Therapeutic Agent

Abstract

The present invention relates to agents which modulate the effect of a RAMP (Receptor Activity Modifying Protein) protein on a Calcitonin Receptor Like Receptor (CRLR). Also included in the present invention are methods and uses of such agents and assays for identifying such agents. The agents of the present disclosure may be used in the treatment of, for example, cancer, obesity and other disorders.

1 . An agent which is capable of binding to and or modulating an effect of a calcitonin receptor-like receptor (CRLR) of one or more RAMP proteins (Receptor Activity Modifying Protein) selected from (i) a RAMP-3, (ii) a RAMP-2 and (iii) a RAMP-1 protein. 
     
     
         2 . An agent according to  claim 1  which binds to an extracellular domain of a RAMP protein. 
     
     
         3 . An agent according to  claim 2 , which is capable of modulating interaction of RAMP-3 and CRLP. 
     
     
         4 . An agent according to  claim 1 , which specifically binds to the extracellular domain of a RAMP-3 protein. 
     
     
         5 . An agent according to  claim 1  which binds at least one ligand selected from:
 (a) a peptide moiety of 1 to 31 amino acid residues including a sequence of contiguous amino acid residues comprised in the sequence of contiguous amino acids from position 1 to position 31 of a human RAMP-3 protein as shown in SEQ ID NO: 6;   (b) a peptide moiety of 1 to 15 amino acid residues including a sequence of contiguous amino acid residues comprised in the sequence of contiguous amino acids from position 32 to position 46 of a human RAMP-3 protein as shown in SEQ ID NO: 6; and   (c) a peptide moiety of 1 to 53 amino acid residues including a sequence of contiguous amino acid residues comprised in the sequence of contiguous amino acids from position 47 to position 99 of human RAMP-3 protein as shown in SEQ ID NO: 6.   
     
     
         6 . An agent according to  claim 1  which binds to at least one ligand selected from:
 (a) a peptide moiety of 1 to 32 amino acid residues including a sequence of contiguous amino acid residues comprised in the sequence of contiguous amino acids from position 1 to position 32 of a human RAMP-3 protein as shown in SEQ ID NO: 6;   (b) a peptide moiety of 1 to 14 amino acid residues including a sequence of contiguous amino acid residues comprised in the sequence of contiguous amino acids from position 33 to position 46 of a human RAMP-3 protein as shown in SEQ ID NO: 6; and   (c) a peptide moiety of 1 to 53 amino acid residues including a sequence of contiguous amino acid residues comprised in the sequence of contiguous amino acids from position 47 to position 99 of human RAMP-3 protein as shown in SEQ ID NO: 6.   
     
     
         7 . (canceled) 
     
     
         8 . An agent according to  claim 1  which binds to a fragment of a human RAMP-3, wherein said fragment is produced by enzyme digestion of a RAMP-3 extracellular domain using human caspase-3 and human calpain-1. 
     
     
         9 . An agent according to  claim 1 , which is capable of inhibiting proliferation of a human SW-13 cell by at least 10%, wherein said inhibition is measured using a MTT Cell Proliferation assay. 
     
     
         10 . An agent according to  claim 9 , which is capable of inhibiting proliferation by at least 12%. 
     
     
         11 - 12 . (canceled) 
     
     
         13 . An agent according to  claim 1 , which is capable of reducing or inhibiting production of cAMP in a human MG63 osteosarcoma cell, when stimulated by adrenomedullin, by at least about 15%. 
     
     
         14 . (canceled) 
     
     
         15 . An agent according to  claim 1 , wherein the RAMP-1 protein is selected from
 i) a polypeptide, or variant thereof, encoded by a nucleic acid molecule consisting of a nucleic acid sequence as represented by SEQ ID NO: 1;   ii) a polypeptide encoded by a nucleic acid molecule which hybridises under stringent conditions to a nucleic acid molecule as defined in (i) above and which modulates CRLR function; and   iii) a polypeptide encoded by a nucleic acid which is degenerate as a result of the genetic code to the nucleic acid sequence defined in (i) and (ii), characterised in that said agent is for use as a pharmaceutical,   and wherein the RAMP-2 protein is selected from:   i) a polypeptide, or variant thereof, encoded by a nucleic acid molecule consisting of a nucleic acid sequence as represented by SEQ ID NO: 3;   ii) a polypeptide encoded by a nucleic acid molecule which hybridises under stringent conditions to a nucleic acid molecule as defined in (i) above and which modulates CRLR function; and   iii) a polypeptide comprising a nucleic acid which is degenerate as a result of the genetic code to the nucleic acid sequence defined in (i) and (ii), characterised in that said agent is for use as a pharmaceutical,   and further wherein the RAMP-3 protein is selected from:   i) a polypeptide, or variant thereof, encoded by a nucleic acid molecule consisting of a nucleic acid sequence as represented by SEQ ID NO: 5;   ii) a polypeptide encoded by a nucleic acid molecule which hybridises under stringent conditions to a nucleic acid molecule as defined in (i) above and which modulates CRLR function; and   iii) a polypeptide comprising a nucleic acid which is degenerate as a result of the genetic code to the nucleic acid sequence defined in (i) and (ii).   
     
     
         16 . An agent that modulates the effect of a polypeptide on calcitonin receptor like receptor (CRLR) function wherein said polypeptide is selected from the group consisting of:
 i) a polypeptide, or variant thereof, encoded by a nucleic acid molecule consisting of a nucleic acid sequence as represented by SEQ ID NO: 1, 3 or 5;   ii) a polypeptide encoded by a nucleic acid molecule which hybridises under stringent conditions to a nucleic acid molecule as defined in (i) above and which modulates CRLR function; and   iii) a polypeptide comprising a nucleic acid which is degenerate as a result of the genetic code to the nucleic acid sequence defined in (i) and (ii), characterised in that said agent is for use as a pharmaceutical.   
     
     
         17 . An agent according to  claim 1 , wherein the agent is an antagonist and which optionally interferes with binding between a RAMP protein and the CRLR and/or interferes with binding of a ligand to CRLR and/or a RAMP protein. 
     
     
         18 . An agent according to  claim 1  wherein the agent is an agonist. 
     
     
         19 . An agent according to  claim 1 , which is an antibody product selected from antibodies and antibody fragments; a protein; a polypeptide; a fusion protein; an aptamer; and a compound. 
     
     
         20 . An agent according to  claim 1 , wherein the agent is an antibody or an active binding part of an antibody. 
     
     
         21 . An agent according to  claim 20  wherein the antibody product is a monoclonal antibody or active binding part thereof. 
     
     
         22 . An agent according to  claim 20  wherein the antibody product is a selected from chimeric antibody antibodies and humanized antibodies. 
     
     
         23 . (canceled) 
     
     
         24 . An agent according to  claim 20 , wherein the antibody product is an antibody fragment. 
     
     
         25 . An agent according to  claim 24  wherein the antibody fragment is selected from a single chain antibody, a single chain variable fragment (scFv), a domain antibody (dAB) and a nanobody, 
     
     
         26 . An agent according to  claim 20 , wherein the antibody product is a conjugate. 
     
     
         27 . An agent according to  claim 1  wherein the agent has associated therewith or crosslinked thereto a chemotherapeutic agent. 
     
     
         28 . An agent according to  claim 1 , wherein the agent comprises a detectable marker. 
     
     
         29 . An agent according to  claim 1  wherein the agent is a nucleic acid molecule. 
     
     
         30 . An agent according to  claim 29  wherein the nucleic acid is an antisense nucleic acid, an aptamer or a small interfering RNA. 
     
     
         31 . (canceled) 
     
     
         32 . A pharmaceutical formulation comprising an agent as claimed in  claim 1  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         33 . A vector which is adapted for the expression of an antibody according to  claim 19 . 
     
     
         34 . A cell which has been transformed or transfected with a vector as claimed in  claim 33 . 
     
     
         35 . (canceled) 
     
     
         36 . A hybridoma cell line which produces a monoclonal antibody as claimed in  claim 20 . 
     
     
         37 - 48 . (canceled) 
     
     
         49 . A method as claimed in  claim 53  wherein the inflammatory disorder is selected from the group consisting of atherosclerosis, rheumatoid arthritis, osteoarthritis, sepsis and polyarthritis. 
     
     
         50 - 52 . (canceled) 
     
     
         53 . A method for treating a disorder in a subject, comprising administering to the subject an agent according to  claim 1 , wherein the disorder is selected from the group consisting of: cancer, osteoporosis, obesity, inflammatory disorders and/or inflammatory responses, angiopathy, diabetic angiopathy, microangiopathy, macroangiopathy, heart failure and wound healing.