USE OF SEMAPHORIN-4D BINDING MOLECULES FOR TREATING NEURODEGENERATIVE DISORDERS

• US 20190322757A1
• Filed: 07/02/2019
• Published: 10/24/2019
• Est. Priority Date: 10/21/2013
• Status: Active Grant

• Current Assignee: Vaccinex, Inc.
• Original Assignee: Vaccinex, Inc.
• Inventors: Smith, Ernest S., Zauderer, Maurice, Bowers, William J., Jonason, Alan
• Granted Patent: US 10,800,853 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/30 characterized by aspects of specificity or valency
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

Provided herein are methods for alleviating symptoms in a subject having a neurodegenerative disorder, comprising administering to the subject an effective amount of an isolated binding molecule which specifically binds to semaphorin-4D (SEMA4D) or to its Plexin-B1 or Plexin-B2 receptors.

Claims

1. A method of treating a subject having a having, determined to have, or suspected of having a neuroinflammatory or neurodegenerative disorder, comprising administering to the subject an effective amount of an isolated binding molecule which specifically binds to semaphorin-4D (SEMA4D), wherein the binding to SEMA4D acts to alleviate symptoms associated with the disorder.

2. The method of claim 1, wherein the binding molecule modulates astrocyte-mediated activity of oligodendrocyte-myelin function.

3. The method of claim 1, wherein the binding molecule modulates astrocyte-mediated synaptic activity, thereby preventing neural cell death.

4. The method of claim 1, wherein the binding molecule modulates astrocyte-mediated maintenance of the integrity of the blood-brain barrier.

5. The method of claim 1, wherein the isolated binding molecule specifically binds to the same SEMA4D epitope as a reference monoclonal antibody comprising the heavy chain variable region (VH) amino acid sequence SEQ ID NO:

9 and the light chain variable region (VL) amino acid sequence SEQ ID NO;

10.

6. The method of claim 1, wherein the isolated binding molecule competitively inhibits a reference monoclonal antibody comprising the heavy chain variable region (VH) amino acid sequence SEQ ID NO:

4 and the light chain variable region (VL) amino acid sequence SEQ ID NO;

10 from binding to SEMA4D.

7. The method of claim 1, wherein the isolated binding molecule comprises an antibody or antigen-binding fragment thereof.

8. The method of claim 7, wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) comprising VHCDRs 1-3 comprising SEQ ID NOs 6, 7, and 8, respectively, and a variable light chain (VL) comprising VLCDRs 1-3 comprising SEQ ID NOs 14, 15, and 16, respectively.

9. The method of claim 8, wherein the VH and VL comprise, respectively, SEQ ID NO:

9 and SEQ ID NO;

17 or SEQ ID NO;

10 and SEQ ID NO;

18.

10. The method of claim 1, wherein the neurodegenerative disorder is selected from a group consisting of Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, Down syndrome, ataxia, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), HIV-related cognitive impairment, CNS Lupus, mild cognitive impairment, or a combination thereof.

11. A method of maintaining or restoring astrocyte-mediated trophic support of oligodendrocyte precursor cells (OPCs) in a subject having, determined to have, or suspected of having a neuroinflammatory or neurodegenerative disorder, comprising administering to that subject an effective amount of an isolated binding molecule which specifically binds to SEMA4D, wherein the binding molecule prevents retraction of astrocyte processes and chemotactic movement of OPCs toward regions of damage.

12. The method of claim 11, wherein the isolated binding molecule specifically binds to the same SEMA4D epitope as a reference monoclonal antibody comprising the heavy chain variable region (VH) amino acid sequence SEQ ID NO:

9 and the light chain variable region (VL) amino acid sequence SEQ ID NO;

10.

13. The method of claim 11, wherein the isolated binding molecule competitively inhibits a reference monoclonal antibody comprising the heavy chain variable region (VH) amino acid sequence SEQ ID NO:

4 and the light chain variable region (VL) amino acid sequence SEQ ID NO;

10 from binding to SEMA4D.

14. The method of claim 11, wherein the isolated binding molecule comprises an antibody or antigen-binding fragment thereof.

15. The method of claim 14, wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) comprising VHCDRs 1-3 comprising SEQ ID NOs 6, 7, and 8, respectively, and a variable light chain (VL) comprising VLCDRs 1-3 comprising SEQ ID NOs 14, 15, and 16, respectively.

16. The method of claim 15, wherein the VH and VL comprise, respectively, SEQ ID NO:

9 and SEQ ID NO;

17 or SEQ ID NO;

10 and SEQ ID NO;

18.

17. The method of claim 11, wherein the neurodegenerative disorder is selected from a group consisting of Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, Down syndrome, ataxia, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), HIV-related cognitive impairment, CNS Lupus, mild cognitive impairment, or a combination thereof.

18. A method of protecting inhibitory neurons from degeneration in early Alzheimer'"'"'s disease, comprising administering to a subject having, determined to have, or suspected of having early Alzheimer'"'"'s disease an effective amount of an isolated binding molecule which specifically binds to SEMA4D, wherein the binding molecule restores the number of somatostatin positive neurons, NYP-positive neurons, or both in the subject.

19. The method of claim 18, wherein the isolated binding molecule specifically binds to the same SEMA4D epitope as a reference monoclonal antibody comprising the heavy chain variable region (VH) amino acid sequence SEQ ID NO:

9 and the light chain variable region (VL) amino acid sequence SEQ ID NO;

10.

20. The method of claim 18, wherein the isolated binding molecule competitively inhibits a reference monoclonal antibody comprising the heavy chain variable region (VH) amino acid sequence SEQ ID NO:

4 and the light chain variable region (VL) amino acid sequence SEQ ID NO;

10 from binding to SEMA4D.

21. The method of claim 18, wherein the isolated binding molecule comprises an antibody or antigen-binding fragment thereof.

22. The method of claim 21, wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) comprising VHCDRs 1-3 comprising SEQ ID NOs 6, 7, and 8, respectively, and a variable light chain (VL) comprising VLCDRs 1-3 comprising SEQ ID NOs 14, 15, and 16, respectively.

23. The method of claim 22, wherein the VH and VL comprise, respectively, SEQ ID NO:

9 and SEQ ID NO;

17 or SEQ ID NO;

10 and SEQ ID NO;

18.