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Publication Number
US-9150652-B2
Publication Date
2015-10-06
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
The invention relates to humanized or superhumanized anti-endoglin antibodies and antigen-binding fragments that bind endoglin (CD105) and inhibit angiogenesis. The antibodies comprise heavy chain variable region and light chain variable region amino acid sequences set forth as SEQ ID NO: 89 and SEQ ID NO: 93, with frameworks and CDRs described using Kabat numbering.
The disclosure also specifies Kabat-position substitutions in the heavy chain variable region and light chain variable region, including substitutions at heavy chain positions 49, 51, 52b, and 78, and light chain positions 4, 19, 22, 48, and 51. It refers to deimmunization, immunogenicity reduction, and in silico and/or T-cell epitope analysis concepts.
The antibodies and antigen-binding fragments are described for treating endoglin- and angiogenesis-associated diseases, including specified cancers, macular degeneration, age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, proliferative vitreoretinopathy, and cancer including metastasis. The disclosure further describes anti-angiogenic mechanisms in terms of angiogenesis inhibition, Smad signaling changes, and CD105/ALK1/TGF-β pathway involvement, and allows optional combination with angiogenesis inhibitors and other anti-angiogenic agents.
Claims Coverage
The independent claims cover administration of an endoglin-binding antibody or antigen-binding fragment with variable regions defined by SEQ ID NO: 89 and SEQ ID NO: 93 for treating specified cancers, macular degeneration, and age-related macular degeneration, with some claims further requiring Kabat-position substitutions. The inventive features center on the defined heavy and light chain variable regions and the specified modification sets, with optional co-administration of angiogenesis inhibitors in related dependent claims.
Endoglin-binding variable regions defined by SEQ ID NO: 89 and SEQ ID NO: 93 for treating specified cancers
A composition comprising an antibody or antigen-binding fragment thereof that binds endoglin, wherein the antibody comprises a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 89 and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 93, for treating a kidney cancer, a liver cancer, a colorectal cancer, a lung cancer, a sarcoma, or a brain cancer.
Kabat-position modifications on SEQ ID NO: 89 and SEQ ID NO: 93 for treating specified cancers
A composition comprising an antibody or antigen-binding fragment thereof that binds endoglin, wherein the antibody comprises 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, the heavy chain variable region further comprising one or more Kabat-position substitutions selected from the listed substitution sets, and the light chain variable region further comprising one or more Kabat-position substitutions selected from the listed substitution sets, for treating a kidney cancer, a liver cancer, a colorectal cancer, a lung cancer, a sarcoma, or a brain cancer.
Endoglin-binding variable regions defined by SEQ ID NO: 89 and SEQ ID NO: 93 for treating macular degeneration
A composition comprising an antibody or antigen-binding fragment thereof that binds endoglin, wherein the antibody comprises a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 89 and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 93, for treating macular degeneration.
Kabat-position modifications on SEQ ID NO: 89 and SEQ ID NO: 93 for treating age-related macular degeneration
A composition comprising an antibody or antigen-binding fragment thereof that binds endoglin, wherein the antibody comprises a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 89 and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 93, the heavy chain variable region further comprising one or more Kabat-position substitutions selected from the listed substitution sets, and the light chain variable region further comprising one or more Kabat-position substitutions selected from the listed substitution sets, for treating age-related macular degeneration (AMD).
Across the independent claims, the core coverage is administration of an endoglin-binding antibody or antigen-binding fragment whose variable regions are defined by SEQ ID NO: 89 and SEQ ID NO: 93, with two independent claims further requiring particular Kabat-numbering substitution sets in the heavy and/or light chain variable regions. Separate independent coverage is provided for specified cancers and for macular degeneration and AMD.
Stated Advantages
Provides methods of treating endoglin-associated disease states, including specified cancers and macular degeneration (including age-related macular degeneration).
Includes co-administration of one or more angiogenesis inhibitors alongside the endoglin-binding antibody in some embodiments.
Documented Applications
Treating kidney cancer, liver cancer, colorectal cancer, lung cancer, sarcoma, or brain cancer.
Treating macular degeneration, including age-related macular degeneration.
Treating choroidal neovascularization, diabetic retinopathy, proliferative vitreoretinopathy, and cancer including metastasis.
Optional combination with one or more angiogenesis inhibitors and other anti-angiogenic agents in the disclosed treatment methods.
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