FR104 offers control of graft-versus-host disease

OSE Immunotherapeutics’ study of the CD28 antagonist was published in Journal of Clinical Investigation

Lori Lesko
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NANTES, France—In a game-changing preclinical study targeted toward controlling graft-versus-host disease (GvHD), OSE Immunotherapeutics SA has shown new efficacy results evaluating FR104 and whether a transplant takes. This study, announced Aug. 22, showed strong evidence in the value of targeting CD28 in GvHD for potential clinical applications in autoimmune diseases and transplantation. GvHD is a condition that occurs when donor bone marrow or stem cells attack the recipient. FR104 is an antagonist of CD28, a receptor which controls the activity of effector T lymphocytes.
“The sum total of all preclinical and clinical data is now available on our CD28-antagonist FR104, which has built a strong basis to open its further development to various potential indications in immune-mediated diseases,” states Alexis Peyroles, CEO of OSE Immunotherapeutics. “This is indicative of the product’s interest and confirms it as a valuable asset for the company.”
Led by OSE and partners—Emory University of Atlanta, the University of Minnesota and the Fred Hutchinson Cancer Research Center of Seattle—the study shows new peer-reviewed evidence from the August 2018 issue of the Journal of Clinical Investigation that blocking CD28 with the selective antagonist FR104 prevents GvHD in a preclinical non-human primate model of bone marrow transplant by controlling T cell activation.
More specifically, the study focused on the evaluation of selective CD28-antagonist FR104 to determine its impact on T cell activation and GvHD when used both as a monotherapy or combined with immunosuppressant rapamycin in a preclinical model of bone marrow transplant, according to researchers. The results demonstrated that FR104 efficiently controlled GvHD when used as a monotherapy or in combination, and that this control was superior to the one observed with non-selective CD28-antagonist CTLA4-Ig.
Previous studies conducted with FR104 in preclinical models of transplant and other immune-mediated diseases have generated significant immune data related to the product, and in particular, demonstrated its ability to promote immunological tolerance and to reinforce immunosuppression, the company states.
The key to the promising preclinical trial is FR104, which generates significant immune data and promotes immunological tolerance, Peyroles says.
“During its Phase 1 clinical trial, FR104 demonstrated both good clinical safety and immunosuppressive activity,” he adds. “Our partner Janssen Biotech is planning to initiate a Phase 2a clinical trial of FR104 in autoimmune diseases.”
The OSE team preclinical study research “was conducted in primates, using a primate graft-versus-host disease model,” Peyroles tells DDNews. These data are one of a number of preclinical studies already completed to determine if the potential applications of FR104 (and therefore CD28 blockade) in immune-mediated disorders, such as transplant surgery or rheumatoid arthritis, can be successful. The next planned trial for FR104 is the Phase 2 trial in rheumatoid arthritis, which is a human trial.
Peyroles attributes OSE’s success to having a fully translational platform and collaborating with academic centers with expertise in immunotherapy. By leveraging these collaborations, the team acquired unique expertise and knowledge focused on novel target discovery to generate innovative agonists or antagonists of the immune response.
“These novel targets include CD28 that is part of a potent T cell co-stimulation pathway that plays an important role in immune responses to transplanted tissue, as well as in autoimmune diseases,” he remarks. “From preclinical studies we determined, among other things, that FR104 could promote immunological tolerance in a human skin allograft mouse model system.”
The critical finding from that study “was that selective CD28 blockade promotes Treg function in vivo and synergizes with adoptive Treg therapy to promote transplant survival,” Peyroles says. “Additional preclinical studies using allograft model systems showed that FR104 reinforces immunosuppression by inhibiting alloantibody development and increasing Helios‐negative Tregs in the blood and within the allograft. This led us to investigate, in this study, whether CD28 blockade helps to control T cell activation in a primate model of GvHD.”
“This study, in addition to the studies that came before it, has created a strong foundational understanding of the role of CD28 in both autoimmune diseases, as well as in transplantation used as excellent models of blockage of T cells associated with disease control,” Peyroles concludes. “The long-term goals of our partner Janssen will be to explore the value of CD28 blockade using FR104 in specific indications, starting with a Phase 2a clinical trial.”

Lori Lesko

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