Anti-PDGF antibodies and methods for producing engineered antibodies
First Claim
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1. A method for providing an engineered antibody or antibody fragment comprising:
- providing a panel of antibodies having specificity for a target, the panel of antibodies including a plurality of antibody members derived from a first species;
determining the sequence of at least a portion of a first member of the panel of antibodies;
comparing sequence of said first member of the panel to a reference library of antibody sequences or antibody fragment sequences from a target species, the target species being different from the first species;
selecting at least one sequence from a first member of the reference library which demonstrates a high degree of homology to the sequence of said first member of the panel and which contains a FR3 region;
obtaining the CDR3 region from said first member of the panel; and
incorporating the CDR3 region from said first member of the panel adjacent to the FR3 region of the at least one sequence from the first member of the reference library to form an engineered antibody or antibody fragment.
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Abstract
Methods of making and selecting engineered antibodies and/or antibody fragments provide maximized binding affinity for a predetermined target and minimized immunogenicity when such antibodies are administered to a target species. Libraries containing variants of the engineered antibodies are also provided. In particularly useful embodiments, anti-PGDF antibodies and compositions are produced which are useful in the treatment of various cancers.
64 Citations
64 Claims
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1. A method for providing an engineered antibody or antibody fragment comprising:
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providing a panel of antibodies having specificity for a target, the panel of antibodies including a plurality of antibody members derived from a first species;
determining the sequence of at least a portion of a first member of the panel of antibodies;
comparing sequence of said first member of the panel to a reference library of antibody sequences or antibody fragment sequences from a target species, the target species being different from the first species;
selecting at least one sequence from a first member of the reference library which demonstrates a high degree of homology to the sequence of said first member of the panel and which contains a FR3 region;
obtaining the CDR3 region from said first member of the panel; and
incorporating the CDR3 region from said first member of the panel adjacent to the FR3 region of the at least one sequence from the first member of the reference library to form an engineered antibody or antibody fragment. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)
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29. A method for providing an engineered antibody or antibody fragment comprising:
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providing a panel of antibodies having specificity for a target, the panel of antibodies including a plurality of antibody members derived from a first species;
selecting a first member of the panel having desired binding properties with respect to said target;
determining the sequence of at least a portion of a plurality of members of the panel of antibodies to determine a consensus sequence for the plurality of members;
comparing the consensus sequence to a reference library of antibody sequences or antibody fragment sequences from a target species, the target species being different from the first species;
selecting at least one sequence from a first member of the reference library which demonstrates a high degree of homology to the consensus sequence and which contains a FR3 region;
obtaining the CDR3 region from said first member of the panel; and
incorporating the CDR3 region from the first member of the panel adjacent to the FR3 region of the at least one sequence from the first member of the library to form an engineered antibody or antibody fragment. - View Dependent Claims (30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)
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51. A reference library of engineered antibodies or antibody fragments for selecting antibodies or antibody fragments, the library including variants of engineered antibodies or fragments, the variants having framework regions derived from an antibody native to a target species, the framework regions exhibiting a high degree of homology to the framework region of a first antibody having specificity for a predetermined target, a CDR3 region derived from the first antibody having specificity for a predetermined target, a combination of CDR1 and CDR2 regions from either the first antibody or the antibody native to the target species, and a combination of amino acids in the VHNL interface and/or Vernier zone, the combination of amino acids representing those present in the antibody native to the target species and those present in the first antibody.
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52. A humanized composite antibody or functional fragment of a humanized composite antibody comprising framework regions from one or more human antibody sequences and CDR regions from two different sources, at least one of which is non-human.
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53. A humanized composite antibody or functional fragment of a humanized composite antibody comprising framework regions from both germline and re-arranged human antibody sequences and CDR regions from two different sources, at least one of which is non-human.
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54. A humanized composite antibody or functional fragment of a humanized composite antibody comprising framework regions from one or more human antibody sequences, a non-human CDR3 and at least one of CDR1 or CDR2 being derived from a consensus of non-human antibody sequences.
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55. A method of providing a humanized composite antibody or functional fragment of a humanized composite antibody comprising combining framework regions from one or more human antibody sequences with CDR regions from two different sources, at least one of which is non-human, the framework regions being derived from human antibody sequences selected by:
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(i) establishing an antibody consensus sequence for a plurality of members from a panel of non-human antibodies that bind to a target;
(ii) substituting a CDR3 from an individual member of the panel of non-human antibodies for the CDR3 of the consensus sequence to form a composite sequence; and
(iii) comparing the composite sequence to a database of human antibody sequences and selecting at least one human antibody sequence based on homology to the composite sequence.
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56. A method of providing a humanized composite antibody or functional fragment of a humanized composite antibody comprising combining framework regions from two different human antibody sequences with CDR regions from two different sources, at least one of which is non-human, the framework regions being derived from two human antibody sequences selected by:
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(i) establishing an antibody consensus sequence for a plurality of members from a panel of non-human antibodies that bind to a target;
(ii) substituting a CDR3 from an individual member of the panel of non-human antibodies for the CDR3 of the consensus sequence to form a composite sequence;
(iii) comparing a first portion of the composite sequence to a database of human germline antibody sequences and selecting at least one human antibody sequence based on homology to the first portion of the composite sequence; and
(iv) comparing a second portion of the composite sequence to a database of human re-arranged antibody sequences and selecting at least one human antibody sequence based on homology to the second portion of the composite sequence.
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57. An engineered composite antibody sequence comprising CDR3 from an individual member of a panel of non-human antibodies that bind to a target, the balance of the engineered composite antibody sequence being derived from an antibody consensus sequence for a plurality of members from the panel of non-human antibodies.
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58. In a method of preparing a humanized antibody comprising the steps of incorporating CDR regions from a non-human donor antibody into framework regions from a human acceptor antibody, the improvement comprising selecting the human acceptor antibody sequence by:
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(i) establishing an antibody consensus sequence for a plurality of members from a panel of non-human antibodies that bind to a target;
(ii) substituting a CDR3 from an individual member of the panel of non-human antibodies for the CDR3 of the consensus sequence to form a composite sequence; and
(iii) comparing the composite sequence to a database of human antibody sequences and selecting at least one human acceptor antibody sequence based on homology to the composite sequence.
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59. An antibody light chain comprising at least one CDR derived from a CDR selected from the group consisting of CDR1, CDR2 and CDR3 of antibody C1.
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60. An antibody heavy chain comprising at least one CDR derived from a CDR selected from the group consisting of CDR1, CDR2 and CDR3 of antibody C1.
- 61. A method for treating a tumor comprising administering to a subject in need thereof an effective amount of an anti-PDGF antibody.
Specification