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Publication Number
US-8221753-B2
Publication Date
2012-07-17
Expiration Date
Abstract
The present application relates to compositions of humanized and humanized/deimmunized anti-endoglin antibodies and antigen-binding fragments thereof. One aspect relates to antibodies having one or more modifications in at least one amino acid residue of at least one of the framework regions of the variable heavy chain, the variable light chain or both. Another aspect relates to antibodies which bind endoglin and inhibit angiogenesis. Another aspect relates to the deimmunization of humanized antibodies to reduce immunogenicity. Another aspect relates to the use of humanized and humanized/deimmunized antibodies which bind endoglin for the detection, diagnosis or treatment of a disease or condition associated with endoglin, angiogenesis or a combination thereof.
Core Innovation
Humanized or humanized-deimmunized anti-endoglin (CD105) antibodies and antigen-binding fragments are provided. The antibodies bind endoglin (CD105) and inhibit angiogenesis, and the disclosed antibody sequence architectures include heavy-chain and light-chain variable-region amino-acid sequence definitions together with Kabat numbering framework-position amino-acid substitutions directed to reducing T-cell epitope immunogenicity.
The disclosed embodiments define heavy chain variable-region and light chain variable-region sequences by SEQ ID NO: 89 for the heavy chain variable region and SEQ ID NO: 93 for the light chain variable region. Additional variant sequence options and framework-position substitution sets are described using Kabat numbering, and immunogenicity assessment is discussed using in silico immunogenicity assessment mapping and MHC class II epitope mapping.
Use cases described include purification, detection, diagnosis, and therapeutic treatment of angiogenesis-associated diseases. The document also describes cancer treatment and diagnostic/functional evaluation frameworks centered on endoglin (CD105) and angiogenesis inhibition, including humanized anti-endoglin antibodies and antigen-binding fragments in combination regimens with angiogenesis inhibition strategies.
Claims Coverage
The independent claims define endoglin-binding isolated antibodies or antigen-binding fragments in feature groupings centered on specified heavy- and light-chain variable-region sequences and, in some claims, additional Kabat-position substitutions or sequence-identity options.
Endoglin-binding antibody or fragment defined by SEQ ID NO: 89 and SEQ ID NO: 93
An isolated antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region having the amino acid sequence set forth as SEQ ID NO: 89 and a light chain variable region having the amino acid sequence set forth as SEQ ID NO: 93.
Endoglin-binding antibody or fragment with specified Kabat-position substitutions
An isolated antibody that binds endoglin, or antigen-binding fragment thereof, wherein the heavy chain variable region further comprises one or more modifications selected from substitutions at position 49 (G by A or S), position 51 (A by I), position 52 (K by R or Q), and position 78 (L by V) using the Kabat numbering system, and the light chain variable region further comprises one or more modifications selected from substitutions at position 4 (M by L), position 19 (A by V), position 22 (T by S), position 48 (A by I), and position 51 (T by S) using the Kabat numbering system.
Endoglin-binding isolated antibody with specified variable-region substitutions
An isolated antibody that binds endoglin, or antigen-binding fragment thereof, comprising specified heavy-chain and light-chain variable-region sequences and further reciting specified Kabat-position substitutions or enumerated sequence identity options.
Overall, the independent claims are anchored in endoglin-directed isolated antibodies or antigen-binding fragments defined by heavy-chain and light-chain variable-region sequences set forth as SEQ ID NO: 89 and SEQ ID NO: 93, with additional claim narrowing by specified Kabat-numbered substitutions and endoglin-binding requirements.
Stated Advantages
Inhibits angiogenesis.
Reduces T-cell epitope immunogenicity through deimmunization concepts.
Documented Applications
Purification.
Detection.
Diagnosis.
Therapeutic treatment of angiogenesis-associated diseases, including ocular diseases such as macular degeneration, CNV, diabetic retinopathy, and proliferative vitreoretinopathy.
Therapeutic treatment of cancer, solid tumors, and metastases.
Cancer treatment and diagnostic/functional evaluation frameworks centered on endoglin (CD105) and angiogenesis inhibition.
Biomarker-detection methods for predicting sensitivity or resistance to angiogenesis inhibitors.
Kit/package concepts for biomarker detection and anti-endoglin antibody delivery.
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