title: First-in-Human Study in Healthy Subjects with FR104, a Pegylated Monoclonal Antibody Fragment Antagonist of CD28.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1064, Nantes F44093, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire, Université de Nantes, Nantes F44000, France.|OSE Immunotherapeutics S.A., Nantes F44200, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poirier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1064, Nantes F44093, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire, Université de Nantes, Nantes F44000, France.|Centre Hospitalier Universitaire Nantes, Laboratoire d'Immunologie, Centre d'immunomonitorage Nantes-Atlantique, Nantes, F44000, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
authors.affiliation: OSE Immunotherapeutics S.A., Nantes F44200, France.
authors.forename: Maryvonne
authors.initials: M
authors.lastname: Hiance
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1064, Nantes F44093, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire, Université de Nantes, Nantes F44000, France.|OSE Immunotherapeutics S.A., Nantes F44200, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Mary
authors.affiliation: SGS Life Science Services, Clinical Pharmacology Unit Antwerp, Antwerp 2060, Belgium.
authors.forename: Tim
authors.identifier: 0000-0002-8958-1117
authors.initials: T
authors.lastname: Van Assche
authors.affiliation: SGS Life Science Services, Clinical Pharmacology Unit Antwerp, Antwerp 2060, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: Lempoels
authors.affiliation: SGS Life Science Services, Clinical Pharmacology Unit Antwerp, Antwerp 2060, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ramael
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA 19477.
authors.forename: Weirong
authors.initials: W
authors.lastname: Wang
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1064, Nantes F44093, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire, Université de Nantes, Nantes F44000, France.|OSE Immunotherapeutics S.A., Nantes F44200, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Thepenier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1064, Nantes F44093, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire, Université de Nantes, Nantes F44000, France.|LabEx ImmunoGraft Oncology, Nantes F44000, Nantes, France; and.
authors.forename: Cecile
authors.initials: C
authors.lastname: Braudeau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1064, Nantes F44093, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire, Université de Nantes, Nantes F44000, France.|Centre Hospitalier Universitaire Nantes, Laboratoire d'Immunologie, Centre d'immunomonitorage Nantes-Atlantique, Nantes, F44000, France.|LabEx ImmunoGraft Oncology, Nantes F44000, Nantes, France; and.
authors.forename: Nina
authors.initials: N
authors.lastname: Salabert
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1064, Nantes F44093, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire, Université de Nantes, Nantes F44000, France.|Centre Hospitalier Universitaire Nantes, Laboratoire d'Immunologie, Centre d'immunomonitorage Nantes-Atlantique, Nantes, F44000, France.|LabEx ImmunoGraft Oncology, Nantes F44000, Nantes, France; and.
authors.forename: Regis
authors.identifier: 0000-0001-7900-7413
authors.initials: R
authors.lastname: Josien
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA 19477.
authors.forename: Ian
authors.initials: I
authors.lastname: Anderson
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA 19477.
authors.forename: Ian
authors.identifier: 0000-0002-8676-5690
authors.initials: I
authors.lastname: Gourley
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1064, Nantes F44093, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire, Université de Nantes, Nantes F44000, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.affiliation: Copexis S.A., Pully CH-1009, Switzerland.
authors.forename: Didier
authors.identifier: 0000-0001-8270-3831
authors.initials: D
authors.lastname: Coquoz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1064, Nantes F44093, France; bernard.vanhove@ose-immuno.com.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire, Université de Nantes, Nantes F44000, France.|OSE Immunotherapeutics S.A., Nantes F44200, France.|LabEx ImmunoGraft Oncology, Nantes F44000, Nantes, France; and.
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D018106:CD28 Antigens / Q000037:antagonists & inhibitors / Q000276:immunology; D002985:Clinical Protocols; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D064368:Healthy Volunteers; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D007166:Immunosuppressive Agents; D007167:Immunotherapy / Q000379:methods*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents