| 摘要 |
Disclosed is a humanized antibody or antibody fragment which is specific to an antigen other than IL-6, containing at least one heavy and light chain polypeptide wherein the light chain polypeptide is a humanized light chain polypeptide which contains at least the following (i) the amino acid residues spanning the first residue of FR1 through the terminus of FR3 including the CDR1 and CDR2 regions of a human light chain germ line sequence that is selected from a library of human germ line sequences based on its greater homology, which is defined as at least 90 percent sequence identity, of the selected amino acid residues spanning FR1 through FR3, and further wherein the percentage sequence identity is the highest relative to other human germ line sequences in the library, to the corresponding amino acid residues of the light chain of a parent rabbit antibody having specificity to a desired antigen that is to be humanized and (ii) further wherein the CDR residues in CDR1 and CDR2 corresponding to "selectivity determining residues" in the light chain of the same parent rabbit antibody are replaced with the corresponding rabbit selectivity determining residues; (iii) the amino acid residues encompassing the entire CDR3 region of the same parent rabbit antibody; (iv) the amino acid residues encompassing the entire FR4 region of an antibody light chain derived from a library of human germ line sequences based on its greater homology, which is defined as at least 90% sequence identity to the corresponding FR4 region contained in the light chain of the same parent rabbit antibody relative to the other germ line sequences in the library; and (v) wherein few or none of the FR residues of the human FR1, FR2, FR3 and FR4 regions in the selected homologous human FR regions are substituted with the corresponding rabbit FR residues, and wherein the heavy chain is a humanized heavy chain polypeptide which contains at least the following (i) the amino acid residues spanning the first residue of FR1 through the terminus of FR3 including the CDR1 and CDR2 regions encoded by a human germ line sequence that is selected from a library of human germ line sequences based on its greater homology, which is defined as at least 90% sequence identity, of the selected amino acid residues spanning FR1 through FR3, relative to other human germ line sequences in the library, to the corresponding amino acid residues of the heavy chain of a parent rabbit antibody having specificity to a desired antigen that is to be humanized and (ii) further wherein the CDR residues in the CDR1 and CDR2 regions of the human heavy chain corresponding to "selectivity determining residues" in the CDR1 and CDR2 regions of the heavy chain of the same parent rabbit antibody are replaced with the corresponding heavy chain selectivity determining residues contained in the CDR1 and CDR2 regions of the rabbit heavy chain; (iii) the amino acid residues encompassing the entire CDR3 region of the same parent rabbit antibody; (iv) the FR4 region derived from a library of human germ line sequences based on its greater homology, which is defined as at least 90% sequence identity, to the corresponding FR4 region contained in the heavy chain of the same parent rabbit antibody; and (v) wherein the final 1-3 amino acids of the human heavy FR1 region are optionally replaced with the terminal 1-3 amino acids of the corresponding rabbit heavy chain FR1 residues; and/or the terminal amino acid of the human heavy chain framework 2 region is optionally replaced with the corresponding terminal amino acid residue of the rabbit heavy chain framework 2; and/or the fourth amino acid from the terminus of the rabbit heavy chain CDR2, typically a tryptophan, is optionally replaced with the corresponding human CDR2 residue, typically a serine; and (vi) wherein few of none of the remaining FR residues of the selected homologous human FR regions are substituted with the corresponding rabbit FR residues.
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