Researchers led by Bernard Vanove of OSE Immunotherapeutics report in the December 7, 2016 issue of the Journal of Immunology on the first-in-human study of FR1041. OSE and collaborators at the University of Nantes and Janssen conducted a detailed phase I evaluation of safety, pharmacokinetics, pharmacodynamics and potency of FR104 in healthy volunteers.

FR104 is a humanized pegylated monovalent antibody and an antagonist of CD28 that has been shown to inhibit T-cell proliferation through pathways independent of CTLA4 and PD-1. The researchers speculate that FR014 may have success as an immune suppressor drug with better activity in transplant tolerance and other applications compared to drugs targeting CTLA4. OSE conducted this phase I study in 46 human subjects and using ex vivo methods.

Safety testing was of primary concern and all doses were well-tolerated with no adverse events or evidence of cytokine release syndrome. The authors believe that this validates their development strategy with FR104 as a monovalent Fab’ and avoiding issues such as those that halted development of another CD28 antagonist, TGN1412, in 2006.

Pharmacokinetic and pharmacodynamic results were positive, with dose response data suggesting that even low doses would provide the necessary biological activity.

Biological activity of FR104 was assessed using the Immucothel method from Biosyn, which relies on a dose of keyhole limpet hemocyanin (KLH) to induce immune responses. FR104 treatments were shown to inhibit KLH induced responses by measuring the levels of anti-KLH antibodies. Both the time to response and the level of response were inhibited by FR104 in a dose-dependent manner.

The TruCulture® ex vivo blood collection and culturing system was also used to monitor the effect of LPS/SEB stimulations in conjunction with FR104 treatment. IL-2 secretion was suppressed by FR104 in a dose-dependent manner. The secretion of IFNg and IL-8 was more variable, probably since these cytokines are also secreted by non-CD28 cells that would not be inhibited by FR104.

In summary, the results of this phase I study of FR104 are positive and suggest that this anti-CD28 molecule could have applications in multiple areas where immune suppression is important, such as transplantation and auto-immune disease. This potential was recognized by Janssen soon after the results of this study were available and prompted the acquisition of FR104 from OSE in a deal valued at up to $173M2.

1First-in-Human Study in Healthy Subjects with FR104, a Pegylated Monoclonal Antibody Fragment Antagonist of CD28. Poirier N, Blancho G, Hiance M, et al. J Immunol. 2016, 197 (12) 4593-4602; DOI: 10.4049/jimmunol.1601538

2 Taylor, NP. “UPDATED: J&J Bags CD28 Antagonist from OSE in €155M Autoimmune Deal.” FierceBiotech. Questex, 05 July 2016.