Anti-extended type I glycosphingolipid antibody, derivatives thereof and use
Inventors
Chang, Tong-Hsuan • Ting, Jerry • Hong, Tsai-Hsia • Yang, Mei-Chun • Liu, Liahng-Yirn • Chang, Shu-Yen • Chen, Ying-Jin • Wen, Jaw-Yuan • Handa, Kazuko • Hakomori, Sen-itiroh
Assignees
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Publication Number
US-8163497-B2
Publication Date
2012-04-24
Expiration Date
Abstract
Human antibodies and antigen-binding portions of those antibodies that specifically bind extended Type I chain glycosphingolipids are provided.
Core Innovation
The invention relates to an isolated human monoclonal antibody, or antigen binding portion thereof, that specifically binds an epitope comprising an extended Type I chain comprising Le(b). The epitope is expressed on a cancer cell, and the antibody or antigen binding portion thereof does not bind to human erythrocytes. The antibody contains a heavy chain variable region including all the complementarity-determining regions of SEQ ID NO:15 and a light chain variable region including all the complementarity-determining regions of SEQ ID NO:17.
The disclosed antibody is characterized for binding specificity to extended Type I structures, including fucosylated extended Type I structures such as Le(b)-Le(a), while lacking binding to related structures such as LeX, LeY, and LeY-LeX. Epitope characterization is described using defucosylation and competitive ELISA with synthetic glycans, supporting the defined extended Type I epitope comprising Le(b).
The document also describes therapeutic compositions and an article of manufacture format that can include sealed sterile container(s) and an optional buffer container, intended to provide a liquid formulation containing the extended Type I glycosphingolipid-targeting antibody. In addition, the document discusses gene therapy approaches using nucleic acids encoding the antibody or antigen binding portions via expression vectors and delivery methods including viral and non-viral approaches, and it relates these approaches to treatment of extended Type I glycosphingolipid-associated diseases.
Claims Coverage
The independent claim set centers on an isolated human monoclonal antibody or antigen binding portion that targets an epitope comprising an extended Type I chain comprising Le(b) on cancer cells while not binding human erythrocytes, and includes specified CDR complements from SEQ ID NO:15 and SEQ ID NO:17. Coverage is further shaped by dependent claims that refine epitope specificity and format constraints.
Extended Type I Le(b) epitope on cancer cells without erythrocyte binding
An isolated human monoclonal antibody or antigen binding portion thereof specifically binds an epitope comprising an extended Type I chain comprising Le(b), wherein the epitope is expressed on a cancer cell, and wherein the antibody or antigen binding portion thereof does not bind to human erythrocytes.
Cdr-defined heavy and light variable regions by SEQ ID NO:15 and SEQ ID NO:17
The antibody or antigen binding portion includes a heavy chain variable region including all the complementarity-determining regions of SEQ ID NO:15 and a light chain variable region including all the complementarity-determining regions of SEQ ID NO:17.
Exclusion of LeX binding
An isolated antibody or antigen binding portion thereof does not bind to LeX.
Le(b)-Le(a) cancer-cell antigen expression
The isolated antibody or antigen binding portion thereof binds to a cancer cell expressing Le(b)-Le(a).
Epithelial cancer cell source restricted to specified organs
The epithelial cell that the antibody binds comprises one of colon, rectum, esophagus, lung, prostate, breast, or pancreas.
Antigen binding portion as an scFv
The antigen binding portion is an scFv.
Overall claim coverage emphasizes a human monoclonal antibody or antigen binding portion with specified SEQ ID-defined CDRs that specifically binds an extended Type I Le(b) epitope expressed on cancer cells without binding human erythrocytes, with further refinements including avoidance of LeX binding, specificity for Le(b)-Le(a) expression on cancer cells, restriction to epithelial origins in listed organs, and an scFv binding format.
Stated Advantages
Specific binding of an epitope comprising an extended Type I chain comprising Le(b) that is expressed on cancer cells.
Does not bind to human erythrocytes.
Excludes binding to certain related Lewis antigens, including LeX and, in the described embodiments, Le(a), Le(x), Le(y), and Le(y)-Le(x).
Provides complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity activity against Colo205.
In vivo inhibition of Colo205 xenografts, with tumor-free survival in a subset.
Documented Applications
Diagnosis and therapy of diseases including cancers with aberrant extended Type I glycosphingolipid expression.
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