QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life

• Published in: Journal of pharmacokinetics and pharmacodynamics 2024-12, Vol.52 (1), p.7
• Main Authors: Khera, Eshita, Dharmarajan, Lekshmi, Hainzl, Dominik, Engelhardt, Volker, Vostiarova, Helena, Davis, John, Ebel, Nicolas, Wuersch, Kuno, Romanet, Vincent, Sharaby, Sherif, Kearns, Jeffrey D.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Cell Line, Tumor; Half-Life; Humans; Immunoconjugates - administration & dosage; Immunoconjugates - pharmacokinetics; Immunoconjugates - pharmacology; Immunoconjugates - therapeutic use; Mice; Models, Biological; Neoplasms - drug therapy; Neoplasms - immunology; Network Pharmacology - methods; Original Paper; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Pharmacy; Tumors; Veterinary Medicine/Veterinary Science; Xenograft Model Antitumor Assays
• ISSN: 1567-567X; 1573-8744; 1573-8744
• DOI: 10.1007/s10928-024-09956-1

Antibody drug conjugates (ADC) are a promising class of oncology therapeutics consisting of an antibody conjugated to a payload via a linker. DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. To assess the impact of FR inactivation on DYP688 pharmacology and clinical developability, we performed translational modeling of preclinical PK and tumor growth inhibition (TGI) data, accompanied by mechanistic Krogh cylinder tumor modeling. Using a PK-TGI model, we identified a composite exposure-above-tumorostatic concentration (AUC TSC ) metric as the PK-driver of efficacy. To underpin the mechanisms behind AUC TSC as the driver of efficacy, we performed quantitative systems pharmacology (QSP) modeling of DYP688 intratumoral pharmacokinetics and pharmacodynamics. Through exploratory simulations, we show that by deviating from canonical ADC design dogma, DYP688 has optimal FR900359 activity despite its transient inactivation. Finally, we performed the successful preclinical to clinical translation of DYP688 PK, including the payload inactivation kinetics, evidenced by good agreement of the predicted PK to the observed interim clinical PK. Overall, this work highlights early quantitative pharmacokinetics as a missing link in the ADC design-developability chasm.