Human monoclonal antibodies against EPHA4 and their use
Inventors
Ip, Nancy Yuk-yu • Fu, Kit Yu • Fu, Wing Yu • Dimitrov, Dimiter S. • Ying, Tianlei
Assignees
Hong Kong University of Science and Technology • US Department of Health and Human Services
Publication Number
US-10934360-B2
Publication Date
2021-03-02
Expiration Date
2035-07-31
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Abstract
The present invention provides new, fully human EphA4 monoclonal antibodies with distinct binding characteristics. Also disclosed are antigen binding fragments of these antibodies, bispecific forms of these antibodies, and conjugates of these antibodies. In addition, nucleic acids encoding these antibodies, antigen binding fragments, bispecific antibodies and conjugates are disclosed. These monoclonal antibodies, antigen binding fragments, bispecific antibodies, conjugates, nucleic acids and vectors are of use for identifying and treating a subject with a disease or condition involving abnormal EphA4-mediated signaling.
Core Innovation
This invention provides new, fully human monoclonal antibodies that specifically bind the human EphA4 receptor, exhibiting distinct binding characteristics and effects. These include antigen binding fragments, bispecific forms, conjugates of these antibodies, nucleic acids encoding them, and expression vectors containing these nucleic acids. The antibodies and derivatives are designed for use in identifying and treating conditions involving abnormal EphA4-mediated signaling, including tumors, neurodegenerative disorders, and mood disorders.
EphA4 is a receptor tyrosine kinase found on various tissues and implicated in multiple pathologies, including cancer types and central nervous system (CNS) disorders. Modulation of EphA4-ephrin interactions is therapeutic for diseases such as breast cancer, non-small cell lung carcinoma, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and depression. There is a significant unmet need for antibodies that bind human EphA4 with high affinity and modulate its signaling, to aid diagnosis and treatment of these conditions.
The invention discloses fully human monoclonal antibodies, including IgG1 m101, m105, and m119, that recognize the ligand binding domain of EphA4 with high affinity. IgG1 m105 uniquely acts as an EphA4 antagonist selectively inhibiting EphA4-ephrin interactions without affecting EphB2 receptor binding. Some antibodies act as agonists stimulating EphA4 activation. The specificity and binding properties provide tools for diagnosis and therapeutic intervention in neurodegenerative diseases, affective disorders, and various cancers.
Claims Coverage
The patent includes multiple claims focused on human monoclonal antibodies and antigen binding fragments that specifically bind the EphA4 ligand binding domain, including their compositions and diagnostic and therapeutic uses. The main inventive features are summarized below.
Monoclonal antibodies binding EphA4 ligand binding domain
Isolated monoclonal antibodies or antigen binding fragments thereof comprising a heavy chain variable domain of SEQ ID NO:3 or SEQ ID NO:4 and a light chain variable domain of SEQ ID NO:6 or SEQ ID NO:7, specifically binding the EphA4 ligand binding domain.
Use of antibodies as IgG and antigen binding fragments
The monoclonal antibodies are IgGs, and antigen binding fragments include scFv, Fv, Fab, or F(ab)2 fragments.
Antibody conjugates with effector molecules
The antibodies or fragments are conjugated to effector molecules which can be detectable labels (fluorescent, radiolabel, avidin, biotin, enzyme), toxins (e.g., Pseudomonas exotoxin), or chemotherapeutic agents.
Pharmaceutical compositions containing the antibodies
Pharmaceutical compositions comprising the monoclonal antibodies or antigen binding fragments and a pharmaceutically acceptable carrier are claimed.
Bispecific antibodies incorporating the disclosed antibodies
Bispecific antibodies comprising the antibodies or antigen binding fragments specifically binding EphA4 are included.
Nucleic acid sequences encoding the antibodies
Polynucleotide sequences encoding the disclosed monoclonal antibodies or antigen binding fragments, optionally operably linked to a promoter, are claimed.
Diagnostic methods for tumor detection
Methods for detecting the presence of a tumor in a subject by contacting a biological sample with the monoclonal antibody or antigen binding fragment and detecting increased binding compared to a control, where the tumor includes breast carcinoma, esophageal cancer, non-small cell lung cancer, gastric cancer, or pancreatic cancer.
The claims cover fully human monoclonal antibodies specifically binding the EphA4 ligand binding domain, their fragments, conjugates, encoding nucleic acids, pharmaceutical compositions, bispecific forms, and their use in tumor detection and therapy, specifically including diagnostic methods and therapeutic compositions targeting various cancers.
Stated Advantages
The antibodies specifically bind human EphA4 with high affinity and exhibit distinct functional activities, including antagonistic and agonistic effects.
The antibodies provide specificity in blocking EphA4 interactions without affecting other Eph receptors, improving targeted therapeutic potential.
IgG1 m105 acts as a potentially highly effective therapeutic tool for neurodegenerative diseases by attenuating EphA4 activation.
The antibodies and derivatives offer valuable tools for diagnosis, prognosis, and treatment of tumors, neurodegenerative disorders, and affective disorders.
Documented Applications
Use of monoclonal antibodies, antigen binding fragments, bispecific antibodies, and conjugates to diagnose and treat tumors expressing EphA4, including breast carcinoma, esophageal cancer, non-small cell lung cancer, gastric cancer, and pancreatic cancer.
Use in identifying and treating neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.
Use in identifying and treating affective disorders such as depression.
Use in diagnostic methods for detecting EphA4 expression in biological samples for tumor presence, neurodegeneration risk, and disease prognosis.
Therapeutic applications in treating neurodegenerative diseases with antibodies that inhibit EphA4 signaling, potentially slowing disease progression.
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