Day Two Agenda

7:30 am Morning Check In & Coffee

8:25 am Chairs Opening Remarks

  • Robert Lutz Chief Scientific Officer, Iksuda Therapeutics

Reviewing Current & Novel In Vitro & Pre-Clinical Models to Better Predict ADC Toxicity in the Clinic

8:30 am Overcoming the Limitations of In Vitro Models to Predict ADC Toxicity

Synopsis

  • Exploring why in vitro efficacy and in vivo toxicity results often fail to correlate by discussing the disconnect between cytotoxicity assays and whole-organ toxicity and identifying better biomarkers for in vitro screening
  • Discussing whether 2D monocultures are sufficient for predicting ADC-induced off-target toxicity, bystander effects, and immune-related toxicities
  • Understanding the role computational modelling and AI play in improving in vitro predictions – how can mathematical models integrate in vitro data to predict clinical toxicity outcomes?

9:00 am Targeted Delivery of BCL-XL Selective Inhibitor Alleviates On-Target Toxicity of Systemically Dosed Inhibitors in Preclinical Models

Synopsis

  • Understanding how a pre-clinical mechanism-based cardiotoxicity of BCL-XL small molecule inhibitors led to the utilization of an antibody-targeted approach that has potential to differentiate from known platforms
  • Reviewing the ADC approach manifested a novel BCL-XL toxicity in kidney
  • Considering payload property modification contributed to establishing a TI suitable for clinical dosing 

9:30 am Exploring How Advanced Human-Derived Pre-Clinical Systems Can Be Optimized for ADCs to Predict & Mitigate Toxicities

  • Sonia Jain Research Associate Radiation Oncology, Mayo Clinic

Synopsis

  • Examining the benefits of patient-derived xenograft (PDX) models in replicating tumor microenvironment-driven toxicity, specifically when developing neuronal cultures in vitro to evaluate the cytotoxicity index with the efficacy and on neurons
  • Discussing the neuronal toxicities mediated by the bystander capable payload to manage the heterogeneity of Glioblastoma
  • Evaluating the limitations of scalability, reproducibility, and long-term viability of patientderived cell cultures for ADC toxicity testing

10:00 am High-throughput Functional & Morphological Neurotoxicity Screening in Human NerveSim®

Synopsis

  • Understanding the valuable in vitro model for sensitively studying potential compound induced functional and morphological toxicities in the peripheral nervous system
  • Utilizing a 24-well format to provide high-throughput electrophysiological characterization amenable to testing multi-drug panels for neurotoxicity on a clinically relevant nerve model
  • Case study – A multidimensional assessment of toxicity for chemotherapeutic compounds and ADCs

Leveraging Your ADC Design to Minimize Toxicity Whilst Maintaining Efficacy

11:00 am Evaluating Emerging ADC Designs to Understand Their Impact on Safety Profiles – Where Are We Headed?

  • Robert Lutz Chief Scientific Officer, Iksuda Therapeutics

Synopsis

  • Reviewing new ADC designs and how they may lead to improved safety profiles such as reduced neutropenia and GI toxicities
  • Discussing the challenges of preclinical to clinical translation of safety profiles – how can we design ADCs to be safer based on preclinical evaluation?
  • Exploring how ADC design innovations will support future differentiation and improve clinical benefit in the future

11:30 am Leveraging ADME Characterization of Linker Payloads for ADCs to Minimize Toxicity

  • Raymond Evers Senior Director, Global Translational ADME, Translational PK/PD & Investigative Toxicology, Johnson & Johnson

Synopsis

  • Exploring the extent of what early ADME characterization of free payloads is relevant from a safety perspective
  • Discussing what the key ADME properties contributing to developing a safe ADC payload are
  • Diving into what the translatable assay platforms are to measure bystander effect

12:00 pm Highlighting Emerging Linker Technologies That Optimize Payload Release & Clearance to Improve Safety Profiles

Synopsis

  • How can we engineer linkers to control payload clearance and mitigate toxicity? – Understanding how modifying linker chemistry can influence payload retention and off-target effects
  • Targeting linker cleavage mechanisms for precision payload release – how tumor-specific protease linkers can help reduce systemic exposure, and why protease expression in normal tissues complicates ADC safety
  • Exploring linker technologies that optimize stability, selective cleavage, and controlled clearance to create the next generation of safer ADCs

12:30 pm Lunch Break

1:30 pm Roundtable discussion: Navigating Evolving Regulatory Expectations for ADC Toxicity Models – Bridging In Vivo/Vitro Approaches

Synopsis

Join this roundtable discussion to gain a better understanding of what is currently approved by regulatory agencies, how they are adopting to new safety models, and how we can navigate regulatory challenges with ADC toxicity models.

  • What models are currently approved by regulatory agencies (FDA, EMA, etc.) for ADC safety assessments?
  • Are there species-specific limitations when evaluating ocular, pulmonary, or systemic toxicities – and how can we improve predictability of these toxicities while meeting regulatory requirements?
  • How are FDA and EMA responding to the adoption of humanized in vitro models for ADC safety testing?
  • What validation criteria are required for in vitro models to be considered acceptable alternatives to traditional in vivo models?

Investigating Protein-Drug Conjugates to Compare the Benefits & Challenges With Both & Predict Better Toxicity Mitigating Strategies

2:30 pm Exploring Peptide-Drug Conjugates & Comparing Their Toxicity Profiles With Antibody-Drug Conjugates to Improve Reverse Translation

Synopsis

  • Examining case studies where peptide-drug conjugates have translated toxicity data successfully into the clinic – learn from the successes
  • Assessing where we can look to optimize the translation of toxicity data with ADCs by comparing ADCs with PDCs – using a reverse translational approach to minimize toxicities in preclinical studies
  • Differentiating the biology of PDCs with ADCs and understanding how models can recapitulate the difference in clinical exposure

3:00 pm Chair’s Closing Remarks

  • Robert Lutz Chief Scientific Officer, Iksuda Therapeutics

3:15 pm End of Scientific Program Day Two