Recombinant anti-VLA-4 antibody molecules

A DNA encoding an antibody molecule, or an α4-binding fragment thereof, comprising:

• at least one antibody heavy chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107);
• and
• at least one antibody light chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

A vector comprising DNA encoding an antibody molecule or an α4-binding fragment thereof comprising:

• at least one antibody heavy chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107);
• and
• at least one antibody light chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

An expression vector comprising DNA encoding an antibody molecule, or an α4-binding fragment thereof, comprising:

• at least one antibody heavy chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107);
• and
• at least one antibody light chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100),
• wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

A host cell transformed with a vector comprising DNA encoding an antibody molecule or an α4-binding fragment thereof comprising:

• at least one antibody heavy chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107);
• and
• at least one antibody light chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

A process for the production of a humanized recombinant anti-α4 antibody, or an α4-binding fragment thereof, comprising:

• (a) producing a first expression vector comprising an operon having a DNA sequence encoding an antibody heavy chain, or an α4-binding fragment thereof, or light chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin;
• (b) producing a second expression vector comprising an operon having a DNA sequence encoding a complementary antibody light chain, or an α4-binding fragment thereof, or heavy chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin;
• (c) transfecting a host cell with the first and second expression vector;
• and
• (d) culturing the transfected cell line to produce the humanized recombinant anti-α4 antibody molecule, or α4-binding fragment thereof,
• provided that the light chain, or an α4-binding fragment thereof, comprises non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

A process for the production of a humanized recombinant anti-α4 antibody, or an α4-binding fragment thereof, comprising:

• (a) producing an expression vector comprising (i) an operon having a DNA sequence encoding an antibody heavy chain, or an α4-binding fragment thereof, or light chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin, and (ii) an operon having a DNA sequence encoding a complementary antibody light chain, or an α4-binding fragment thereof, or heavy chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin;
• (b) transfecting a host cell with said vector;
• and
• (c) culturing the transfected cell line to produce the humanized recombinant anti-α4 antibody molecule, or α4-binding fragment thereof,
• provided that the light chain, or an α4-binding fragment thereof, comprises non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

A process for the production of a humanized recombinant anti-α4 antibody, or an α4-binding fragment thereof, comprising:

• (a) producing a first expression vector comprising an operon having a DNA sequence encoding an antibody heavy chain, or an α4-binding fragment thereof, or light chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin;
• (b) producing a second expression vector comprising an operon having a DNA sequence encoding a complementary antibody light chain, or an α4-binding fragment thereof, or heavy chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin;
• (c) transfecting a host cell with the first and second expression vector;
• and
• (d) culturing the transfected cell line to produce the humanized recombinant anti-α4 antibody molecule, or an α4-binding fragment thereof,
• provided that the heavy chain, or an α4-binding fragment thereof, comprises non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107).

A process for the production of a humanized recombinant anti-α4 antibody, or an α4-binding fragment thereof, comprising:

• (a) producing an expression vector comprising (i) an operon having a DNA sequence encoding an antibody heavy chain, or an α4-binding fragment thereof, or light chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin, and (ii) an operon having a DNA sequence encoding a complementary antibody light chain, or an α4-binding fragment thereof, or heavy chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin;
• (b) transfecting a host cell with said vector;
• and
• (c) culturing the transfected cell line to produce the humanized recombinant anti-α4 antibody molecule, or an α4-binding fragment thereof,
• provided that the heavy chain, or an α4-binding fragment thereof, comprises non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107).

A process for the production of a humanized recombinant anti-α4 antibody, or an α4-binding fragment thereof, comprising:

• (a) producing a first expression vector comprising an operon having a DNA sequence encoding an antibody heavy chain, or an α4-binding fragment thereof, or light chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin;
• (b) producing a second expression vector comprising an operon having a DNA sequence encoding a complementary antibody light chain, or an α4-binding fragment thereof, or heavy chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin;
• (c) transfecting a host cell with the first and second vector;
• and
• (d) culturing the transfected cell line to produce the humanized recombinant anti-α4-antibody molecule or an α4-binding fragment thereof,
• provided that (i) the heavy chain, or an α4-binding fragment thereof, comprises non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107);
• and (ii) the light chain, or an α4-binding fragment thereof, comprises non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

A process for the production of a humanized recombinant anti-α4 antibody, or an α4-binding fragment thereof, comprising:

• (a) producing an expression vector comprising (i) an operon having a DNA sequence encoding an antibody heavy chain, or an α4-binding fragment thereof, or light chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin, and (ii) an operon having a DNA sequence encoding a complementary antibody light chain, or an α4-binding fragment thereof, or heavy chain, or an α4-binding fragment thereof, wherein the CDRs of the variable domain are derived from a mouse anti-α4 antibody and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin;
• (b) transfecting a host cell with said vector;
• and
• (c) culturing the transfected cell line to produce the humanized recombinant anti-α4 antibody molecule or an α4-binding fragment thereof,
• provided that (i) the heavy chain, or an α4-binding fragment thereof, comprises non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107);
• and (ii) the light chain, or an α4-binding fragment thereof, comprises non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

A therapeutic composition comprising an antibody molecule, or an α4-binding fragment thereof, having one or both of:

• an antibody heavy chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107);
• and
• an antibody light chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107,
• in combination with a pharmaceutically acceptable diluent, excipient or carrier.

A diagnostic composition comprising an antibody molecule, or an α4-binding fragment thereof, having in a detectably labeled form one or both of:

• an antibody heavy chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107), and
• an antibody light chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

A method for treating inflammation associated with a VCAM-1/VLA-4 adhesion pathway in a mammalian subject which comprises providing to a subject in need of such treatment an amount of an anti-inflammatory agent sufficient to suppress the inflammation, wherein the anti-inflammatory agent comprises an antibody, or an α4-binding fragment thereof, having one or both of:

• an antibody heavy chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107);
• and
• an antibody light chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107.

A humanized recombinant anti-α4 antibody molecule, or α4-binding fragment thereof, which comprises a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of:

• SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51, and SEQ ID NO:
• 55, in combination with a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of:
• SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67.

A DNA encoding a humanized recombinant anti-α4 antibody molecule or α4-binding fragment thereof, comprising DNA encoding:

• a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of:
• SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51, and SEQ ID NO:
• 55, and a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of:
• SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67.

A vector comprising DNA encoding a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of:

• SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51, and SEQ ID NO:
• 55, and a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of:
• SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67.

An expression vector comprising DNA encoding a humanized antibody molecule, or α4-binding fragment thereof, wherein the humanized recombinant anti-α4 antibody molecule, or α4-binding fragment thereof, comprises a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of:

• SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51, and SEQ ID NO:
• 55, and a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of:
• SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67.

A host cell transformed with a vector comprising DNA encoding a humanized recombinant anti-α4 antibody molecule, or α4-binding fragment thereof, comprising a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of:

• SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51, and SEQ ID NO:
• 55, and a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of:
• SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67.

A host cell transformed with an expression vector comprising DNA encoding an antibody molecule, or α4-binding fragment thereof, comprising a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of:

• SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51, and SEQ ID NO:
• 55, and a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of:
• SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67.

A therapeutic composition comprising, in combination with a pharmaceutically acceptable diluent, excipient or carrier, an antibody molecule, or α4-binding fragment thereof, which comprises a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of:

• SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51, and SEQ ID NO:
• 55, and a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67.

A diagnostic composition comprising an antibody molecule, or α4-binding fragment thereof, which comprises a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of:

• SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51 and SEQ ID NO:
• 55, and a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67, in a detectably labeled form.

A method for treating inflammation associated with a VCAM-1/VLA-4 adhesion pathway in a mammalian subject, the method comprising providing to a subject in need of such treatment an amount of an anti-inflammatory agent sufficient to suppress the inflammation, wherein the anti-inflammatory agent comprises an antibody, or α4-binding fragment thereof, which comprises a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of:

• SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51 and SEQ ID NO:
• 55, and a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of SEQ ID NO:
• 31, SEQ ID NO:
• 63 and SEQ ID NO:
• 67.

A composition comprising a humanized anti-α4 antibody molecule, or an α4-binding fragment thereof which comprises a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of SEQ ID NO:

• 39, SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51, SEQ ID NO:
• 55, in combination with a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67 in combination with a pharmaceutically acceptable diluent, excipient or carrier.

A method for treating inflammation associated with a VCAM-1/VLA-4 adhesion pathway in a mammalian subject, the method comprising providing to a subject in need of such treatment an amount of an anti-inflammatory agent sufficient to suppress the inflammation, wherein the anti-inflammatory agent comprises a humanized recombinant anti-α4 antibody molecule, or an α4-binding fragment thereof, which comprises a humanized heavy chain, or an α4-binding fragment thereof, comprising a variable heavy chain region selected from the group consisting of SEQ ID NO:

• 39, SEQ ID NO:
• 43, SEQ ID NO:
• 47, SEQ ID NO:
• 51, SEQ ID NO:
• 55, in combination with a humanized light chain, or an α4-binding fragment thereof, comprising a light chain variable region selected from the group consisting of SEQ ID NO:
• 31, SEQ ID NO:
• 63, and SEQ ID NO:
• 67 in combination with a pharmaceutically acceptable diluent, excipient or carrier.

A humanized recombinant anti-α4 antibody molecule, or α4-binding fragment thereof, comprising:

• at least one antibody heavy chain, or an α4-binding fragment thereof, comprising three non-human CDRs from the HP1/2 murine monoclonal antibody (SEQ ID NO:
• 6 and SEQ ID NO:
• 10);
• and
• at least one antibody light chain, or an α4-binding fragment thereof, comprising three non-human CDRs from the HP1/2 murine monoclonal antibody (SEQ ID NO:
• 6 and SEQ ID NO:
• 10);
• wherein said humanized antibody has a binding affinity, as defined by half maximal binding constant, from about 20% to about 100% of the binding affinity of the HP1/2 murine monoclonal antibody.

A therapeutic composition comprising an antibody molecule or an α4-binding fragment thereof, comprising:

• at least one antibody heavy chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein said positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30 (SEQ ID NO:
• 107);
• and
• at least one antibody light chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) from a mouse anti-α4 antibody and framework regions from the REI monoclonal antibody (SEQ ID NO:
• 100), wherein said REI framework regions have at least one non-human framework residue and the amino acid sequence Val 104, Glu 105 and Lys 107, in combination with a pharmaceutically acceptable diluent, excipient or carrier.