First-in-Human Study in Healthy Subjects with FR104, a Pegylated Monoclonal Antibody Fragment Antagonist of CD28

Autor: Steven Ramael, Jean-Paul Soulillou, Tim Van Assche, Weirong Wang, Ian Gourley, Maryvonne Hiance, Didier Coquoz, Caroline Mary, Cécile Braudeau, Régis Josien, Nicolas Poirier, Gilles Blancho, Virginie Thepenier, Jos Lempoels, Bernard Vanhove, Nina Salabert, Ian Anderson
Přispěvatelé: Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), OSE Immunotherapeutics [Nantes, France], Clinical Pharmacology Unit Antwerp [Antwerp, Belgium], SGS Life Science Services (SGS), SGS (SGS)-SGS (SGS), Janssen Research & Development [Spring House, PA, USA], Laboratoire d’Immunologie [CHU Nantes] (Centre d’Immunomonitorage Nantes Atlantique - CIMNA), Centre hospitalier universitaire de Nantes (CHU Nantes), Copexis S.A. [Pully, Switzerland], LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes], Le Bihan, Sylvie, LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)
Rok vydání: 2016
Předmět:
Adult
Graft Rejection
Male
0301 basic medicine
medicine.drug_class
Immunology
chemical and pharmacologic phenomena
Pharmacology
Monoclonal antibody
Autoimmune Diseases
Cohort Studies
Immunoglobulin Fab Fragments
03 medical and health sciences
0302 clinical medicine
CD28 Antigens
Clinical Protocols
Pharmacokinetics
medicine
Humans
Immunology and Allergy
Potency
Lymphocyte Count
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
biology
business.industry
Antagonist
Antibodies
Monoclonal
Organ Transplantation
Middle Aged
Healthy Volunteers
Immunity
Humoral
Blockade
030104 developmental biology
Pharmacodynamics
biology.protein
Administration
Intravenous
Female
Immunotherapy
Antibody
business
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Immunosuppressive Agents
Keyhole limpet hemocyanin
Follow-Up Studies
030215 immunology
Zdroj: Journal of Immunology
Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2016, 197 (12), pp.4593-4602. ⟨10.4049/jimmunol.1601538⟩
Journal of Immunology, 2016, 197 (12), pp.4593-4602. ⟨10.4049/jimmunol.1601538⟩
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.1601538
Popis: FR104 is a monovalent pegylated Fab′ Ab, antagonist of CD28, under development for treatment of transplant rejection and autoimmune diseases. In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals. In the present work, FR104 has been evaluated in a first-in-human study to evaluate the safety, pharmacokinetics, pharmacodynamics, and potency of i.v. administrations in healthy subjects. Sixty-four subjects were randomly assigned to four single ascending dose groups, two double dose groups and four single ascending dose groups challenged with keyhole limpet hemocyanin. Subjects were followed up over a maximum of 113 d. Overall, the pharmacokinetics of FR104 after a single and double infusions was approximately linear at doses ≥0.200 mg/kg. CD28 receptor occupancy by FR104 was saturated at the first sampling time point (0.5 h) at doses above 0.02 mg/kg and returned to 50% in a dose-dependent manner, by day 15 (0.020 mg/kg) to 85 (1.500 mg/kg). FR104 was well tolerated, with no evidence of cytokine-release syndrome and no impact on blood lymphocyte subsets. Inhibition of anti-keyhole limpet hemocyanin Ab response was dose-dependent in FR104 recipients and was already apparent at a dose of 0.02 mg/kg. Abs to FR104 were detected in 22/46 (48%) of FR104 recipients and only 1/46 (2.2%) was detected during drug exposure. In conclusion, selective blockade of CD28 with FR104 was safe and well tolerated at the doses tested. The observed immunosuppressive activity indicated that FR104 has potential to show clinical activity in the treatment of immune-mediated diseases.
Databáze: OpenAIRE
Externí odkaz: