{"id":16881,"date":"2026-03-04T14:24:19","date_gmt":"2026-03-04T14:24:19","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/blog\/our-learnings-from-world-adc-london-designing-the-next-generation-of-smarter-safer-adcs\/"},"modified":"2026-03-04T14:24:19","modified_gmt":"2026-03-04T14:24:19","slug":"our-learnings-from-world-adc-london-designing-the-next-generation-of-smarter-safer-adcs","status":"publish","type":"blog","link":"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/our-learnings-from-world-adc-london-designing-the-next-generation-of-smarter-safer-adcs\/","title":{"rendered":"Our Learnings from World ADC London: Designing the Next Generation of Smarter, Safer ADCs"},"content":{"rendered":"\n<p>At this year\u2019s 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\u2013drug conjugates (ADCs)?<\/p>\n\n\n\n<p>The conversation brought together voices from across the ADC ecosystem, including:<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Dr. Allan Jordan<\/strong> (Moderator), Vice President, Oncology Drug Discovery, Sygnature Discovery<\/li>\n\n\n\n<li><strong>Dr. Josh Greally<\/strong>, ADC lead and Scientific Business development manager, Sygnature Discovery<\/li>\n\n\n\n<li><strong>Dr. Mohit Trikha,<\/strong> President &amp; COO, Kivu Bioscience<\/li>\n\n\n\n<li><strong>Dr. Bob Lutz,<\/strong> Chief Scientific Officer, Iksuda Therapies<\/li>\n\n\n\n<li><strong>Dr. Ya\u2011Chi Chen,<\/strong> Chief Scientific Officer, OBI Pharma<\/li>\n<\/ul>\n\n\n\n<p>Before the discussion began, we ran a live poll to get a real\u2011time pulse from the room.<\/p>\n\n\n\n<p>From <strong>46 respondents,<\/strong> the top areas believed to define <a href=\"https:\/\/www.sygnaturediscovery.com\/blog\/transformative-changes-in-adc-development-over-the-next-decade\/\">next\u2011generation ADCs<\/a> were:<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>More selective payloads<\/li>\n\n\n\n<li>Linker chemistry and stability<\/li>\n\n\n\n<li>Conjugation strategies<\/li>\n\n\n\n<li>Bispecific approaches<\/li>\n<\/ul>\n\n\n\n<p>These priorities shaped what became an insightful, technical, and refreshingly honest discussion. Below, we share our key learnings, combining Sygnature\u2019s perspective with expert viewpoints from our panel.<\/p>\n\n\n\n<p class=\"has-text-2-xl-font-size\"><strong>Tolerability is becoming the critical differentiator in ADC development<\/strong><\/p>\n\n\n\n<p>One of the strongest themes from the panel was the growing importance of tolerability. Potency isn\u2019t the bottleneck anymore; chronic <a href=\"https:\/\/www.sygnaturediscovery.com\/blog\/toxicity-efficacy-in-adcs\/\">toxicity<\/a> often is. But the panel also noted that we have new ways to overcome these challenges. As <strong>Allan Jordan <\/strong>noted:<\/p>\n\n\n\n<p><em>\u201cWe talk of selectivity squared\u2026 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.\u201d<\/em><\/p>\n\n\n\n<p><strong>Mohit Trikha<\/strong> reinforced this transformation, from the day-to-day patient perspective:<\/p>\n\n\n\n<p><em>\u201cA patient doesn\u2019t really care whether they\u2019re having neutropenia or interstitial lung disease. What matters to them is, hey, I\u2019ve got to deal with cytopenias\u2026 I don\u2019t know what ocular tox is. Patients are worried about the GI tox, vomiting or diarrhoea.\u201d<\/em><\/p>\n\n\n\n<p>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.<\/p>\n\n\n\n<p>Explore how medicinal chemistry influences modern ADC design in our blog: <a href=\"https:\/\/www.sygnaturediscovery.com\/blog\/evolving-role-of-med-chem-in-adc-development\/\" type=\"link\" id=\"https:\/\/www.sygnaturediscovery.com\/blog\/evolving-role-of-med-chem-in-adc-development\/\">https:\/\/www.sygnaturediscovery.com\/blog\/evolving-role-of-med-chem-in-adc-development\/.<\/a><\/p>\n\n\n\n<p class=\"has-text-2-xl-font-size\"><strong>Linkers and conjugation chemistry are now strategic design levers<\/strong><\/p>\n\n\n\n<p>Our panelists agreed that <a href=\"https:\/\/www.sygnaturediscovery.com\/blog\/linker-technologies-in-adcs\/\">linker<\/a> and conjugation innovations will help shape the next evolution of ADC performance toward these goals.<\/p>\n\n\n\n<p><strong>Ya\u2011Chi Chen <\/strong>summarized it well:<\/p>\n\n\n\n<p><em>\u201cThe 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.\u201d<\/em><\/p>\n\n\n\n<p>For Sygnature, this resonates strongly with what our integrated <a href=\"https:\/\/www.sygnaturediscovery.com\/modalities\/antibody-drug-conjugates\/\">ADC<\/a> discovery team observes in client programs: site\u2011specific conjugation, tumor\u2011responsive linkers, and solubility\u2011tuned ADCs consistently produce more predictable PK\/PD behavior.<\/p>\n\n\n\n<p>But improved ADCs will not come just form improved chemistry \u2013 our understanding of biological mechanism also needs to become part of the critical path toward better therapeutics.&nbsp; As <strong>Josh Greally<\/strong> added:<\/p>\n\n\n\n<p><em>\u201cWhen we look at the payloads, we don\u2019t yet have guidelines to understand what makes a good payload\u2026 We also have to understand antibody\u2013antigen engagement, internalization, linker cleavage, and then endosomal escape. I don\u2019t think we fully understand the payload biochemical properties required for the desired outcome.\u201d<\/em><\/p>\n\n\n\n<p class=\"has-text-2-xl-font-size\"><strong>Bispecific and dual\u2011payload ADCs offer real value when guided by biology<\/strong><\/p>\n\n\n\n<p>The panel explored the promise and pitfalls of newer ADC formats.<\/p>\n\n\n\n<p>When bispecific ADCs can be viable:<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>A greater level of payload delivery is required (or gating)<\/li>\n\n\n\n<li>More selective delivery is required using heterogenous antigen fingerprints (and gating)<\/li>\n<\/ul>\n\n\n\n<p>Dual\u2011payload ADCs can also help overcome resistance and engineer synergistic mechanisms. <\/p>\n\n\n\n<p><strong>Ya-Chi Chen<\/strong> highlighted some common pairings:<\/p>\n\n\n\n<p><em>\u201cWe see Topo\u2011I payloads damaging the DNA and dual payloads also blocking the DNA repair pathway. We also see MMAE plus Topo\u2011I targeting two checkpoints of the cell cycle to prevent escape.\u201d<\/em><\/p>\n\n\n\n<p>But the panel was also clear that complexity isn\u2019t inherently an advantage and leads to challenges in deconvoluting the path to clinic.<\/p>\n\n\n\n<p>As <strong>Mohit Trikha<\/strong> cautioned:<\/p>\n\n\n\n<p><em>\u201cIf we get the dual payload ratio wrong, for example 4:2 versus 2:4, you only get one shot at it. You don\u2019t know from a tox perspective which component will dominate.\u201d<\/em><\/p>\n\n\n\n<p><strong>Sygnature\u2019s perspective:<\/strong><\/p>\n\n\n\n<p>These technologies can be transformative, but biological rationale must lead the ADC design choices, not the reverse.&nbsp;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\u2019t address the payload toxicity issues, we believe payloads selection for dual payload strategies need to be carefully thought through to ensure that it doesn\u2019t just double the toxicity of the ADC.<\/p>\n\n\n\n<p class=\"has-text-2-xl-font-size\"><strong>Internalization may be a stronger predictor of ADC success than expression<\/strong><\/p>\n\n\n\n<p>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.<\/p>\n\n\n\n<p>As <strong>Mohit Trikha <\/strong>reflected:<\/p>\n\n\n\n<p><em>\u201cIt\u2019s not about expression, it\u2019s about internalization. Precious things can come in small packages.\u201d<\/em><\/p>\n\n\n\n<p>This is a pivotal shift for ADC developers. <\/p>\n\n\n\n<p>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.<\/p>\n\n\n\n<p class=\"has-text-2-xl-font-size\"><strong>The field is re\u2011thinking DAR, dose and delivery as an integrated system<\/strong><\/p>\n\n\n\n<p>The relationship between dose, drug-antibody ratio (DAR) and delivery came up repeatedly.<\/p>\n\n\n\n<p>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.<\/p>\n\n\n\n<p>As <strong>Josh Greally<\/strong> explained:<\/p>\n\n\n\n<p><em>\u201cWe need to understand exactly what the payload mechanisms are. We often go in with a prerequisite DAR, but we need to ask if that\u2019s the right approach based on delivery. Because specific parameters have worked well for one molecule doesn\u2019t 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\u201d<\/em><\/p>\n\n\n\n<p><strong>Bob Lutz<\/strong> added:<\/p>\n\n\n\n<p><em>\u201cI think as we go along we\u2019ll be able to reduce the DAR more and more as we select patients better. That translates to improved safety. I do think we\u2019re going to be moving in all cases to the lowest DAR that works.\u201d<\/em><\/p>\n\n\n\n<p>This mindset aligns with the shift toward precision tuning, rather than \u201cmaximum payload loading.\u201d<\/p>\n\n\n\n<p class=\"has-text-2-xl-font-size\"><strong>\u201cFallen\u2011angel\u201d payloads may be the most under\u2011used innovation opportunity<\/strong><\/p>\n\n\n\n<p>A particularly exciting conversation centred around payloads that once failed as systemic drugs, often because they were:<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Dose limiting toxicity<\/li>\n\n\n\n<li>Too short\u2011lived<\/li>\n\n\n\n<li>Poorly distributed<\/li>\n\n\n\n<li>Prone to off\u2011target effects<\/li>\n<\/ul>\n\n\n\n<p>As <strong>Allan Jordan <\/strong>explained:<\/p>\n\n\n\n<p><em>\u201cThe fallen\u2011angel payloads\u2026 all the forgotten assets that had systemic toxicity or poor tissue penetration\u2026 they are positioned beautifully to be ADC payloads.\u201d<\/em><\/p>\n\n\n\n<p>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.<\/p>\n\n\n\n<p>This is a high\u2011value opportunity for biotechs looking to expand their pipelines quickly and efficiently.<\/p>\n\n\n\n<p>To see how the field is exploring unconventional payloads, mechanisms and delivery strategies, read our blog: <a href=\"https:\/\/www.sygnaturediscovery.com\/blog\/exploring-new-paths-in-adc-development\/.*\">https:\/\/www.sygnaturediscovery.com\/blog\/exploring-new-paths-in-adc-development\/.<\/a><\/p>\n\n\n\n<p class=\"has-text-2-xl-font-size\"><strong>Looking ahead: ADCs are becoming more precise, not just more potent<\/strong><\/p>\n\n\n\n<p>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:<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Designing for tolerability as much as for potency<\/li>\n\n\n\n<li>Engineering linkers and conjugation strategies that enhance selective delivery<\/li>\n\n\n\n<li>Choosing formats (bispecifics, dual payloads) based on biological need<\/li>\n\n\n\n<li>Measuring internalization, not relying solely on expression<\/li>\n\n\n\n<li>Tuning DAR and dose as a coupled system<\/li>\n\n\n\n<li>Revisiting \u201cfallen\u2011angel\u201d payloads with fresh eyes<\/li>\n<\/ul>\n\n\n\n<p>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.<\/p>\n","protected":false},"excerpt":{"rendered":"","protected":false},"featured_media":16882,"template":"","category":[1409],"class_list":["post-16881","blog","type-blog","status-publish","has-post-thumbnail","hentry","category-adcs"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.4 - 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