Day One

• Employing a matched-pair strategy using inert payloads and non-binding antibodies, to systematically isolate and quantify the contributions of payload and target engagement to overall observed toxicity, providing a clear mechanistic attribution for dose-limiting adverse events
• Utilizing tissue microarrays with quantitative immunohistochemistry for target expression, to map the biodistribution of target antigens in critical normal organs,creating a preclinical risk assessment tool for on-target toxicity before candidate selection
• Developing computational toxicology models that partition free payload and intact ADC concentrations, to predict which component is driving clinical adverse events, informing linker design strategies to minimize systemic payload release

• Rationally designing Auristatin S to improve the tolerability of auristatin payloads through the tuning of permeability and bystander activity
• Explaining how Auristatin S maintains key auristatin properties, including strong tubulin binding affinity and induction of immunogenic cell death
• Exploring Auristatin S improved preclinical therapeutic window

This informal session offers the perfect opportunity to connect with industry front-runners and key opinion leaders specializing in pathology and toxicity within the ADC field. This is your chance to build meaningful connections to carry through the rest of the conference, while gaining exclusive, first-hand insights into the latest research and developments.

As ADC development continues to expand across increasingly diverse targets, payloads, and antibody formats, 

understanding which molecular and physicochemical properties most strongly influence safety is critical to widening the 

therapeutic window. This panel will explore which variables can be modulated to improve safety and how mechanistic insights 

can be translated into smarter candidate selection by:

• Identifying the most critical determinants of ADC safety by examining how payload characteristics, antibody properties, conjugation parameters, and overall molecular design contribute to off-target toxicity and therapeutic window
• Exploring how payload and antibody properties can be strategically modulated by assessing the impact of payload physicochemical characteristics, Fc-mediated interactions, non-specific uptake mechanisms, and other molecular features on ADC distribution, cellular uptake, and toxicity
• Debating emerging strategies to improve ADC safety by design including Fc-silencing, alternative antibody formats, bispecific and biparatopic approaches, masked antibodies, and other engineering technologies, while considering how these approaches can translate mechanistic understanding into improved candidate selection and clinical safety

• The rapid expansion of ADC development is exposing the limitations of traditional approaches to safety assessment and monitoring
• Tissue-of-origin cfDNA provides a new window into treatment-induced injury
• One translational platform can support ADC safety from preclinical studies to patients, and better safety insight enables better ADC development decisions

• Analyzing recent regulatory feedback to interpret how the FDA’s Project Optimus guidance is being applied to dose selection and toxicity mitigation strategies, providing a clear roadmap for designing Phase I dose-finding studies
• Designing clinical dose-optimization strategies for antibody–drug conjugates that balance therapeutic exposure and tolerability, to proactively address regulatory expectations
• Applying lessons from Ligachem Bio’s ADC pipeline to integrate translational toxicology, pharmacokinetics, and early safety signals into adaptive Phase I study designs

• Traditional nonclinical models often fail to predict clinical outcomes for complex ADCs, creating a need for more advanced and biologically relevant preclinical approaches.
• Novel in vitro systems can improve decision-making in drug discovery by providing better insights into key factors such as target uptake, payload characteristics, and tissue toxicity
• Integrating these systems into a broader translational strategy, along with improved species selection, biomarker use, and mechanistic data, can produce more predictive nonclinical packages and enable faster, more confident go/no-go decisions

• Leveraging HiLung’s iPSC-based technology, we develop lung CIVMs that include organoids as well as immune cells such as tissue-resident alveolar macrophages to accelerate drug discovery.
• Our system enables pathophysiologically relevant assays through organoid histopathology and biomarker analyses
• Overview of ADC toxicity evaluation at HiLung as an application of lung CIVMs

• Developing a reproducible non-clinical monkey ILD model using repeated dosing of DXd-based ADCs to characterize pulmonary toxicities and establish translational relevance to clinical interstitial lung disease findings
• Longitudinally profiling plasma, BALF, and BALF-derived extracellular vesicles using high-dimensional proteomics to identify early biomarker candidates associated with ADC-induced lung injury progression
• Integrating single-cell RNA sequencing with extracellular vesicle proteomic signatures to map alveolar epithelial, macrophage, monocyte, and fibroblast responses, enabling mechanistic insight into DXd-ADC–associated ILD and improving translation from preclinical models to clinical outcomes

• Introducing an advanced ex vivo human skin platform that maintains native skin architecture and immune responsiveness for up to ~1 month across diverse human donors
• Demonstrating sustained, disease-relevant inflammatory responses and pharmacologic modulation through longitudinal histopathology, soluble biomarkers, and transcriptomics
• Applying the platform across diverse therapeutic modalities and biological targets using dose-ranging and multimodal endpoints to investigate target-associated effects and the onset and progression of inflammatory, tissue stress, and toxicity responses
• Advancing a human-relevant NAM to bridge the gap between preclinical models and clinical translation, support earlier safety decisions, and help de-risk therapies before patient exposure

Connect with peers in a relaxed atmosphere and continue building new and existing relationships while exploring the latest advancements in ADC Toxicity Research. To submit a poster, please contact info@hansonwade.com

• Engineering an ADC panel with varying payload hydrophobicity to quantify how lipophilic payloads passively diffuse across cell membranes, establishing a predictive relationship between logD and off-target toxicities
• Investigating the contribution of membrane transporters to the bystander effect, including how influx and efflux mechanisms regulate intracellular payload accumulation and intercellular transfer, to determine their impact on off-target toxicity and therapeutic selectivity
• Correlating in vitro bystander killing potential in 3D spheroid co-cultures with in vivo outcomes to establish a predictive screening assay, enabling optimization of payload properties for an improved therapeutic index

The FDA’s landmark guidance to reduce and ultimately replace animal testing has sent shockwaves through the toxicology community. The central question asks how to build a compelling, regulator-friendly safety package without decades of historical precedent.

Join regulatory experts, translational scientists, and industry pioneers as they chart a practical path forward for implementing NAMs in ADC development by:

• Building confidence in in vitro models, evaluating how organoids, microphysiological systems, and iPSC-derived tissue panels can be benchmarked against historical clinical data for known ADC toxicities like ILD and ocular keratopathy to establish predictive thresholds that regulators will trust
• Constructing a weight-of-evidence framework, discussing how to integrate high-content imaging, computational modeling, and mechanistic biomarker data into a cohesive safety package that compensates for the absence of traditional animal toxicology endpoints
• Collaborating with regulators on validation, exploring how to engage the FDA early in the NAMs development process through pre-IND meetings and qualification programs, ensuring that novel testing strategies are aligned with agency expectations and positioned for successful adoption

• Applying detailed clinical phenotyping and electrophysiologic assessment to distinguish between immune-mediated and direct payload-related neurologic toxicities, enabling more precise dose modification and management strategies
• Characterizing neuromuscular toxicity patterns across ADC-treated patients to identify early clinical signals and correlate toxicity phenotypes with dosing exposure, supporting safer therapeutic windows
• Developing a clinician-led framework to differentiate subtypes of peripheral neuropathy, informing mechanism-driven management approaches and guiding multidisciplinary decision-making for treatment continuation or discontinuation