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Mechanistic Projection of First-in-Human Dose for Bispecific Immunomodulatory P-Cadherin LP-DART: An Integrated PK/PD
X Chen1, N Haddish-Berhane2,3, P Moore4
1Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts, USA.
Clinical Pharmacology and Therapeutics
|May 13, 2016
Summary
A novel bispecific immunomodulatory molecule, P-cadherin LP-DART, shows preclinical antitumor efficacy. Its dose was determined using a pharmacokinetic/pharmacodynamic (PK/PD) model focused on the drug-target-immune cell synapse, not just drug concentration.
Area of Science:
- Immunology
- Pharmacology
- Biotechnology
Background:
- A bispecific immunomodulatory biotherapeutic molecule, P-cadherin LP-DART, utilizing the Dual Affinity Re-Targeting (DART) scaffold, has demonstrated preclinical antitumor efficacy.
- Its immune agonistic properties necessitate careful dose determination for first-in-human (FIH) studies, employing a Minimal Anticipated Biological Effect Level (MABEL) approach.
Purpose of the Study:
- To explore a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) approach to determine the MABEL dose for P-cadherin LP-DART.
- To understand the exposure-response relationship based on tri-molecular synapse concentration for efficacy.
Main Methods:
- Utilized a PK/PD modeling approach focusing on the concentration of the tri-molecular synapse (drug, T cell, tumor cell).
- Investigated orthogonal methods including PK-driven calculations and receptor occupancy.
- Applied MABEL approach for FIH dose projection.
Main Results:
- Demonstrated that synapse concentration, not solely drug concentration, drives pharmacological activity and efficacy.
- Successfully applied PK/PD modeling to project a MABEL dose for the bispecific molecule.
- Validated the PK/PD modeling approach with orthogonal methods.
Conclusions:
- PK/PD modeling based on synapse concentration is a viable strategy for dose determination of bispecific immunomodulatory molecules.
- This approach can inform the development of P-cadherin LP-DART and potentially other bispecific biotherapeutics in immuno-oncology.
- Highlights the importance of understanding complex drug-target-cell interactions for effective therapeutic development.
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