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

Nicolas Poirier; Gilles Blancho; Maryvonne Hiance; Caroline Mary; Tim Assche; Jos Lempoels; Steven Ramael; Weirong Wang; Virginie Thepenier; Bernard Braudeau; Nina Salabert; Régis Josien; Ian Anderson; Vanhove Gourley; Jean-Paul Soulillou; Didier Coquoz; Bernard Vanhove

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

Nicolas Poirier ^{1, 2, 3} Gilles Blancho ^{1, 2} Maryvonne Hiance ³ Caroline Mary ^{1, 2, 3} Tim Assche ⁴ Jos Lempoels ⁴ Steven Ramael ⁴ Weirong Wang ⁵ Virginie Thepenier ^{1, 2, 3} Bernard Braudeau ^{1, 2} Nina Salabert ^{1, 2, 6} Régis Josien ^{1, 2, 6} Ian Anderson ⁵ Vanhove Gourley ⁵ Jean-Paul Soulillou ^{1, 2} Didier Coquoz ⁷ Bernard Vanhove ^{1, 2, 3, 8, *}

* Corresponding author

1 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie

2 ITUN - Institut de transplantation urologie-néphrologie

3 OSE Immunotherapeutics [Nantes, France]

4 Clinical Pharmacology Unit Antwerp [Antwerp, Belgium]

5 Janssen Research & Development [Spring House, PA, USA]

6 Centre d’Immunomonitorage Nantes Atlantique - CIMNA - Laboratoire d’Immunologie [CHU Nantes]

7 Copexis S.A. [Pully, Switzerland]

8 LabEx IGO “Immunotherapy, Graft, Oncology” [Nantes]

Abstract : FR104 is a monovalent pegylated Fab9 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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Human health and pathology

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https://www.hal.inserm.fr/inserm-02150993
Contributor : Ana Paula Dutra Azevedo <>
Submitted on : Friday, June 7, 2019 - 3:58:22 PM
Last modification on : Saturday, June 8, 2019 - 1:25:36 AM

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

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

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