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-10273299-B2
Publication Date
2019-04-30
Expiration Date
2031-11-14
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 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. These antibodies detect tumor endothelial marker 8 (TEM8) in its native and cell-surface expressed form. Included are improved methods for producing monoclonal antibodies, pharmaceutical compositions and kits.
Tumor markers are substances produced by tumor cells or by other cells of the body in response to cancer. Current tumor marker strategies in cancer therapy are limited because they cannot separate physiological and pathological angiogenesis, leading to undesirable effects. Tumor endothelial marker 8 (TEM8), an 85 kDa integrin-like cell surface receptor, is overexpressed in tumor blood vessels but not in normal vessels. However, traditional antibodies failed to recognize the native cell surface form of TEM8 due to masking by alpha-smooth muscle actin and transgelin, cellular factors involved in the actin cytoskeleton.
Using an innovative approach, the inventors produced new anti-TEM8 antibodies that recognize the predominant form of TEM8 on live cell surfaces, independent of its conformational status. These antibodies and fragments can selectively target abnormal vasculature by binding native cell surface-expressed TEM8. The invention includes isolated and purified antibodies or fragments, including humanized, chimeric, single chain, bivalent antibodies, and antibody-drug conjugates. These antibodies have applications in treatment or prevention of diseases associated with abnormal vascular proliferation, such as cancer, by targeting TEM8, which promotes pathological but not physiological angiogenesis.
Claims Coverage
The patent includes one independent claim focusing on a method of treating subjects with vascularized tumors using antibodies or antibody fragments that specifically bind native cell-surface expressed TEM8 with defined complementarity determining region sequences.
Method of treating vascularized tumors with anti-TEM8 antibodies or fragments
Administering to a subject an antibody or antibody fragment binding immunologically to native cell-surface expressed TEM8, characterized by comprising specific amino acid sequences of six complementarity determining regions in heavy and light chain variable regions (SEQ ID NOs:45-50).
Antibody configurations
The antibody or fragment can be an IgG antibody, humanized, single chain, or bivalent, including Fab' or F(ab')2 fragments.
Conjugation to therapeutic or detectable agents
The antibody or fragment may be conjugated to a therapeutic agent such as chemotherapeutic, radiotherapeutic, or toxin, or a detectable label which may be colorimetric, fluorescent, enzymatic, or radioactive.
Use in diverse tumor types
Method is applicable to treating a wide range of vascularized tumors including brain, ocular, head & neck, skin, lung, esophageal, pancreatic, stomach, liver, prostate, colon, rectal, breast, ovarian, uterine, cervical tumors, lymphoma, and testicular tumors.
Administration and combination therapies
Antibodies or fragments may be administered systemically, regionally, or locally via intratumoral injection or injection into tumor vasculature or resected tumor bed, multiple times, and may be administered alongside other cancer therapies such as surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, before, during, or after antibody administration.
Prior evaluation of TEM8 expression
Includes detecting TEM8 expression on cells of the subject prior to administration of the antibody.
Antibody-drug conjugates with linker
Antibody or fragment conjugated to a drug by a linker to form drug-linker-antibody conjugates as defined in formula VI.
Overall, the claims cover methods of treating vascularized tumors by administering specific anti-TEM8 antibodies or fragments with defined sequences, configurations, and conjugates, applicable across tumor types, including combination therapies and diagnostic steps.
Stated Advantages
The antibodies can recognize the predominant native form of TEM8 on the cell surface, which was previously unrecognizable by traditional antibodies.
Selectivity for abnormal vasculature through binding native cell surface-expressed TEM8.
Potential for effective targeting of tumor vasculature leading to improved anti-cancer efficacy with reduced normal tissue toxicity.
Antibody drug conjugates enhance selective tumor blood vessel destruction while reducing side effects.
Humanized and chimeric antibody formats allow for therapeutic compatibility and reduced immunogenicity.
Documented Applications
Use of described antibodies and antibody fragments in detection, prevention, or treatment of diseases and disorders associated with abnormal angiogenesis, particularly cancer.
Treatment of vascularized tumors including brain, ocular, head & neck, skin, lung, esophageal, pancreatic, stomach, liver, prostate, colon, rectal, breast, ovarian, uterine, cervical tumors, lymphoma, and testicular tumors.
Treatment of recurrent cancer, metastatic cancer, or multi-drug resistant cancer.
Administration of antibody or antibody fragment conjugated to therapeutic or diagnostic agents for cancer therapy or imaging.
Use in combination with other cancer therapies including surgery, radiotherapy, chemotherapy, immunotherapy, toxin therapy, cryotherapy, or gene therapy.
Detection of TEM8 expression for diagnostic or prognostic purposes prior to treatment.
Interested in licensing this patent?