Antibodies to human il 1-beta

Abstract

An IL-1β binding molecule, in particular an antibody to human IL-1β, especially a human antibody to human IL-1β is provided, wherein the CDRs of the heavy and light chains have amino acid sequences as defined, for use in the treatment of an IL-1 mediated disease or disorder, e.g. osteoarthritis, osteroporosis and other inflammatory arthritides.

1 . An IL-1β binding molecule which comprises an antigen binding site comprising at least one immunoglobulin heavy chain variable domain (V H ) which comprises in sequence hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence Ser-Tyr-Trp-Ile-Gly, said CDR2 having the amino acid sequence Ile-Ile-Tyr-Pro-Ser-Asp-Ser-Asp-Thr-Arg-Tyr-Ser-Pro-Ser-Phe-Gln-Gly, and said CDR3 having the amino acid sequence Tyr-Thr-Asn-Trp-Asp-Ala-Phe-Asp-Ile; and direct equivalents thereof.  
     
     
         2 . An IL-1β binding molecule comprising both heavy (V H ) and light chain (V L ) variable domains in which said IL-1β binding molecule comprises at least one antigen binding site comprising: 
 a) an immunoglobulin heavy chain variable domain (VH) which comprises in sequence hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence Ser-Tyr-Trp-Ile-Gly, said CDR2 having the amino acid sequence Ile-Ile-Tyr-Pro-Ser-Asp-Ser-Asp-Thr-Arg-Tyr-Ser-Pro-Ser-Phe-Gln-Gly, and said CDR3 having the amino acid sequence Tyr-Thr-Asn-Trp-Asp-Ala-Phe-Asp-Ile, and  
 b) an immunoglobulin light chain variable domain (V L ) which comprises a CDR3′ hypervariable region having the amino acid sequence Gln-Gln-Arg-Ser-Asn-Trp-Met-Phe-Pro;  
 and direct equivalents thereof.  
 
     
     
         3 . An IL-1β binding molecule according to  claim 2 , in which the immunoglobulin light chain variable domain (V L ) comprises in sequence hypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ having the amino acid sequence Arg-Ala-Ser-Gln-Ser-Val-Ser-Ser-Tyr-Leu-Ala, said CDR2′ having the amino acid sequence Asp-Ala-Ser-Asn-Arg-Ala-Thr, and said CDR3′ having the amino acid sequence Gln-Gln-Arg-Ser-Asn-Trp-Met-Phe-Pro; and direct equivalents thereof.  
     
     
         4 . An Il-1β binding molecule according to  claim 1 ,  2  or  3  which is a human antibody.  
     
     
         5 . An IL-1 binding molecule which comprises at least one antigen binding site comprising either a first domain having an amino acid sequence substantially identical to that shown in Seq. Id. No. 1 starting with amino acid at position 1 and ending with amino acid at position 128 or a first domain as described above and a second domain having an amino acid sequence substantially identical to that shown in Seq. Id. No. 2, starting with amino acid at position 1 and ending with amino acid at position 107.  
     
     
         6 . An IL-1β binding molecule according to any one of claim  1 - 5 , for use in for the treatment of an IL-1 mediated disease or disorder  
     
     
         7 . A first DNA construct encoding a heavy chain or fragment thereof which comprises 
 a) a first part which encodes a variable domain comprising alternatively framework and hypervariable regions, said hypervariable regions being in sequence CDR1, CDR2 and CDR3 the amino acid sequences of which are shown in Seq. Id. No. 1; this first part starting with a codon encoding the first amino acid of the variable domain and ending with a codon encoding the last amino acid of the variable domain, and    b) a second part encoding a heavy chain constant part or fragment thereof which starts with a codon encoding the first amino acid of the constant part of the heavy chain and ends with a codon encoding the last amino acid of the constant part or fragment thereof, followed by a stop codon.    
     
     
         8 . A second DNA construct encoding a light chain or fragment thereof which comprises 
 a) a first part which encodes a variable domain comprising alternatively framework and hypervariable regions; said hypervariable regions being CDR3′ and optionally CDR1′ and CDR2′, the amino acid sequences of which are shown in Seq. Id. No. 2; this first part starting with a codon encoding the first amino acid of the variable domain and ending with a codon encoding the last amino acid of the variable domain, and    b) a second part encoding a light chain constant part or fragment thereof which starts with a codon encoding the first amino acid of the constant part of the light chain and ends with a codon encoding the last amino acid of the constant part or fragment thereof followed by a stop codon.    
     
     
         9 . An expression vector able to replicate in a prokaryotic or eukaryotic cell line which comprises at least one DNA constructs according to  claim 7  or  claim 8 .  
     
     
         10 . A process for the product of an IL-1β binding molecule which comprises (i) culturing an organism which is transformed with an expression vector according to  claim 9  and (ii) recovering the IL-1β binding molecule from the culture.  
     
     
         11 . An antibody to IL-1β which has antigen binding specificity for an antigenic epitope of mature human IL-1β which includes the loop comprising residues Gly 22, Pro 23, Tyr 24 and Glu 25 and which is capable of inhibiting the binding of IL-1β to its receptor.  
     
     
         12 . i) use of an antibody to IL-1β, which has antigen binding specificity for an antigenic epitope of mature human IL-1β which includes the loop comprising residues Gly 22, Pro 23, Tyr 24 and Glu 25 and which is capable of inhibiting the binding of IL-1β to its receptor, for the treatment of an IL-1 mediated disease or disorder; 
 ii) a method for the treatment of an IL-1 mediated disease or disorders in a patient which comprises administering to the patient an effective amount of an antibody to IL-1β, which has antigen binding specificity for an antigenic epitope of mature human IL-1β which includes the loop comprising residues Gly 22, Pro 23, Tyr 24 and Glu 25 and which is capable of inhibiting the binding of IL-1β to its receptor;  
 iii) a pharmaceutical composition comprising an antibody to IL-1β, which has antigen binding specificity for an antigenic epitope of mature human IL-1β which includes the loop comprising residues Gly 22, Pro 23, Tyr 24 and Glu 25 and which is capable of inhibiting the binding of IL-1β to its receptor, in combination with a pharmaceutically acceptable excipient, diluent or carrier; and  
 iv) use of an antibody to IL-1β, which has antigen binding specificity for an antigenic epitope of mature human IL-1β which includes the loop comprising residues Gly 22, Pro 23, Tyr 24 and Glu 25 and which is capable of inhibiting the binding of IL-1β to its receptor, for the preparation of a medicament for the treatment of an IL-1 mediated disease or disorder.