Event Details

September 18-19, 2019 | Waltham, MA

Applied BioMath Presence 

Wednesday, September 18 | 12:00pm | Translational & Clinical Track 

Alison Betts, Senior Director of Scientific Collaborations and Fellow of Modeling & Simulation is presenting "A Translational Quantitative Systems Pharmacology Model for CD3 Bispecific Molecules: Application to Quantify T-Cell-Mediated Tumor Cell Killing by P-cadherin LP DART"

  • A translational quantitative systems pharmacology (QSP) model is proposed for CD3 bispecific molecules capable of predicting trimolecular complex (trimer) concentration between drug, T-cell and tumor cell, and linking it to tumor cell killing.
  • The model was used to quantify the PK/PD relationship of a CD3 bispecific targeting P-cadherin (PF-06671008). It describes disposition of PF-06671008 in the central compartment and tumor in mouse xenograft models, including binding to target and T-cells in the tumor to form the trimer. The model incorporates T-cell distribution to the tumor, proliferation and contraction.
  • The model was translated to the clinic and used to predict the disposition of PF-06671008 in patients, including the impact of binding to soluble P-cadherin. The model was also used to predict clinical efficacy of PF-06671008 and to investigate sensitive factors which impact efficacy.

 

Wednesday, September 18 | 4:15pm 

John Burke, PhD, Co-Founder, President and CEO is chairing the session "Pioneering Quantitative Models to Predict Optimal Bispecific Properties."

Within this session are the following three presentations:

Utilizing QSP Modeling to Inform Clinical and Nonclinical Development of Zymeworks’ Azymetric™ Biparatopic Platforms: Pharmacokinetic/Pharmacodynamic Modeling and Therapeutic Index Estimation

Presented by Rupert Davies, PhD, Senior Scientist, Preclinical Development, Zymeworks and Gerry Rowse, PhD, Director, Toxicology & Pharmacokinetics, Zymeworks

  • Inclusion of biparatopic binding stoichiometry drives more precise fit of PK data in cynos and humans

  • Development of novel pharmacodynamic parameter to evaluate effective of dose concentration and regimen on efficacy

  • Estimated delivery of toxin to four compartments: tumor, on-target organ toxicity and off-target toxicities associated with free toxin and FcGammaR2a binding of the antibody

  • Therapeutic index estimation with different doses and dose frequencies


Model-Based Approach to Design Bi-Specific Modalities in Early Discovery

Presented by Jennifer Fretland, PhD, Head Drug Metabolism & Pharmacokinetics, Sanofi

  • Bispecific antibodies are an attractive modality to modulate multiple targets in a disease indication. Each antigen may exhibit similar or different kinetic values like half-life, internalization rates, and expression rates. Target coverage for each antigen may also differ or be similar

  • Understanding your drug targets is critical to building an appropriate drug that specifically binds to and elicits the magnitude and duration of response needed for a particular indication

  • Here we used a tiered model-based approach to first determine feasibility of a bispecific antibody to appropriately cover multiple antigen pairs

  • Once feasibility was assessed, further modeling was performed to determine ideal affinity ranges for each target in bispecific format at the site of action. Sensitivity analysis was performed to understand each parameter and its impact on predicted target coverage

  • This approach guided teams for informed antibody design, prioritization of experiments, and triaging of challenging antigen pairs


The Next Generation of T-Cell Redirecting Antibodies

Presented by Werner Meier, CSO, Revitope Oncology

  • Harnessing the immune system has revolutionized cancer treatment

  • In particular redirected T-cells can kill tumor cells in therapeutically useful ways

  • However, off-target toxicity and lack of sufficient Ag limit the therapeutic potential of these approaches

  • Revitope is developing two-component systems composed of conditionally activated T cell Engaging Antibody Circuits (TEAC) that initiate and focus cytotoxic immunity accurately on the tumor

  • The core idea of TEAC is to split the anti-CD3 paratope of a bi-specific antibody to separately target each half-paratope to the tumor and only permit reconstitution after protease cleavage of the stabilizing dummy domains.

  • TEAC can be tumor-targeted with one or two different solid-tumor antigens (requirement for two antigens (an “AND” gate) that may enable greater tumor-specificity

  • The discussion will cover protein engineering considerations, activity measurements and the use of quantitative systems pharmacology modeling approaches aid mechanistic understanding