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CN-115505041-B - Anti-EphA 2 antibodies and uses thereof

CN115505041BCN 115505041 BCN115505041 BCN 115505041BCN-115505041-B

Abstract

The present application relates to the field of antibodies, in particular to anti-EphA 2 antibodies and uses thereof. The present application provides anti-EPH receptor A2 (EphA 2) antibodies and uses thereof. The application also provides chimeric and humanized antibody forms of anti-EphA 2 antibodies. These antibodies have high affinity for human EphA2 protein and are a promising antibody molecule for the prevention and/or treatment of EphA 2-related diseases, such as EphA 2-related tumors, osteoporosis, alzheimer's disease, and the like.

Inventors

  • XU QINZHI
  • GAO XIN
  • QIAN NILIANG
  • ZHANG JIANQING
  • WANG MENG
  • LI HONGJIE
  • Yang Cuima
  • LIU YUNHUI
  • WANG FUYU

Assignees

  • 北京免疫方舟医药科技有限公司

Dates

Publication Date
20260505
Application Date
20210622

Claims (6)

  1. 1. An antibody that specifically binds EphA2, comprising a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3: the amino acid sequence of the HCDR1 is shown as SEQ ID No. 1; The amino acid sequence of the HCDR2 is shown as SEQ ID No. 2; The amino acid sequence of the HCDR3 is shown as SEQ ID No. 3; the light chain variable region comprises LCDR1, LCDR2 and LCDR3: The amino acid sequence of the LCDR1 is shown as SEQ ID No. 4; the amino acid sequence of the LCDR2 is shown as SEQ ID No. 5; the amino acid sequence of LCDR3 is shown in SEQ ID No. 6.
  2. 2. The antibody of claim 1, wherein the antibody is a murine antibody, a chimeric antibody, or a humanized antibody.
  3. 3. The antibody of claim 1, wherein EphA2 is primate EphA2.
  4. 4. The antibody of claim 3, wherein said primate EphA2 is selected from the group consisting of human EphA2 and monkey EphA2.
  5. 5. The antibody of claim 4, further comprising a constant region of the heavy chain of the antibody that is any one of human IgG1, igG2, igG3, or IgG4, and wherein the constant region of the light chain of the antibody is kappa-type or lambda-type.
  6. 6. A medicament comprising the antibody of any one of claims 1 to 5.

Description

Anti-EphA 2 antibodies and uses thereof Technical Field The present invention relates to the field of antibodies, in particular to anti-EphA 2 antibodies and uses thereof. Background Tumorigenesis is the result of somatic gene mutation, and the tumor microenvironment, extracellular matrix, and immune system play an important role in tumorigenesis and development. When cancerous cells escape immune surveillance, overcoming control of immune function, the tumor can progress or kill the host. Therefore, improving the human immune system and regulating the immune microenvironment are important means for treating or preventing tumorigenesis and development. With the deep understanding of tumor immunity mechanism, tumor immunity treatment technology is developed rapidly, and the tumor immunity treatment technology becomes a selectable treatment mode for many patients with middle and late stage cancer, so that the life cycle and the life quality of the patients are greatly improved. Pancreatic cancer is one of the most challenging malignancies in tumor treatment, characterized by strong aggressiveness, early metastasis, and high resistance to treatment. The average 5-year survival rate of patients is only 4%. Surgical resection is currently the only treatment available, however, 80% -85% of pancreatic cancer patients have advanced first diagnosis and lost surgical opportunity. Poor prognosis of cancers such as pancreatic cancer has prompted researchers to find new therapeutic targets. EphA2 (EPHRIN TYPE-a receptor 2) was a tyrosine kinase receptor molecule identified in 1990 and its ligand was EphrinA1.EphA2 protein is highly expressed in many tumors such as skin cancer, digestive tract tumor, prostate cancer, ovarian cancer, breast cancer and the like, and is a molecular marker for poor prognosis of tumor patients. Two modes of EphA2 function, namely, ligand independent oncogene mode, wherein EphA2 promotes cell proliferation and migration by activating a downstream PI3K, rho/Rac1 GTPase/MAPK signal path, and two modes of EphrinA1 ligand dependent oncogene inhibition mode, ephrinA1-EphA2 can inhibit MAPK path in a feedback way after being combined, and inhibit tumor cell proliferation and migration. Teachings of Ye Hu et al have found that some pancreatic cancer patients develop the targeted drug gemcitabine resistance, which is transmitted between tumor cells, mediated by exosomes, whose internalization is EphA 2-dependent. EphA2 overexpression is also involved in mediating therapeutic resistance to breast cancer, cervical cancer and melanoma. Recent studies have shown that inhibition of EphA2 reduces the aggressiveness of pancreatic cancer, increases melanoma sensitivity to vemurafenib and breast cancer to tamoxifen, suggesting that EphA2 is promising as a target for cancer immunotherapy. EphA2 agonist antibodies in 2018 were prepared by japanese scientists and have internalizing properties, and in vitro experiments demonstrated that EphA2 antibody-conjugated immunotoxic agents can kill melanoma cells. At present, no therapeutic EphA2 antibody is marketed at home and abroad, and the research and development stage is preclinical. These data suggest that EphA2 may be a promising therapeutic target for the treatment of pancreatic cancer and other EphA2 positive tumors. Alzheimer's Disease (AD) is a progressive degenerative disorder of the nervous system. Clinically, global dementia such as dysmnesia, agnostic dysfunction and personality and behavior changes are characterized. Current development directions for alzheimer's disease focus mainly on amyloid plaques and neurofibrillary tangles. The study found that Eph/Ephrin proteins are involved in the learning and memory process of the brain, where EphB2 proteins are involved in regulating presynaptic terminal differentiation, soluble amyloid oligomer molecules can alter NMDA receptor homeostasis, and EphB2 interactions with NMDA receptors suggest that Eph proteins may be involved in the progression of alzheimer's disease. In addition, studies have found that miR-214 and EphrinA2 levels are greatly up-regulated in serum exosomes of patients with osteoporosis, and these exosomes interact with EphA2 receptors on osteoblast membranes through EphrinA2, thereby inhibiting bone cell activity and causing osteoporosis. These data suggest that EphA2 may also be a target for the treatment of alzheimer's disease and osteoporosis. Therefore, it is of great practical importance to provide anti-EphA 2 antibodies and uses thereof. Disclosure of Invention In view of this, the present invention provides anti-EphA 2 antibodies and uses thereof. The antibody or antigen binding portion thereof that specifically binds EphA2 is capable of inducing an EphA 2-mediated anti-tumor immune response, and/or inhibiting tumor growth and alzheimer's disease and osteoporosis, and the like. In order to achieve the above object, the present invention provides the following technical solutions: The pr