The CD28/CTLA-4 pathway controls both T-cell activation and regulatory T-cell down regulation. CD28 receptor is expressed on the surface of the majority of naïve T-cells and is the major co-stimulatory molecule to generate T-cell activation.

In contrast, CTLA-4, a CD28 homologue, is expressed on activated T-cells, especially regulatory T-cells (T-Reg), and has been historically described as the essential component of the regulation of immune self-reactivation. Therefore, the CD28/CTLA-4 pathway is believed to be at the heart of different autoimmune diseases such as rheumatoid arthritis.

FR104, a monoclonal antibody fragment and CD28 antagonist, selectively blunts CD28 co-stimulation while sparing the CTLA-4 co-inhibitory signal. The net effect of CD28 antagonism is down regulating effector T-cells while promoting T-Reg activity.


FR104’s Phase 1 clinical study has shown initial signals of efficacy, a good safety profile and the recommended dose for a Phase 2, further supporting the continued clinical development of this asset in autoimmune diseases or in transplantation.

N. Poirier et al. ; First-in-Human Study in Healthy Subjects with FR104, a Pegylated Monoclonal Antibody Fragment Antagonist of CD28 ; Journal of Immunology; 2016

Early December 2020, the French National Agency for Medicines and Health Products Safety (ANSM) and the French Central Ethics Committee (CPP) approved the initiation of a Phase 1/2 trial evaluating first administration of FR104, in patients undergoing renal transplant. This study will be conducted as part of a collaboration agreement between OSE Immunotherapeutics and the University Hospital of Nantes, the trial’s sponsor.

The purpose of this Phase 1/2 clinical trial is to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of FR104 in renal transplant patients.

A long-term follow up assessment will be performed one year after the end of the study. Long term safety and efficacy will be evaluated in terms of renal function, incidence of rejection and all suspected FR104 related adverse events.

Pr. Gilles Blancho, Head of the ITUN (Institute of Urology and Nephrology Transplantation) within the University Hospital, will serve as the coordinating investigator.

OSE Immunotherapeutics is also working on a new Phase 2 clinical trial with FR104 in a niche indication in autoimmune diseases as the product has showcased a strong development potential in a number of indications.