ABSTRACT
The random amino acid copolymer poly(Y,E,A,K)(n) (Copaxone®) is widely used in multiple sclerosis treatment and a second generation copolymer poly(Y,F,A,K)(n) with enhanced efficacy in experimental autoimmune encephalomyelitis in mice has been described. A major mechanism through which copolymers function to ameliorate disease is the generation of immunosuppressive IL-10-secreting regulatory T cells entering the CNS. In addition, the antigen presenting cell to which these copolymers bind through MHC Class II proteins may have an important role. Here, both CCL22 (a Th2 cell chemoattractant) in large amounts and CXCL13 in much smaller amounts are shown to be secreted after administration of YFAK to mice and to a smaller extent by YEAK parallel to their serum concentrations. Moreover, bone marrow-derived macrophages secrete CCL22 in vitro in response to YFAK and to higher concentrations of YEAK. Strikingly, these chemokines are also secreted into serum of MHC Class II -/- mice, indicating that an innate immune receptor on these cells also has an important role. Thus, both the innate and the adaptive immune systems are involved in the mechanism of EAE amelioration by YFAK. The enhanced ability of YFAK to stimulate the innate immune system may account for its enhanced efficacy in EAE treatment.
Subject(s)
Amino Acids/pharmacology , Chemokines/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Immunity, Innate/immunology , Macrophages/immunology , Peptides/pharmacology , Amino Acid Sequence , Amino Acids/administration & dosage , Amino Acids/blood , Amino Acids/immunology , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/immunology , Cell Line , Chemokine CCL22/metabolism , Chemokine CXCL13/metabolism , Chemokines/blood , Encephalomyelitis, Autoimmune, Experimental/pathology , Glatiramer Acetate , Histocompatibility Antigens Class II/immunology , Immunity, Innate/drug effects , Interleukin-3/metabolism , Kinetics , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Molecular Sequence Data , Organ Specificity/drug effects , Peptides/administration & dosage , Peptides/blood , Peptides/immunology , Spleen/cytology , Spleen/drug effects , Spleen/immunologyABSTRACT
PI-2301 is an amino acid copolymer acting as an immunomodulator for the treatment of autoimmune diseases. The present study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics of PI-2301 in a single ascending dose, first-in-human study involving healthy, male adult volunteers. A total of 56 subjects were given a subcutaneous injection of PI-2301 ranging from 0.035 to 60 mg. The only consistent side effect was transient injection site reactions. We describe, for the first time, a pharmacokinetic assay to monitor amino acid copolymer concentration in human serum. PI-2301 was detected in the serum of subjects in the 10-, 30-, and 60-mg cohorts. Maximum serum concentration was achieved between 10 and 30 minutes postdosing with some compound detected 4 hours after dosing. PI-2301's lasting immunological properties were evident by an ex vivo recall assay showing T-cell proliferation and IL-13 production in subjects dosed with 1, 3, or 10 mg of PI-2301, up to 6 months after dosing. A transient increase in chemokine CXCL9 and CXCL10 plasma levels was seen in subjects dosed with 30 or 60 mg of PI-2301. These results are highly consistent with our preclinical findings and suggest that PI-2301 could facilitate the expansion of a favorable immune posture in patients with autoimmune disorders.
