Pharmacokinetics, pharmacodynamics, and safety of GS-3583, a FLT3 agonist Fc fusion protein, from single-ascending-dose phase I study in healthy participants.
Humans
Adult
Male
Healthy Volunteers
Female
Middle Aged
Recombinant Fusion Proteins
/ pharmacokinetics
fms-Like Tyrosine Kinase 3
/ antagonists & inhibitors
Young Adult
Immunoglobulin Fc Fragments
/ administration & dosage
Dose-Response Relationship, Drug
Dendritic Cells
/ drug effects
Double-Blind Method
Infusions, Intravenous
Journal
Clinical and translational science
ISSN: 1752-8062
Titre abrégé: Clin Transl Sci
Pays: United States
ID NLM: 101474067
Informations de publication
Date de publication:
Aug 2024
Aug 2024
Historique:
revised:
26
07
2024
received:
12
06
2024
accepted:
05
08
2024
medline:
22
8
2024
pubmed:
22
8
2024
entrez:
22
8
2024
Statut:
ppublish
Résumé
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.
Substances chimiques
Recombinant Fusion Proteins
0
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
FLT3 protein, human
EC 2.7.10.1
Immunoglobulin Fc Fragments
0
Types de publication
Journal Article
Clinical Trial, Phase I
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
e70011Informations de copyright
© 2024 Gilead Sciences, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
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