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-12037404-B2
Publication Date
2024-07-16
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 vector are of use for identifying and treating a subject with a disease or condition involving abnormal EphA4-mediated signaling.
Core Innovation
The invention provides new fully human monoclonal antibodies that specifically bind EphA4 with high affinity and distinct effects. These include antigen binding fragments, bispecific antibodies, and conjugates, such as fusion proteins with effector molecules for detection or biological activity. The invention also includes nucleic acids encoding these antibodies and corresponding expression vectors and host cells. These biological molecules can be used for diagnosing and treating diseases involving abnormal EphA4-mediated signaling, including tumors and neurodegenerative and mood disorders.
EphA4 is a receptor tyrosine kinase expressed in multiple tissues including brain and is involved in processes such as tyrosine phosphorylation and synaptic regulation. Its deregulation is linked to various pathologies such as tumors, central nervous system disorders, and affective disorders. Current therapeutic options for diseases influenced by EphA4 signaling, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and depression, are limited or ineffective, highlighting the need for new diagnositic and treatment approaches. The invention addresses this need by providing antibodies that bind EphA4 with high affinity and specificity, with some acting as antagonists that modulate EphA4 activity.
Specifically, the invention describes monoclonal antibodies such as IgG1 m101, m105, and m119 that recognize the ligand binding domain of EphA4. Among these, m105 acts as a potent antagonist blocking EphA4 interaction with ephrins and attenuating EphA4 activation with subnanomolar affinity. This antibody does not interfere with EphB2 receptor-ligand interactions, displaying specificity. In contrast, m119 stimulates EphA4 activation acting as an agonist. These distinct functional activities enable precise modulation of EphA4 signaling pathways, offering valuable tools for diagnosis, prognosis, and therapy of EphA4-related diseases.
Claims Coverage
The patent presents two main independent claims focusing on therapeutic methods using specific monoclonal antibodies that bind EphA4.
Method for treating neurodegenerative and affective disorders using specific monoclonal antibodies
A method comprising administering to a subject an isolated monoclonal antibody or antigen binding fragment comprising either (a) a heavy chain variable domain with the amino acid sequence SEQ ID NO:3 and a light chain variable domain with SEQ ID NO:6; or (b) a heavy chain variable domain with SEQ ID NO:4 and a light chain variable domain with SEQ ID NO:7, wherein the antibody specifically binds the EphA4 ligand binding domain.
Specific treatment indications using EphA4-targeting antibodies
The method targets neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, and affective disorder such as depression, using the aforementioned monoclonal antibodies or antigen binding fragments thereof.
The claims center on therapeutic methods employing fully human monoclonal antibodies specifically binding the EphA4 ligand binding domain with defined heavy and light chain variable domain sequences, for treating neurodegenerative and affective disorders including AD, PD, MS, ALS, and depression.
Stated Advantages
The antibodies bind human EphA4 with high affinity and show distinct effects including antagonistic and agonistic activities.
The m105 antibody acts as a specific antagonist that blocks EphA4-ephrin interactions and attenuates EphA4 activation, useful for treating neurodegenerative diseases.
The antibodies exhibit specificity, not interfering with EphB receptor interactions, reducing off-target effects.
The antibodies serve as valuable diagnostic and therapeutic tools for diseases involving deregulated EphA4 signaling, including various cancers and CNS disorders.
Documented Applications
Identification and treatment of subjects with tumors, including breast carcinoma, esophageal cancer, non-small cell lung cancer, gastric cancer, and pancreatic cancer.
Identification and treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.
Identification and treatment of affective disorders such as depression.
Use of antibodies for diagnosing and prognosing patients at risk of or suffering from EphA4-related diseases by measuring EphA4 levels in biological samples such as blood, serum, plasma, sputum, or biopsy.
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