Super humanized antibodies
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Abstract
Disclosed herein are methods for humanizing antibodies based on selecting variable region framework sequences from human antibody genes by comparing canonical CDR structure types for CDR sequences of the variable region of a non-human antibody to canonical CDR structure types for corresponding CDRs from a library of human antibody sequences, preferably germline antibody gene segments. Human antibody variable regions having similar canonical CDR structure types to the non-human CDRs form a subset of member human antibody sequences from which to select human framework sequences. The subset members may be further ranked by amino acid similarity between the human and the non-human CDR sequences. Top ranking human sequences are selected to provide the framework sequences for constructing a chimeric antibody that functionally replaces human CDR sequences with the non-human CDR counterparts using the selected subset member human frameworks, thereby providing a humanized antibody of high affinity and low immunogenicity without need for comparing framework sequences between the non-human and human antibodies. Chimeric antibodies made according to the method are also disclosed.
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Citations
89 Claims
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1-46. -46. (canceled)
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47. A method of designing a molecule that binds an antigen, comprising,
determining a canonical CDR structure type for at least two CDRs in a variable region of a subject antibody that binds the antigen; -
selecting an object variable region from an object antibody based on whether the object variable region has the same canonical CDR structure types at corresponding locations in the object variable region as the at least two canonical CDR structure types of the subject variable region; and
designing a molecule that binds the same antigen as the subject antibody comprising a chimeric variable region having the at least two CDRs from the subject variable region grafted into a framework sequence of the selected object variable region at the corresponding locations, where the framework sequence of the chimeric variable region differs from the framework sequence of the selected object variable region by no more than 10 amino acid residues. - View Dependent Claims (48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78)
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79. A humanized antibody variable region assembled into a molecule that binds an antigen, comprising
a chimeric antibody variable region containing at least two non-human CDR sequences grafted into a human variable region framework sequence, the chimeric variable region being characterized by having no more than 10 amino acid residues that differ from a framework sequence of a candidate human antibody variable region having at least two human CDR sequences with the same canonical structure type as the non-human CDR sequences for at least two corresponding CDR positions.
Specification