Day Two

• Demonstrate how a non-cytotoxic, mechanism-selective payload approach can address key limitations of traditional cytotoxic ADCs by improving tolerability while maintaining therapeutic activity
• Explore the rationale for targeting TGF-β biology to overcome immunosuppression, resistance mechanisms, and fibrotic disease progression across a range of disease settings
• Highlight opportunities to expand ADC applications beyond conventional oncology paradigms by leveraging targeted biological modulation to improve therapeutic index, unlock novel indications, and create differentiated treatment strategies

• Will the future of ADC therapy be driven by a standardized sequence of dominant payload classes, or will tumor-specific biology determine payload choice from the outset?
• To what extent is resistance increasingly driven by payload mechanism rather than target biology, and does this undermine traditional linear sequencing models?
• How does tumor heterogeneity challenge the feasibility of a single, universal payload roadmap across indications?
• What does long-term success look like for next-generation payload strategies in terms of portfolio design, partnering models, and defining clinical value beyond potency?
• What are the implications for pipeline strategy, portfolio design, and payload partnering models?

• Analyze ADC resistance mechanisms in topoisomerase and tubulin payloads, including drug efflux pumps and tumor bypass pathways, and distinguish where evidence remains strong versus where it is still incomplete
• Explore approaches to overcoming resistance through rational payload selection, including combining topoisomerase inhibitors with PARP or ATR inhibitors and using translation inhibition strategies to prevent efflux pump expression and resensitize tumors
• Define key requirements for effective dual payload ADC design, including matched payload potency, coordinated intracellular release timing, and engineering strategies that ensure both payloads reach and act in tumor cells simultaneously

• Mechanism-Driven Optimization: Moving past rigid "me-too" platforms to systematically tune payload selection, potency, ratios, and DAR to maximize initial efficacy while mitigating overlapping toxicities
• An Expanding Modular Library: Translating proven trends across multiple ongoing target programs into a scalable, target-specific linker–payload matching platform
• Robust In Vivo Validation: Utilizing a well-characterized Ab to rigorously validate the engineering blueprint and overcome TOP1i class resistance
• Immune-Stimulating Integration: Expanding the platform to integrate immunestimulating conjugates, unlocking a dual-attack mechanism for difficult-to-treat cancers

• Enabling rapid synthesis and screening of diverse dual-payload ADCs using a fully integrated discovery platform
• Identifying novel payload combinations and resistance-relevant hits through largescale screening in PDX models
• Revealing disease-dependent variability in payload efficacy to guide smarter, data-driven ADC design

This interactive networking session is designed to move beyond traditional open networking by bringing together participants in small, pre-curated roundtables aligned to shared scientific and strategic challenges. Attendees will have freedom to rotate between focused discussions, enabling deeper exchange on key ADC payload issues and creating targeted opportunities to identify collaborators.

• Join carefully matched discussion groups built around shared scientific challenges, development needs, and partnership opportunities rather than random networking
• Exchange practical insights on critical payload topics including overcoming resistance, translating novel payloads, balancing potency and safety, and identifying the right development partners
• Rotate through challenge-focused discussions to compare strategies, uncover new solutions, and identify the most valuable follow-up conversations and collaborations

• The Hypothesis: Examine the scientific rationale for leveraging RNA splicing modulation as a novel ADC payload mechanism that delivers a dual anti-tumor effect through direct cytotoxicity and immune system activation, offering differentiation beyond traditional microtubule inhibitors and DNA-damaging payloads
• The Journey: Engineering desired features such as MDR resistance and development of payload-specific conjugation strategies. Why cleavable vs non-cleavable strategies need to be revisited for each novel payload.
• The Pay-off: Early translational and preclinical data supporting anti-tumor cytotoxic activity, including evidence of immune activation and activity across oncogenic driver-driven cancer models
• Future Directions: How next-generation RNA splicing modulator payloads could expand the ADC therapeutic landscape through differentiated mechanisms of cell death, potential combination synergy with immunotherapies, and opportunities for broader antigen targeting strategies

• Gain a clear understanding of how degrader antibody conjugates introduce new opportunities and risks compared to classical cytotoxic payload approaches
• Learn how medicinal chemistry strategies are evolving beyond potency to optimize broader property space including DMPK and developability considerations
• Explore practical frameworks for evaluating emerging payload modalities and determining when ADC delivery adds value over small molecule approaches