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CA-3219114-C - PHARMACEUTICAL COMPOSITION FOR TREATING BRAIN DISEASES COMPRISING ANTIBODY SPECIFICALLY BINDING TO ASM PROTEIN AS ACTIVE INGREDIENT

CA3219114CCA 3219114 CCA3219114 CCA 3219114CCA-3219114-C

Abstract

Disclosed is use of an antibody or antigen-binding fragment thereof that specifically binds to an acid sphingomyelinase (ASM) protein, wherein the antibody or antigen-binding fragment thereof specifically binds to an ASM protein with high binding affinity, significantly inhibits the activity of an ASM protein present in the cellular membrane, and shows effects of improving cognitive memory, inhibiting ASM protein activity, inhibiting the accumulation of amyloid-β and tau proteins, and inhibiting the production of neuroinflammation even without toxicity in Alzheimer's disease animal models, and thus can be advantageously used in the treatment of a brain disease.

Inventors

  • Seung Beom Hong
  • Jae Sung BAE
  • Hee Kyung Jin

Assignees

  • ISU ABXIS CO., LTD.
  • KYUNGPOOK NATIONAL UNIVERSITY INDUSTRY-ACADEMIC COOPERATION FOUNDATION

Dates

Publication Date
20260505
Application Date
20220526
Priority Date
20210527

Claims (4)

  1. 58 WHAT IS CLAIMED IS: 1. A pharmaceutical composition for preventing or treating a brain disease, wherein the pharmaceutical composition comprises an antibody or antigen-5 binding fragment thereof that specifically binds to an acid sphingomyelinase (ASM) protein, together with a carrier, a diluent, an excipient, or a mixture thereof, wherein the antibody or antigen-binding fragment 10 thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 consisting of the amino acid sequences set forth in SEQ ID NOS: 31, 32, and 33, respectively, and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 consisting of the amino acid 15 sequences set forth in SEQ ID NOS: 49, 50, and 51, respectively, wherein the brain disease is Alzheimer’s disease.
  2. 2. The pharmaceutical composition of claim 1, wherein 20 the ASM protein is derived from a mammal.
  3. 3. The pharmaceutical composition of claim 1, wherein the ASM protein is a polypeptide consisting of an amino acid sequence set forth in SEQ ID NO: 66 or 67. 59
  4. 4. An antibody or antigen-binding fragment thereof that specifically binds to an ASM protein for use in manufacturing of a pharmaceutical composition for treating a brain disease, wherein the antibody or antigen-5 binding fragment thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 consisting of the amino acid sequences set forth in SEQ ID NOS: 31, 32, and 33, respectively, and a light chain variable region comprising 10 light chain CDR1, CDR2, and CDR3 consisting of the amino acid sequences set forth in SEQ ID NOS: 49, 50, and 51, respectively, wherein the brain disease is Alzheimer’s disease.

Description

PHARMACEUTICAL COMPOSITION FOR TREATING BRAIN DISEASES COMPRISING ANTIBODY SPECIFICALLY BINDING TO ASM PROTEIN AS ACTIVE INGREDIENT BACKGROUND OF THE INVENTION 1. Field of the invention The present disclosure relates to use of antibodies specifically binding to acid sphingomyelinase (ASM) protein. 2. Description of the Prior Art Sphingolipid metabolism regulates normal cellular signaling, and abnormal changes in sphingolipid metabolism cause various neurodegenerati ve diseases including 15 Alzheimer's disease. Acid sphingomyelinase (ASM) protein, an enzyme that regulates sphingolipid metabolism, is a protein expressed in almost all types of cells and plays an important role in sphingolipid metabolism and cell membrane turnover. 20 In the brain of patients with neurodegenerative diseases such as Alzheimer's disease, the activity of ASM protein is significantly increased compared with that of normal people. In this connection, Korean Patent No. 10-1521117 discloses that the inhibition of the activity of over-expressed ASM 25 protein or the inhibition of the expression into ASM protein suppresses the accumulation of amyloid-~ and improves learning ability and memory and thus can treat neurodegenerative diseases. It has been recently known that the activity of ASM protein is also increased in neurological 5 diseases, such as depression, and thus the inhibition of the expression or activity of ASM protein is effective in the amelioration of depression. However, substances that directly inhibit the expression or activity of ASM protein have not been 10 developed, and several types of inhibitors that indirectly inhibit the expression of ASM proteins have been identified. For example, there are tricyclic antidepressants used in the treatment of depression, and examples thereof include ami triptyline, desipramine, mi pr amine and the like. Al though 15 these tricyclic antidepressants were not developed as ASM protein inhibitors, various studies have demonstrated that such antidepressants exhibit ASM protein inhibitory effects. A major pharmacological mechanism of tricyclic antidepressants is that the activity thereof is increased by 20 inhibiting the reuptake of neurotransmitters in nerve cells, and their action as an ASM inhibitor was confirmed to be a subordinate action. However, tricyclic antidepressants may act on the nervous system and nerve cells, causing side effects, such as blurred vision, increased light sensitivity, 25 and vomiting. 2 SUMMARY OF THE INVENTION 5 An aspect of the present disclosure is to provide use of an antibody specifically binding to ASM protein. In accordance with aspects of the present disclosure, the present disclosure provides a pharmaceutical composition 10 for preventing or treating a brain disease, the pharmaceutical composition including as an active ingredient an antibody or antigen-binding fragment thereof that specifically binds to an acid sphingomyelinase (ASM) protein. In accordance with aspects of the present disclosure, 15 the present disclosure provides a health functional food for preventing or alleviating a brain disease, the health functional food including as an active ingredient an antibody or antigen-binding fragment thereof that specifically binds to an ASM protein. 20 In accordance with aspects of the present disclosure, the present disclosure provides a method for preventing, alleviating, or treating a brain disease, the method including a step of administering to a subject an antibody or antigen-binding fragment thereof that specifically binds 25 to an ASM protein. 3 In accordance with aspects of the present disclosure, the present disclosure provides an antibody or antigenbinding fragment thereof that specifically binds to an ASM protein for use in a method for preventing, alleviating, or 5 treating a brain disease. The antibody or antigen-binding fragment thereof according to the present disclosure specifically binds to an ASM protein with high binding affinity, significantly 10 inhibits the activity of an ASM protein present in the cellular membrane, and shows effects of improving cognitive memory, inhibiting ASM protein activity, inhibiting the accumulation of amyloid-~ and tau proteins, and inhibiting the production of neuroinflammation even without toxicity in 15 Alzheimer's disease animal models, and thus can be advantageously used in the treatment of a brain disease. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates a schematic diagram showing amino acid sequences of heavy and light chain variable regions of antibodies produced according to an example of the present disclosure. FIG. 2 illustrates a graph showing the binding of the 25 antibodies produced according to an example of the present 4 disclosure to ASM protein, as confirmed by ELISA analysis. FIG. 3 illustrates a schematic diagram showing the antigen binding sites of the antibodies produced according to an example of the present disclosure on ASM protein, in 5 an ASM protein structure model.