Therapeutic Uses of Monoclonal Antibodies to the Angiotensin-II Type-1 Receptor

Abstract

The use of monoclonal antibodies to the angiotensin-II type-I receptor is provided for the treatment of cancer and vascular smooth muscle cell proliferation. Specifically, use is provided of a monoclonal antibody or a fragment thereof to a peptide comprising the N-terminal portion of the angiotensin-II type-1 receptor defined by the sequence (SEQ ID NO: 1) MILNSSTEDG IKRIQDDCPK AGRHNYIFVM IPTLYSIIFV VGIFG in the preparation of a medicament for the treatment of cancer or in the preparation of a medicament for the treatment of vascular smooth muscle (VSM) cell proliferation.

1 . A single chain Fv (scFv) molecule that binds to a peptide comprising the N-terminal portion of the angiotensin-II type-1 receptor. 
     
     
         2 . The scFv according to  claim 1  wherein the peptide comprising the N-terminal portion of the angiotensin-II type-1 receptor comprises Glu-Asp-Gly-Ile-Lys-Arg-Ile-Gln-Asp-Asp (SEQ ID NO:2), wherein, independently, Glu can be replaced with Asp or Gln, Asp can be replaced with Glu, Gly can be replaced with Ala, Ile can be replaced with Ala, Lys can be replaced with Arg, Arg can be replaced with Lys, and Gln can be replaced with Asn. 
     
     
         3 . The scFv according to  claim 1  wherein the peptide comprising the N-terminal portion of the angiotensin-II type-1 receptor comprises Glu-Asp-Gly-Ile-Lys-Arg-Ile-Gln-Asp-Asp (SEQ ID NO:2). 
     
     
         4 . The scFv according to  claim 1  wherein the peptide comprising the N-terminal portion of the angiotensin-II type-1 receptor comprises Met-Ile-Leu-Asn-Ser-Ser-Thr-Glu-Asp-Gly-Ile-Lys-Arg-Ile-Gln-Asp-Asp-Cys-Pro-Lys-Ala-Gly-Arg-His-Asn-Tyr-Ile-Phe-Val-Met-Ile-Pro-Thr-Leu-Tyr-Ser-Ile-Ile-Phe-Val-Val-Gly-Ile-Phe-Gly (SEQ ID NO:1). 
     
     
         5 . The scFv according to  claim 1  which is an scFv derived from monoclonal antibody 6313/G2 produced by the hybridoma cell line designated by European Collection of Animal Cell Cultures (ECACC) accession number 93072117. 
     
     
         6 . The scFv according to  claim 1  which is humanised. 
     
     
         7 . The scFv according to  claim 5  which is humanised. 
     
     
         8 . A composition comprising the scFv according to  claim 1 . 
     
     
         9 . A composition comprising a peptide sequence comprising the N-terminal portion of the angiotensin-II type-1 receptor defined by the sequence_MILNSSTEDG IKRIQDDCPK AGRHNYIFVM IPTLYSIIFV VGIFG (SEQ ID NO:1) or a fragment thereof comprising at least five amino acid residues. 
     
     
         10 . The composition according to  claim 9 , wherein the peptide is conjugated to a carrier protein. 
     
     
         11 . The composition according to  claim 9  further comprising an adjuvant. 
     
     
         12 . The composition according to  claim 9  wherein the peptide comprises up to 45 amino acids, and comprises EDGIKRIQDD (SEQ ID NO:2). 
     
     
         13 . The composition according to  claim 12 , wherein the peptide is conjugated to a carrier protein. 
     
     
         14 . A method of treating cancer or a disease or condition associated with vascular smooth muscle cell proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a monoclonal antibody, or a fragment thereof, that binds to a peptide; wherein the peptide comprises an N-terminal portion of an angiotensin-II type-1 receptor comprising the sequence MILNSSTEDG IKRIQDDCPK AGRHNYIFVM IPTLYSIIFV VGIFG (SEQ ID NO:1), a conservative mutant thereof, or an active fragment thereof comprising at least five amino acid residues. 
     
     
         15 . The method according to  claim 14  wherein the active fragment is a hexapeptide, heptapeptide, octapeptide, nonapeptide, or decapeptide. 
     
     
         16 . The method according to  claim 14  wherein the peptide comprises the sequence EDGIKRIQDD (SEQ ID NO:2), a conservative mutant thereof, or an active fragment thereof comprising at least five amino acid residues. 
     
     
         17 . The method according to  claim 16  wherein the conservative mutant comprises any one or more of the following amino acid substitutions: position 1 is E, D or Q, position 2 is D or E, position 3 is G or A, position 4 is I or A, position 5 is K or R, position 6 is R or K, position 7 is I or A, position 8 is Q or N, and position 9 and 10, independently, are each either D or E. 
     
     
         18 . The method according to  claim 14  wherein the monoclonal antibody is humanized. 
     
     
         19 . The method according to  claim 14  wherein the antibody fragment is a Fab, F(ab′) 2 , Fv, or scFv fragment. 
     
     
         20 . The method according to  claim 14  wherein the monoclonal antibody is 6313/G2 produced by the hybridoma cell line designated by accession no. 93072117.