Altered antibodies
First Claim
1. An altered antibody or antigen binding fragment thereof, comprising a heavy chain variable domain, said variable domain comprising a set of four human Kabat framework regions (FRs) having an alteration, and three non-human Kabat complementarity determining regions (CDRs), wherein the alteration in said human FRs is at least one replacement of a first amino acid residue with a second amino acid residue, wherein said second amino acid residue is present in an antibody comprising said CDRs and FRs naturally associated with said CDRs at a position corresponding to said first amino acid residue, and wherein a 200% van der Waals surface thrown around said second amino acid residue in said antibody comprising said CDRs and the FRs naturally associated with said CDRs identifies a packing interaction with one or more amino acid residues in said CDRs, and wherein said first amino acid residue in said human FRs is unable to pack with said CDRs in the same way as said second amino acid residue in said FRs naturally associated with said CDRs;
- wherein said alteration enhances the binding of the altered antibody or antigen binding fragment thereof compared to an antibody comprising said CDRs and said human FRs without said alteration.
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Accused Products
Abstract
The invention relates to altered antibodies that have a heavy or light chain variable domain in which the framework regions differ from the framework regions naturally associated with the complementarity determining regions of the variable domain and in which the framework regions are derived from a source of framework regions that differs from the framework regions naturally associated with the complementarity determining regions of the variable regions.
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Citations
49 Claims
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1. An altered antibody or antigen binding fragment thereof, comprising a heavy chain variable domain, said variable domain comprising a set of four human Kabat framework regions (FRs) having an alteration, and three non-human Kabat complementarity determining regions (CDRs), wherein the alteration in said human FRs is at least one replacement of a first amino acid residue with a second amino acid residue, wherein said second amino acid residue is present in an antibody comprising said CDRs and FRs naturally associated with said CDRs at a position corresponding to said first amino acid residue, and wherein a 200% van der Waals surface thrown around said second amino acid residue in said antibody comprising said CDRs and the FRs naturally associated with said CDRs identifies a packing interaction with one or more amino acid residues in said CDRs, and wherein said first amino acid residue in said human FRs is unable to pack with said CDRs in the same way as said second amino acid residue in said FRs naturally associated with said CDRs;
- wherein said alteration enhances the binding of the altered antibody or antigen binding fragment thereof compared to an antibody comprising said CDRs and said human FRs without said alteration.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)
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8. A nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide comprising an altered antibody heavy chain variable domain, said variable domain comprising a set of four human Kabat FRs having an alteration, and three non-human Kabat CDRs, wherein the alteration in said human FRs is at least one replacement of a first amino acid residue with a second amino acid residue, wherein said second amino acid residue is present in an antibody comprising said CDRs and FRs naturally associated with said CDRs at a position corresponding to said first amino acid residue, and wherein a 200% van der Waals surface thrown around said second amino acid residue in said antibody comprising said CDRs and the FRs naturally associated with said CDRs identifies a packing interaction with one or more amino acid residues in said CDRs, and wherein said first amino acid residue in said human FRs is unable to pack with said CDRs in the same way as said second amino acid residue in said FRs naturally associated with said CDRs;
- wherein said alteration enhances the binding of the altered antibody or antigen binding fragment thereof compared to an antibody comprising said CDRs and said human FRs without said alteration.
- View Dependent Claims (9, 10, 11, 12, 13)
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14. A replicable vector comprising a promoter operably linked to a nucleotide sequence encoding a polypeptide comprising an altered antibody heavy chain variable domain, said variable domain comprising a set of four human Kabat FRs having an alteration, and three non-human Kabat CDRs, wherein the alteration in said human FRs is at least one replacement of a first amino acid residue with a second amino acid residue, wherein said second amino acid residue is present in an antibody comprising said CDRs and FRs naturally associated with said CDRs at a position corresponding to said first amino acid residue, and wherein a 200% van der Waals surface thrown around said second amino acid residue in said antibody comprising said CDRs and the FRs naturally associated with said CDRs identifies a packing interaction with one or more amino acid residues in said CDRs, and wherein said first amino acid residue in said human FRs is unable to pack with said CDRs in the same way as said second amino acid residue in said FRs naturally associated with said CDRs;
- wherein said alteration enhances the binding of the altered antibody or antigen binding fragment thereof compared to an antibody comprising said CDRs and said human FRs without said alteration.
- View Dependent Claims (15, 16, 17, 18, 19)
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36. A method of making an altered antibody or antigen binding fragment thereof comprising a heavy chain variable domain, said method comprising the following steps in the order stated:
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(a) constructing a nucleic acid comprising a nucleotide sequence encoding a heavy chain variable domain containing a set of four human Kabat FRs and three non-human Kabat CDRs;
(b) making an alteration in the nucleotide sequence, wherein said alteration is in the nucleotide sequence encoding said human FRs and results in at least one replacement of a first amino acid residue with a second amino acid residue, wherein said second amino acid residue is present in an antibody comprising said CDRs and FRs naturally associated with said CDRs at a position corresponding to said first amino acid residue, and wherein a 200% van der Waals surface thrown around said second amino acid residue in said antibody comprising said CDRs and the FRs naturally associated with said CDRs identifies a packing interaction with one or more amino acid residues in said CDRs, and wherein said first amino acid residue in said human FRs is unable to pack with said CDRs in the same way as said second amino acid residue in said FRs naturally associated with said CDRs;
wherein said alteration enhances the binding of the altered antibody or antigen binding fragment thereof compared to an antibody comprising said CDRs and said human FRs without said alteration;
(c) expressing said nucleic acid in a suitable host cell; and
(d) recovering said altered antibody or antigen binding fragment thereof. - View Dependent Claims (37, 38, 39, 40, 41, 42, 43)
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44. A method of altering a CDR grafted antibody or antigen binding fragment thereof comprising a heavy chain variable domain, said domain comprising a set of four human Kabat FRs and three non-human Kabat CDRs, said method comprising replacing in the FRs of the heavy chain variable domain a first amino acid residue with a second amino acid residue, wherein said second amino acid residue is present in an antibody comprising said CDRs and FRs naturally associated with said CDRs at a position corresponding to said first amino acid residue, and wherein a 200% van der Waals surface thrown around said second amino acid residue in said antibody comprising said CDRs and the FRs naturally associated with said CDRs identifies a packing interaction with one or more amino acid residues in said CDRs, and wherein said first amino acid residue in said human FRs is unable to pack with said CDRs in the same way as said second amino acid residue in said FRs naturally associated with said CDRs;
- wherein said alteration enhances the binding of the altered antibody or antigen binding fragment thereof compared to an antibody comprising said CDRs and said human FRs without said alteration.
- View Dependent Claims (45, 46, 47, 48, 49)
Specification