Recombinant monovalent antibodies and methods for production thereof
AssigneeGenmab A/S
InventorsPaul PARREN, Janine SCHUURMAN, Tom VINK, Willem Karel BLEEKER, Jan VAN DE WINKEL, Patrick VAN BERKEL, Frank BEURSKENS
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Abstract
The present invention provides monovalent antibodies with a long half-life when administered in vivo, methods of making such monovalent antibodies, pharmaceutical compositions comprising such antibodies, and uses of the monovalent antibodies.
Claims21
1-228. (canceled)
A method for producing a monovalent antibody, said method comprising
- a) providing a nucleic acid construct encoding the light chain of said monovalent antibody, said construct comprising a nucleotide sequence encoding the VL region of a selected antigen specific antibody and a nucleotide sequence encoding the constant CL region of an Ig, wherein said nucleotide sequence encoding the VL region of a selected antigen specific antibody and said nucleotide sequence encoding the CL region of an Ig are operably linked together, and wherein, in case of an IgG1 subtype, the nucleotide sequence encoding the CL region has been modified such that the CL region does not contain any amino acids capable of forming disulfide bonds or covalent bonds with other peptides comprising an identical amino acid sequence of the CL region in the presence of polyclonal human IgG or when administered to a human being;
- b) providing a nucleic acid construct encoding the heavy chain of said monovalent antibody, said construct comprising a nucleotide sequence encoding the VH region of a selected antigen specific antibody and a nucleotide sequence encoding a constant CH region of a human Ig, wherein the nucleotide sequence encoding the CH region has been modified such that the region corresponding to the hinge region and, as required by the Ig subtype, other regions of the CH region, such as the CH3 region, does not comprise any amino acid residues which participate in the formation of disulphide bonds or covalent or stable non-covalent inter-heavy chain bonds with other peptides comprising an identical amino acid sequence of the CH region of the human Ig in the presence of polyclonal human IgG or when administered to a human being, wherein said nucleotide sequence encoding the VH region of a selected antigen specific antibody and said nucleotide sequence encoding the CH region of said Ig are operably linked together;
- c) providing a cell expression system for producing said monovalent antibody;
- and
- d) producing said monovalent antibody by co-expressing the nucleic acid constructs of (i) and (ii) in cells of the cell expression system of (iii).
A nucleic acid construct for expression of a monovalent antibody for pharmaceutical use, comprising i) a nucleic acid sequence encoding the CH region of an IgG4, wherein the nucleic acid sequence encoding the CH region has been modified such that the region corresponding to the hinge region in said CH region does not comprise any amino acid residues capable of participating in the formation of stable disulphide bonds with peptides comprising an amino acid sequence identical to the amino acid sequence of said CH region in the presence of polyclonal human IgG or when administered to a human being or (ii) a nucleotide sequence encoding a constant CH region of a human Ig, wherein the nucleotide sequence encoding the CH region has been modified such that the region corresponding to the hinge region and, as required by the Ig subtype, other regions of the CH region, such as the CH3 region, does not comprise any amino acid residues which participate in the formation of disulphide bonds or covalent or stable non-covalent inter-heavy chain bonds with other peptides comprising an identical amino acid sequence of the CH region of the human Ig in the presence of polyclonal human IgG or when administered to a human being or (iii) a sequence complementary thereto.
Dependencies are inferred from the claim text.