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

FR104 is under a global license agreement (April 2021) with Veloxis Pharmaceuticals Inc., a leading transplantation company, to develop, manufacture and commercialize FR104 for all transplant indications. Based on preclinical and Phase 1 successful studies, Veloxis plans to advance FR104 development to provide a new therapeutic option for prophylaxis of organ rejection in patients receiving a solid organ transplant.

A Phase 1/2 trial is evaluating first administration of FR104, in patients undergoing renal transplant. This study is being 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.

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

OSE Immunotherapeutics is also planning 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.