Antibodies to tumor endothelial marker 8
Inventors
Frankel, Arthur E. • Su, Yunpeng • St. Croix, Brad • Leppla, Stephen H.
Assignees
Wake Forest University Health Sciences • Baylor Scott and White Health • US Department of Health and Human Services
Publication Number
US-9309322-B2
Publication Date
2016-04-12
Expiration Date
2031-11-14
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Abstract
The present invention is directed to particular antibodies and fragments thereof that find use in the detection, prevention and treatment of diseases and disorders associated with abnormal angiogenesis. In particular, these antibodies detect tumor endothelial marker 8 (TEM8) in its native and cell-surface expressed form. Also disclosed are improved methods for producing monoclonal antibodies, as well as pharmaceutical compositions and kits.
Core Innovation
The invention relates to particular antibodies and fragments thereof that bind immunologically to native cell-surface expressed Tumor Endothelial Marker 8 (TEM8), which find use in the detection, prevention, and treatment of diseases and disorders associated with abnormal angiogenesis, including cancer. The antibodies detect TEM8 in its native and cell-surface expressed form, overcoming previous limitations where antibodies failed to recognize the predominant cell surface form of TEM8 due to its masking by cellular factors.
TEM8 is overexpressed in tumor vasculature and promotes pathological but not physiological angiogenesis. Previous approaches to generating antibodies faced the problem that the cell surface form of TEM8 was concealed by two actin cytoskeletal proteins, alpha-smooth muscle actin and transgelin, preventing antibody recognition. This invention solves the problem by producing new antibodies that can recognize the predominant form of TEM8 on live cells independent of TEM8's conformational state, thereby enabling selective targeting of abnormal vasculature.
The invention includes methods for producing monoclonal, chimeric, and humanized antibodies or antibody fragments that bind native cell surface TEM8, with sequences specified by various SEQ ID NOs including variable region complementarity determining regions. Antibodies may be conjugated or fused to therapeutic or diagnostic agents, enabling selective delivery of drugs or imaging agents to abnormal vascular tissue expressing TEM8. Pharmaceutical compositions and kits comprising said antibodies or conjugates are also provided.
Claims Coverage
The patent includes one independent claim that defines a humanized or chimeric antibody or antibody fragment binding native cell-surface expressed TEM8, comprising specified complementarity determining regions (CDRs) in heavy and light chains.
Antibody binding specificity
A humanized or chimeric antibody or antibody fragment comprising heavy chain CDR1 (SEQ ID NO:45), CDR2 (SEQ ID NO:46), CDR3 (SEQ ID NO:47), and light chain CDR4 (SEQ ID NO:48), CDR5 (SEQ ID NO:49), and CDR6 (SEQ ID NO:50), wherein the antibody binds immunologically to native cell-surface expressed TEM8.
Immunoglobulin isotype
The antibody is a human IgG antibody.
Chain amino acid sequences
The antibody comprises light chain amino acid sequence of SEQ ID NO:36 and/or heavy chain amino acid sequence of SEQ ID NO:43.
Drug or agent conjugation
The antibody or antibody fragment is conjugated or fused to a drug, wherein the drug is a chemotherapeutic, radiotherapeutic, thrombogenic agent, immunomodulatory domain, lymphocyte binding domain, or toxin.
The claim defines a humanized or chimeric antibody or antibody fragment comprising specified heavy and light chain CDR sequences that binds native cell-surface TEM8 and may be conjugated to various therapeutic or diagnostic agents, representing the core inventive scope of the patent.
Stated Advantages
The antibodies selectively target abnormal vasculature through their ability to bind native cell surface-expressed TEM8.
The antibodies can recognize the predominant form of cell surface TEM8 concealed by actin cytoskeleton-associated proteins.
Antibody drug conjugates using these antibodies facilitate selective destruction of tumor blood vessels, enhancing anti-cancer efficacy and reducing normal tissue toxicities.
The invention provides improved therapeutic and imaging agents for diseases associated with abnormal angiogenesis.
Documented Applications
Detection, prevention, and treatment of diseases and disorders associated with abnormal angiogenesis, including cancer.
Therapeutic targeting of tumor vascular endothelial cells expressing native cell surface TEM8 with antibodies or antibody fragments to reduce tumor growth or pathological angiogenesis.
Conjugation of antibodies with chemotherapeutic drugs, radiotherapeutic agents, toxins, or diagnostic labels for selective drug delivery or imaging of TEM8-expressing tissues.
Therapeutic use in cancers such as breast, colon, lung, ovarian, and neuroblastoma tumors, and ophthalmic diseases associated with abnormal vascularization including macular degeneration and corneal neovascularization.
Imaging tumor vasculature by administering TEM8-binding antibodies conjugated to detectable labels for diagnosis or monitoring of vascularized tumors.
Methods of producing drug-linker-antibody conjugates for treating proliferative diseases.
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