Inhibition of secretion from non-neuronal cells
The present invention relates to treatment of disease by inhibition of cellular secretory processes, to agents and compositions therefor, and to manufacture of those agents and compositions. The present invention relates particularly, to treatment of disease dependent upon the exocytotic activity of endocrine cells, exocrine cells, inflammatory cells, cells of the immune system, cells of the cardiovascular system and bone cells.
1 . A method for inhibiting secretion from a non-neuronal inflammatory cell, said method comprising administering an agent comprising at least first and second domains, wherein the first domain cleaves one or more proteins essential to exocytosis and the second domain translocates the first domain into the inflammatory cell.
2 . The method according to claim 1 , for treatment of disease caused, exacerbated or maintained by secretion from said non-neuronal inflammatory cell.
3 . The method according to claim 1 or 2 , wherein the agent further comprises a third domain for targeting the agent to said non-neuronal inflammatory cell.
4 . The method according to claim 3 wherein the third domain comprises or consists of a growth factor or an integrin-binding protein; or a ligand selected from (i) for mast cells, complement receptors in general, including C4 domain of the Fc IgE, and antibodies/ligands to the C3a/C4a-R complement receptor; (ii) for eosinophils, antibodies/ligands to the C3a/C4a-R complement receptor, anti VLA-4 monoclonal antibody, anti-IL5 receptor, antigens or antibodies reactive toward CR4 complement receptor; (iii) for macrophages and monocytes, macrophage stimulating factor, (iv) for macrophages, monocytes and neutrophils, bacterial IPS and yeast B-glucans which bind to CR3, (v) for neutrophils, antibody to 0X42, an antigen associated with the iC3b complement receptor, or IL8; (vi) for fibroblasts, mannose 6-phosphate/insulin-like growth factor-beta (M6P/IGFII) receptor and PA2.26, antibody to a cell-surface receptor for active fibroblasts in mice.
5 . The method according to claim 1 for the treatment of a disease selected from the group consisting of allergies (seasonal allergic rhinitis (hay fever), allergic conjunctivitis, vasomotor rhinitis and food allergy), eosinophilia, asthma, rheumatoid arthritis, systemic lupus erythematosus, discoid lupus erythematosus, ulcerative colitis, Crohn's disease, hemorrhoids, pruritus, glomerulonephritis, hepatitis, pancreatitis, gastritis, vasculitis, myocarditis, psoriasis, eczema, chronic radiation-induced fibrosis, lung scarring and other fibrotic disorders.
6 . The method according to claim 1 , wherein the agent comprises a first domain that cleaves a protein selected from SNAP-25, synaptobrevin and syntaxin.
7 . The method according to claim 1 wherein the first domain comprises a light chain of a clostridial neurotoxin, or a fragment, variant or derivative thereof which inhibits exocytosis.
8 . The method according to claim 1 , wherein the second domain comprises a HN region of a clostridial polypeptide, or a fragment, variant or derivative thereof that translocates the exocytosis inhibiting activity of the first domain into the cell.
9 . The method according to claim 1 for inhibition of constitutive and regulated release from non-neuronal inflammatory cells.
10 . The method according to claim 1 , wherein the agent is in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
11 . The method according to claim 3 , wherein the third domain is epidermal growth factor.
12 . The method according to claim 3 , wherein the third domain is an integrin-binding protein.
13 . The method according to claim 12 , wherein the third domain comprises the tri-peptide amino acid sequence Arg-Gly-Asp.
14 . The method according to claim 12 , wherein the third domain comprises a sequence selected from Arg-Gly-Asp-Phe-Val (SEQ ID NO: 23); Arg-Gly-Asp-{D-Phe}-{N-methyl-Val} (SEQ ID NO: 23); RGDFV (SEQ ID NO: 23); RGDfNMeV (SEQ ID NO: 23); GGRGDMFGA (SEQ ID NO: 21); GGCRGDMFGCA (SEQ ID NO: 22); GRGDSP (SEQ ID NO: 26); GRGESP (SEQ ID NO: 27); PLAEIDGIEL (SEQ ID NO: 24) and CPLAEIDGIELC (SEQ ID NO: 25), or a sequence having at least 80% identity therewith.
15 . The method according to claim 2 , wherein the agent further comprises a third domain for targeting the agent to said non-neuronal inflammatory cell.