to build ADCs that deliver on all dimensions of therapeutic index.