Day Two

• Leveraging site-selective enzymatic conjugation platforms that recognize native peptide motifs to achieve precise, uniform drug attachment, resulting in ADCs with minimized reduced pre‑tumoral payload loss
• Understanding improvements in enhanced stability over maleimides, to overcome the instability and premature payload release associated with traditional maleimides, increasing in vivo linker durability and lowered systemic toxicity
• Expanding enzymatic conjugation repertoires capable of installing tunable, stimuli-responsive cleavage motifs to fine‑tune payload liberation, enabling highly controlled, tumor-selective drug release

• Incorporating flexible, hydrophilic chains directly on linker cores to create a dynamic solubility shield around the hydrophobic payload, prevent both intermolecular aggregation and non-specific hydrophobic interactions
• Integrating modules into the linker design to leverage innate hydrophilicity and biocompatibility, significantly improving the aqueous solubility and biophysical profile of the entire ADC
• Designing linkers with charged groups to fine-tune the overall hydrophilic-lipophilic balance of the conjugate optimizing its serum stability

• Incorporating branched or linear carbohydrate polymers effectively masking high hydrophobicity and preventing ADC aggregation
• Exploring linkers with enzymatically cleavable triggers, for efficient tumor-localized payload release, to unlock the therapeutic novel payloads
• Understanding linker impact on payload delivery to explore extracellular release and internalizing peptides

• Screening a diverse linker-drug library incorporating variations in payload potency, release triggers and conjugation handles to identify optimal combinations, enabling fine-tuned control over pharmacokinetics and on-target activity
• Validating conjugate solubility and aggregation states through physiochemical analytical methods to provide definitive, accessible monomer quantification
• Demonstrating in vitro cytotoxicity and selectivity for high-DAR (DAR ≥8) conjugates engineered with optimized linker-drug designs that overcome hydrophobicity-driven aggregation

As the field expands beyond traditional cytotoxic payloads toward degraders and other complex, hydrophobic modalities, linker and conjugation chemistry must evolve to solve escalating biophysical challenges. From high-DAR constructs to degrader-antibody conjugates, the central question emerges: how do we push payload complexity and loading capacity without compromising stability, manufacturability, or in vivo performance?

Join leading experts as they discuss how novel linker architectures, advanced analytical precision, and site-selective

conjugation strategies can be integrated into cohesive platforms by:

• Balancing high payload loading with biophysical stability, examining how innovative linker architectures and hydrophobicity mitigating designs can enable DAR 8 and greater while preserving solubility, structural integrity, and favorable pharmacokinetics
• Redefining conjugation control as a platform enabler, debating how pyridazinedione-based site-selective strategies and advanced analytical tools can deliver precise, homogeneous DAR control to unlock reproducible, scalable next-generation constructs
• Harnessing traceless and site-specific linker strategies to enable emerging modalities, evaluating how degrader-compatible, hydrophobicity-masking, and cleavable designs can expand the ADC paradigm to include degrader-antibody conjugates and other novel payload classes without sacrificing developability or therapeutic index

• Advancing beyond traditional ADC linker paradigms with proprietary traceless, site-specific conjugation chemistry that enables stable attachment of cereblonbased degraders while preserving intrinsic payload structure and improving overall conjugate solubility
• Engineering hydrophilicity directly into linker architecture through modular, water-solubilizing elements and conditional intracellular release triggers to systematically mitigate degrader-driven hydrophobicity and reduce aggregation risk
• Leveraging linker–conjugation integration within the PROTAb platform to achieve controlled intracellular release, molecular homogeneity, and biophysical stability, unlocking Degrader-Antibody Conjugates capable of targeting undruggable proteins

• Summarizing the current pyridazinedione (PD)-based linkers that enable precise and programmable control over drug-to-antibody ratio (DAR), including DARs of 8, 4, 2 and 1, generating highly homogeneous antibody conjugates from native antibodies
• Discussing recent advances that enable modular access to DARs 1, 2, 3, 4, 5, 6, 7 and 8 on THIOMAB-based scaffolds, by using the versatility of the PD core, p-anisidine derivatives and various click chemistries

• Understanding PEGylated bidentate β-glucuronidase–cleavable linker design
• Enabling stable site-specific ADCs at DAR 16 to achieve higher efficacy
• Highlighting PEGylation mitigation of hydrophobicity and aggregation to improve pharmacokinetics and enhance in vivo antitumor efficacy

The future of antibody-drug conjugates is accelerating beyond traditional cytotoxic payloads, fueled by rapid innovation in linker engineering, novel conjugation platforms, and the integration of computational biology. As converging technologies redefine what an ADC can deliver, the antibody is evolving into a versatile delivery vehicle capable of transporting an increasingly diverse therapeutic arsenal.

This session explores the feasibility and promise of emerging payload classes, the transformation of the linker from a

passive connector into an active, programmable controller of drug release, and strategies for designing molecules that are translatable and manufacturable from day one.

Join this panel to gain strategic foresight on positioning your ADC programs at the forefront of targeted oncology and beyond by discussing:

• Exploring the transition beyond cytotoxins to integrate degraders, radio nuclides, and immune modulators, focusing on the radical linker and conjugation innovations required to expand the ADC therapeutic arsenal into new disease spaces
• Debating the future role of the linker as a smart, stimuli-responsive "payload traffic controller", evaluating emerging technologies to achieve maximal tumor killing with minimal systemic exposure for an optimized therapeutic window
• Strategizing to build future-proof platforms that integrate predictive in silico modelling of biophysical properties with scalable site-specific conjugation, to de-risk development timelines and accelerate the delivery of next-generation ADCs to patients