Anti-clusterin antibodies and antigen binding fragments and their use to reduce tumor volume
Inventors
Tremblay, Gilles Bernard • Filion, Mario • Sulea, Traian
Assignees
National Research Council of Canada • Alethia Biotherapeutics ULC
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Publication Number
US-8802826-B2
Publication Date
2014-08-12
Expiration Date
Abstract
Antibodies and antigen binding fragments that specifically bind to clusterin are described. In some embodiments, the antibodies block the biological activity of clusterin and are useful in composition in certain cancers, more particularly in cancers, such as endometrial carcinoma, breast carcinoma, hepatocellular carcinoma, prostate carcinoma, a renal cell carcinoma, ovarian carcinoma, pancreatic carcinoma, and colorectal carcinoma. The invention also relates to cells expressing the humanized or hybrid antibodies. Additionally, methods of detecting and treating cancer using the antibodies and fragments are also disclosed.
Core Innovation
The disclosed invention relates to anti-clusterin humanized/hybrid antibodies and antigen-binding fragments that bind clusterin. The antibodies include defined light chain variable regions and heavy chain variable regions set forth by SEQ ID NO. values, and binding to clusterin with cross-reactivity described for human and murine clusterin is characterized.
The invention is directed to functional inhibition of clusterin biology in tumor cells, including epithelial-to-mesenchymal transition (EMT)-related tumor growth, migration, invasion, and metastasis. The described antibody formats include antigen-binding fragments such as scFv, Fab, Fab′, (Fab′)2, and full antibody formats, and the document also includes assessment of binding kinetics and functional effects on internalization of secreted clusterin.
The disclosure states that the antibodies reduce tumor volume in vivo and inhibit tumor growth and related malignant behaviors, and also enhance chemotherapy response when used in combination contexts. The document describes detection use of antibody binding, including h16B5 detection by immunohistochemistry, and positions the antibodies within pharmaceutical compositions that include pharmaceutically acceptable carriers.
Claims Coverage
The document includes two independent claims, covering isolated anti-clusterin antibodies or antigen-binding fragments with specific variable-region sequence sets, and a pharmaceutical composition containing that anti-clusterin antibody or antigen-binding fragment plus a pharmaceutically acceptable carrier. Across these claims, the coverage centers on defined SEQ ID–specified variable regions that bind clusterin.
Isolated antibody or antigen binding fragment binding clusterin with SEQ ID variable regions
An isolated antibody or antigen binding fragment thereof comprising a light chain variable region as set forth in SEQ ID NO.: 8 and a heavy chain variable region as set forth in SEQ ID NO.: 7, wherein the antibody or antigen binding fragment thereof binds clusterin.
Pharmaceutical composition with anti-clusterin antibody or antigen binding fragment and pharmaceutically acceptable carrier
A pharmaceutical composition comprising an antibody or antigen binding fragment thereof, and a pharmaceutically acceptable carrier, wherein the antibody or antigen binding fragment thereof comprises a light chain variable region as set forth in SEQ ID NO.: 8 and a heavy chain variable region as set forth in SEQ ID NO.: 7, and wherein the antibody or antigen binding fragment thereof binds clusterin.
Overall, the independent-claim scope is anchored by defined light and heavy chain variable regions (SEQ ID NO.: 8 and SEQ ID NO.: 7) for binding clusterin, with the second independent claim requiring formulation as a pharmaceutical composition with a pharmaceutically acceptable carrier.
Stated Advantages
Reduces tumor volume and inhibits EMT-related tumor growth, migration, invasion, and metastasis.
Blocks internalization of secreted clusterin.
Enhances chemotherapy response in a combination context.
Documented Applications
Therapeutic use to reduce tumor volume and inhibit tumor growth, migration, invasion, and metastasis related to epithelial-to-mesenchymal transition (EMT).
Combination therapy use with a chemotherapeutic agent, with taxanes described in dependent claims.
Detection use via antibody detection, including h16B5 detection by immunohistochemistry.
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