Publications
Clinical Results of the First-in-Man Single Ascending Dose Study of PI-2301, a Second Generation Peptide Copolymer for the Treatment of Multiple Sclerosis
18th Meeting of the European Neurological Society, Nice France
Objectives: PI-2301 is a novel compound in a class of autoimmune therapeutics called peptide copolymers. Copolymers are random mixtures of peptide sequences comprised of limited numbers of amino acids. Copaxone® is a copolymer which has been approved as a primary treatment for Relapsing Remitting-Multiple Sclerosis (RR-MS). PI-2301, like Copaxone, is an immunomodulator which promiscuously binds to MHC Class II molecules and induces a skewed TH2 T-cell response characterized by the activation and expansion of T-cells and monocytes which secrete IL-4, IL-5, IL-10, IL-13 and CCL22. This regulatory response is believed to interfere with the expansion of autoreactive TH1/TH17 cells. PI-2301 has shown superior therapeutic efficacy as compared to Copaxone in murine experimental allergic encephalomyelitis (EAE), an animal model which resembles multiple sclerosis, in both daily and weekly subcutaneous (SC) dosing regimens. The purpose of the present study was to evaluate the safety, tolerability and early immunological effect(s) following SC administration of PI-2301 in a Single Ascending Dose, first-in-man study involving healthy, male adult volunteers.
Methods: The clinical study was designed in accordance with recommendations as defined in the Duff report and Committee for Human Medicinal Products (CHMP) guidelines issued in July 2007 for potentially immunmodulating therapeutics. Fifty-six subjects (eight cohorts of seven individuals; 5 active and 2 placebo) were given a single subcutaneous injection of PI-2301. The first dose was 0.01mg which is 100-fold below the Minimal Anticipated Biological Effect Level (MABEL) and 50,000-fold below the No Observed Adverse Effect Level (NOAEL) in the most sensitive animal species tested with PI-2301. The parameters evaluated were safety, monitoring, pharmacokinetics, in vitro T-cell recall responses, antibody response to PI-2301 and changes in serum cytokines and chemokines.
Results: PI-2301 was generally well tolerated through the doses tested thus far (6 of the scheduled 8 doses). Evidence of immune priming (as shown by T-cell specific proliferative and cytokine responses) was observed at the projected MABEL dose in humans, i.e., 1mg. Further data collection and analyses are currently underway and will be available in the coming months.
Conclusions: This study represents the initial step in the development of an improved peptide copolymer with immunomodulatory properties for the treatment of multiple sclerosis.
Preclinical and Clinical Development of a Second Generation Peptide Copolymer for the Treatment of Multiple Sclerosis
Federation of Clinical Immunology Societies Meeting 2008
Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells.
Proc Natl Acad Sci U S A
Illés Z, Stern JN, Reddy J, Waldner H, Mycko MP, Brosnan CF, Ellmerich S, Altmann DM, Santambrogio L, Strominger JL, Kuchroo VK.
Center for Neurologic Diseases, Harvard Institute of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. A humanized mouse bearing the HLA-DR2 (DRA/DRB1*1501) protein associated with multiple sclerosis (MS) and the myelin basic protein (MBP) 85-99-specific HLA-DR2-restricted T cell receptor from an MS patient has been used to examine the effectiveness of modified amino acid copolymers poly(F,Y,A,K)n and poly-(V,W,A,K)n in therapy of MBP 85-99-induced experimental autoimmune encephalomyelitis (EAE) in comparison to Copolymer 1 [Copaxone, poly(Y,E,A,K)n]. The copolymers were designed to optimize binding to HLA-DR2. Vaccination, prevention, and treatment of MBP-induced EAE in the humanized mice with copolymers FYAK and VWAK ameliorated EAE more effectively than Copolymer 1, reduced the number of pathological lesions, and prevented the up-regulation of human HLA-DR on CNS microglia. Moreover, VWAK inhibited MBP 85-99-specific T cell proliferation more efficiently than either FYAK or Copolymer 1 and induced anergy of HLA-DR2-restricted transgenic T cells as its principle mechanism. In contrast, FYAK induced proliferation and a pronounced production of the antiinflammatory T helper 2 cytokines IL-4 and IL-10 from nontransgenic T cells as its principle mechanism of immunosuppression. Thus, copolymers generated by using different amino acids inhibited disease using different mechanisms to regulate T cell responses.
Amelioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms.
Proc Natl Acad Sci U S A
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by approximately 30%. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic protein 85-99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with proteolipid protein 139-151 was demonstrated by using three protocols: (i) simultaneous administration of autoantigen and copolymer (termed prevention), (ii) pretreatment with copolymers (vaccination), or (iii) administration of copolymers after disease onset (treatment). Strikingly, in the treatment protocol administration of soluble VWAK and FYAK after onset of disease led to stasis of its progression and suppression of histopathological evidence of EAE. The mechanisms by which these effects are achieved have been examined in several types of assays: binding of copolymers to I-A(s) in competition with proteolipid protein 139-151 (blocking), cytokine production by T cells (T helper 2 polarization), and transfer of protection by CD3(+) splenocytes or, notably, by copolymer-specific T cell lines (induction of regulatory T cells). The generation of these copolymer-specific regulatory T cells that secrete IL-4 and IL-10 and are independent of the immunizing autoantigen is very prominent among the multiple mechanisms that account for the observed suppressive effect of copolymers in EAE.
Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice.
Proc Natl Acad Sci U S A.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. jstern@fas.harvard.edu
IL-10-secreting regulatory T cell lines specific to glatiramer acetate [poly(Y,E,A,K)n] or poly(Y,F,A,K)n have been established from the enlarged spleen and lymph nodes that result from copolymer treatment of SJL mice in which experimental autoimmune encephalomyelitis was induced by PLP139-151. These CD4+CD25+T cell lines secrete high levels of IL-10 and IL-13 but only small amounts of IL-4 and virtually no TGF-beta, IL-17, IL-6, IFN-gamma, or TNF-alpha. Their phenotypes are particularly characterized by the absence of Foxp3 and the presence of two TNFR family members, CD30 and GITR. The lines proliferated specifically to the immunizing copolymers but were autoantigen-nonspecific, in that the same T cell line could suppress autoimmunity induced by three different autoantigens in SJL mice, i.e., PLP139-151(EAE), MBP85-99 (EAE), and bovine peripheral nerve myelin (experimental autoimmune neuritis), indicating they function by bystander suppression.
