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-9512211-B2
Publication Date
2016-12-06
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 invention concerns anti-clusterin humanized and hybrid antibodies and antigen-binding fragments that specifically bind clusterin. The disclosed variable-region sequence sets include defined SEQ ID NO.:8 and SEQ ID NO.:7, as well as alternative combinations using SEQ ID NO.:29, SEQ ID NO.:25, and other listed sequence IDs.
The disclosure addresses cancer cells that express or secrete clusterin and states a need to reduce tumor growth and tumor volume. It links clusterin to tumor progression, including tumor growth, migration/invasion, metastasis, and EMT, and provides clusterin-binding antibodies and antigen-binding fragments for administration to a mammal in need to reduce growth of cancer cells expressing or secreting clusterin and to reduce tumor volume.
The disclosure also describes that secreted clusterin is internalized into cancer cells and that h16B5 blocks this internalization. Antibodies are evaluated in relation to tumor growth, metastatic processes, and EMT, including reported reductions in tumor volume in in vivo xenograft studies and associated findings supported by immunohistochemistry showing clusterin expression.
The disclosure further includes antibody format coverage and humanization effects, including framework/CDR humanization design details and improved binding kinetics after humanization. Pharmaceutical compositions and combination therapy with chemotherapeutic agents are included in the description.
Claims Coverage
Two independent methods are provided. Across both, the core inventive element is administration of an antibody or antigen-binding fragment that specifically binds clusterin and contains selected light- and heavy-chain variable region sequence IDs.
Administering a clusterin-binding antibody with specified variable-region sequence IDs to reduce cancer growth or tumor volume
Administer an antibody or an antigen binding fragment thereof capable of specific binding to clusterin to a mammal in need, where the antibody or antigen binding fragment 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; or 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.:29; or a light chain variable region as set forth in SEQ ID NO.:25 and a heavy chain variable region as set forth in SEQ ID NO.:7, to reduce the growth of a cancer cell expressing clusterin or to reduce volume of a tumor comprising cells expressing or secreting clusterin.
Treating carcinoma with a clusterin-binding antibody with specified variable-region sequence IDs
Administer an antibody or an antigen binding fragment thereof capable of specific binding to clusterin to a mammal in need for treating carcinoma, where the antibody or antigen binding fragment 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; or 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.:29; or a light chain variable region as set forth in SEQ ID NO.:25 and a heavy chain variable region as set forth in SEQ ID NO.:7.
The claim coverage is centered on clusterin-targeting antibody administration with explicitly specified light- and heavy-chain variable region sequence IDs. The independent methods cover reducing cancer cell growth or tumor volume in clusterin-expressing or -secreting settings and treating carcinoma.
Stated Advantages
Reducing the growth of a cancer cell expressing clusterin or reducing volume of a tumor comprising cells expressing or secreting clusterin.
Treating carcinoma.
Documented Applications
In vitro evaluation for migration/invasion effects related to clusterin and EMT, supported by migration/invasion assays and immunohistochemistry showing clusterin expression.
In vivo xenograft studies showing reduced tumor growth and increased response to chemotherapy.
Mechanism-related assessment that secreted clusterin is internalized into cancer cells and that h16B5 blocks this internalization.
Use of pharmaceutical composition and combination therapy with chemotherapeutic agents.
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