Argos Therapeutics announced that an immunotherapy platform based on recombinant human soluble CD83 demonstrated significant promise for renal and heart transplantation.
“The in vivo activity of soluble CD83 continues to be impressive, particularly in its ability to specifically block anti-graft antibodies,” said Charles Nicolette, PhD, chief scientific officer and vice president of research and development of Argos. “This is the first demonstration of inhibiting specific antibody responses without global B cell depletion. Now, we have a greater understanding of how CD83 contributes to graft survival without requiring chronic administration or inducing global immunosuppression. This reinforces the potential role of our technology in addressing this unmet medical need.”
In vivo results from two studies showed CD83 induced kidney allograft tolerance and attenuated both innate and adaptive immune responses preventing chronic renal allograft rejection. In the first study, rat renal transplants were performed to examine both the acute and chronic effects of peritransplant CD83 treatment. Rat recipients treated exhibited a marked decrease in immunoglobulin M (IgM) and IgG deposition in the graft and antidonor antibody levels in the circulation, as early as preoperative day (POD) 14 and persisting until POD 140.
CD83 treatment reduced the infiltration of T cells and monocytes into the graft tissue and inhibited intragraft expression of myeloid differentiation primary response gene 88 and inflammatory cytokine levels during the observation period. CD83-treated grafts demonstrated normal histology beyond POD 140, including dramatic reductions in tubular atrophy and interstitial fibrosis compared with untreated recipients.
In the second study, life-supporting orthotropic kidney transplantation was performed in a mouse model. The study group was treated with CD83 and was compared with untreated controls. Mice treated with CD83 achieved kidney allograft tolerance (>100 days), with negligible antidonor antibody detected. In contrast, kidney grafts in untreated recipients demonstrated severe rejection after 35 days, characterized by cellular infiltration, interstitial hemorrhage and edema, and glomerular and tubular necrosis, as well as high antidonor antibody titers.
In addition, splenic dendritic cells (DCs) of tolerant recipients exhibited significantly decreased levels of surface major histocompatibility complex class II, CD40, CD80, and intracellular interleukin-12, as well as reduced allogeneic stimulatory capacity. Adoptive transfer of CD11c+ DCs from tolerant CD83-treated animals induced kidney allograft tolerance in syngeneic recipients. Blocking indoleamine 2,3-dioxygenase with 1-methyl-tryptophan (15 mg/mouse/day; gavage) prevented the immunosuppressive effect of CD83, abrogating CD83-induced Tol-DCs and graft tolerance, and leading to acute kidney graft rejection in 22 days.
“Combining our knowledge of dendritic cells and expertise in immunology to develop an immunotherapy platform based on CD83 may lead to an effective therapy for solid organ transplantation,” said Jeff Abbey, president and chief executive officer of Argos. “We intend to move into clinical trials to further test the safety and efficacy of our CD83 platform”
Release Date: May 4, 2011
Source: Argos Therapeutics, Inc.