Anti-DR4 agonist antibodies
Inventors
Dimitrov, Dimiter • Feng, Yang
Assignees
US Department of Health and Human Services • Office of Technology Transfer
Publication Number
US-9044457-B2
Publication Date
2015-06-02
Expiration Date
2031-06-16
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Abstract
The present invention provides antibodies and antibody fragments that specifically recognize and agonize the death receptor 4 (DR4). Also provided in the invention are polynucleotides and vectors that encode such molecules and host cells that harbor the polynucleotides or vectors.
Core Innovation
The invention provides antibodies and antibody fragments that specifically recognize and agonize death receptor 4 (DR4). The antibodies can be monoclonal and fully human and are capable of binding to the same or an overlapping epitope on DR4 as monoclonal antibodies m921 or m922. These antibodies comprise defined complementary determining regions (CDRs) in their heavy and light chain variable regions, which confer specificity and agonistic activity toward DR4. The invention also includes polynucleotides and vectors encoding such antibodies, host cells harboring these vectors, and compositions comprising the antibodies with pharmaceutically acceptable carriers.
The problem solved by the invention arises from the need for therapies targeting the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, particularly through DR4, given that DR4 and DR5 are functional TRAIL receptors expressed on a broad range of tumors. Existing recombinant TRAIL proteins suffer from short half-life and potential toxicity, and repeated exposure may result in resistance. While agonistic antibodies targeting DR4 or DR5 can offer longer half-life and lower immunogenicity, additional potent human monoclonal antibodies specific for DR4 were needed. The invention addresses this need by providing fully human agonistic antibodies that specifically bind DR4, induce apoptosis in DR4-expressing cells, and have potential therapeutic advantages over existing agents.
Claims Coverage
The patent includes 21 claims with one independent claim (claim 1) defining the antibody and method claims dependent thereon. The claim coverage focuses on the specific composition and biological activity of anti-DR4 agonist antibodies, and methods and compositions employing them.
Antibody comprising specific heavy and light chain CDRs that agonize DR4
An antibody that binds and is an agonist of DR4, comprising heavy and light chain variable regions each having three CDRs with amino acid sequences as SEQ ID NOs:8 (heavy chain CDR1), 9 (heavy chain CDR2), 10 (heavy chain CDR3), 5 (light chain CDR1), 6 (light chain CDR2), and 7 (light chain CDR3).
Antibody comprising specific variable segments
The antibody comprises a light chain variable segment of SEQ ID NO:1 and a heavy chain variable segment of SEQ ID NO:2.
Antibody with variable regions having defined sequence identity
An antibody comprising a light chain variable region and a heavy chain variable region each having at least 50% or 80% sequence identity to SEQ ID NO:1 and SEQ ID NO:2, respectively.
Human antibody nature
The antibody is a human antibody.
Multivalent and multispecific antibody formats
The antibody may be multivalent, multispecific, bispecific, or cross-linked.
Pharmaceutical composition comprising the antibody
A composition comprising the anti-DR4 agonist antibody and a pharmaceutically acceptable carrier.
Polynucleotide encoding the antibody
Polynucleotides encoding the anti-DR4 agonist antibody.
Expression cassette and host cell
Expression cassettes and host cells harboring polynucleotides encoding the anti-DR4 antibody.
Methods of inducing apoptosis in DR4-expressing cells
Methods comprising contacting a target cancer cell expressing DR4 with the anti-DR4 antibody to induce apoptosis, in vitro or in vivo.
Methods of reducing or inhibiting cancer growth
Methods reducing or inhibiting growth of DR4-expressing cancers by administering a therapeutically effective amount of the antibody, alone or combined with chemotherapeutic drugs or irradiation.
Therapeutic kit
Kits containing the antibody and pharmaceutically acceptable carrier, optionally with co-administration agents including other antibodies or antineoplastic agents.
The claims cover fully human anti-DR4 agonist antibodies defined by specific CDR sequences and variable regions, compositions comprising these antibodies, polynucleotides and expression systems encoding them, therapeutic methods for inducing apoptosis and treating DR4-expressing cancers, and kits for therapeutic use, encompassing a range of antibody formats and combination therapies.
Stated Advantages
The antibodies have high affinity and specificity for DR4 and stimulate apoptosis selectively in DR4-expressing cancer cells.
Fully human antibodies have reduced immunogenicity and longer half-life compared to recombinant TRAIL proteins, improving clinical utility.
The antibodies can be used alone or as targeting moieties in immunotoxins, enabling cytotoxic delivery to DR4-expressing tumor cells.
Anti-DR4 antibodies effectively inhibit growth of DR4-positive cancer cells without affecting DR4-negative cells, indicating selective cytotoxicity.
The antibodies provide potential to overcome limitations of current TRAIL therapies by targeting DR4 specifically and avoiding decoy receptor issues.
Documented Applications
Treatment and prevention of cancers expressing or overexpressing DR4, including solid tumors such as lung cancer, renal cancer, cervical cancer, lymphomas (e.g., Burkitt's lymphoma), myelomas, colorectal cancers, melanoma, hepatoma, pancreatic cancer, and central nervous system cancers such as glioblastoma.
Use in methods of inducing apoptosis in target cells expressing DR4.
Use in reducing, inhibiting or preventing the growth or progression of cancers expressing DR4 in subjects in need thereof.
Combination therapies with anticancer chemotherapeutic drugs and/or irradiation.
Diagnostic detection of DR4 expression in biological samples using the antibodies in immunohistochemistry or immunoassays.
Use as targeting moieties in immunotoxins for selective killing of DR4-expressing cancer cells.
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