Use of semaphorin-4D binding molecules for treating neurodegenerative disorders

• US 9,598,495 B2
• Filed: 10/21/2014
• Issued: 03/21/2017
• 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
• Primary Examiner(s): ULM, JOHN D
• Application Number:
  US14/519,965
• Publication Number:
  US 20150110800A1
• Time in Patent Office: 882 Days
• Field of Search: None
• US Class Current: 1/1
• 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, determined to have, or suspected of having a neurodegenerative disorder, comprising administering to a subject in need of treatment an effective amount of an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D), wherein the antibody or 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, and wherein the antibody or fragment thereof can prevent or reduce reactive astrogliosis in the subject.

2. The method of claim 1, wherein the antibody or fragment thereof modulates astrocyte-mediated maintenance of the integrity of the blood-brain barrier.

3. The method of claim 1, wherein the antibody or fragment thereof inhibits SEMA4D interaction with a SEMA4D receptor or a portion thereof.

4. The method of claim 3, wherein the receptor is selected from the group consisting of Plexin-B1, Plexin-B2, and CD72.

5. The method of claim 4, wherein the antibody or fragment thereof inhibits SEMA4D-mediated Plexin-B1 signal transduction.

6. The method of claim 1, wherein the VH and VL amino acid sequences comprise, respectively, SEQ ID NO:

9 and SEQ ID NO;

17 or SEQ ID NO;

10 and SEQ ID NO;

18.

7. 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.

8. The method of claim 1, wherein the neurodegenerative disorder is Alzheimer'"'"'s Disease, and wherein administration of the antibody or fragment thereof can decrease the density of GABAergic synaptic vesicles in the subject'"'"'s brain.

9. The method of claim 1, wherein the antibody or fragment thereof is administered to the subject in combination with at least one or more other treatments for neurodegenerative disorders, and wherein the other treatment is administered prior to, during, or subsequent to administering the antibody or fragment thereof to the subject.

10. The method of claim 1, wherein the subject is human.

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 antibody or antigen-binding fragment thereof that specifically binds to SEMA4D, wherein the antibody or 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, and wherein the antibody or fragment thereof prevents retraction of astrocyte processes and chemotactic movement of OPCs toward regions of damage.