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Pharmacokinetics, pharmacodynamics, and safety of GS‐3583, a FLT3 agonist Fc fusion protein, from single‐ascending‐dose phase I study in healthy participants
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Pharmacokinetics, pharmacodynamics, and safety of GS‐3583, a FLT3 agonist Fc fusion protein, from single‐ascending‐dose phase I study in healthy participants
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Pharmacokinetics, pharmacodynamics, and safety of GS‐3583, a FLT3 agonist Fc fusion protein, from single‐ascending‐dose phase I study in healthy participants
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Journal Article
Pharmacokinetics, pharmacodynamics, and safety of GS‐3583, a FLT3 agonist Fc fusion protein, from single‐ascending‐dose phase I study in healthy participants
2024
Overview
Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor‐specific CD8+ T cells and their recruitment to tumor microenvironment. However, cDC1s are often underrepresented in the microenvironment. Systemic administration of Fms‐like tyrosine kinase 3 ligand, a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to cDC1 expansion in the periphery and recruitment into the microenvironment. FLT3 pathway stimulation using GS‐3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T‐cell mediated antitumor activity. This was a first‐in‐human, placebo‐controlled study of GS‐3583 in healthy participants to evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) of escalating single doses (75–2000 μg) of GS‐3583. Each dose cohort enrolled 8–12 healthy participants who received GS‐3583 or placebo as single IV infusion at 3:1 ratio. As part of the PD evaluation, the changes in the number of cDC1 cells were investigated. GS‐3583 was well‐tolerated in healthy participants up to the highest evaluated dose (2000 μg). There have been no serious or grade III or higher adverse events. PK analysis suggested a dose‐dependent increase in GS‐3583 exposure with target‐mediated disposition characteristics at low doses. PD analysis shows that administration of GS‐3583 resulted in transient, dose‐dependent increases in cDC1 cells that returned to baseline within 3 weeks of drug administration. The pharmacokinetics and pharmacodynamics of GS‐3583 following single dosing were characterized in this study which enabled subsequent phase Ib assessments in patients with advanced solid tumors.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
Subject
/ Agonists
/ Antigens
/ Dendritic Cells - drug effects
/ Dendritic Cells - immunology
/ Dosage
/ Dose-Response Relationship, Drug
/ Female
/ fms-Like Tyrosine Kinase 3 - antagonists & inhibitors
/ Humans
/ Immunoglobulin Fc Fragments - administration & dosage
/ Immunoglobulin Fc Fragments - adverse effects
/ Immunoglobulin Fc Fragments - pharmacology
/ Kinases
/ Ligands
/ Male
/ Placebos
/ Proteins
/ Recombinant Fusion Proteins - administration & dosage
/ Recombinant Fusion Proteins - adverse effects
/ Recombinant Fusion Proteins - pharmacokinetics
/ Recombinant Fusion Proteins - pharmacology
/ Tumors
