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(12) Patent Application Publication (10) Pub. No.: US 2017/0198053 A1 Smith Et Al US 20170 198053A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0198053 A1 Smith et al. (43) Pub. Date: Jul. 13, 2017 (54) USE OF SEMAPHORN-4D BINDING (60) Provisional application No. 62/012,805, filed on Jun. MOLECULES FOR TREATING 16, 2014, provisional application No. 61/979,384, NEURODEGENERATIVE DSORDERS filed on Apr. 14, 2014, provisional application No. 61/893,814, filed on Oct. 21, 2013. (71) Applicant: Vaccinex, Inc., Rochester, NY (US) Publication Classification (72) Inventors: Ernest S. Smith, Ontario, NY (US); Maurice Zauderer, Pittsford, NY (US); (51) Int. C. William J. Bowers, Webster, NY (US); C07K 6/28 (2006.01) Alan Jonason, Pittsford, NY (US) (52) U.S. C. CPC ...... C07K 16/2896 (2013.01); C07K 2317/56 (21) Appl. No.: 15/465,509 (2013.01); A6 IK 2039/505 (2013.01) (22) Filed: Mar. 21, 2017 (57) ABSTRACT Provided herein are methods for alleviating symptoms in a Related U.S. Application Data Subject having a neurodegenerative disorder, comprising (63) Continuation of application No. 15/420,662, filed on administering to the Subject an effective amount of an Jan. 31, 2017. Continuation of application No. isolated binding molecule which specifically binds to Sema 14/519,965, filed on Oct. 21, 2014, now Pat. No. phorin-4D (SEMA4D) or to its Plexin-B1 or Plexin-B2 9,598,495. receptors. Patent Application Publication Jul. 13, 2017. Sheet 1 of 19 US 2017/O198053 A1 apoiopeñenese? p3&###~3de) Patent Application Publication Jul. 13, 2017. Sheet 2 of 19 US 2017/O198053 A1 §§84 æææ???dp?a?º??do. zraeggwaeano***8äzqww&A2) 2008, Patent Application Publication Jul. 13, 2017. 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Sheet 19 of 19 US 2017/O198053 A1 §§§§ s VW s: peesas: sun anopios US 2017/O 198053 A1 Jul. 13, 2017 USE OF SEMAPHORN-4D BINDING BRIEF SUMMARY OF THE DISCLOSURE MOLECULES FOR TREATING 0006 Methods for using semaphorin 4D binding mol NEURODEGENERATIVE DSORDERS ecules to alleviate symptoms in a subject having neurode generative disorders are disclosed herein. According to CROSS-REFERENCE TO RELATED aspects of the disclosure illustrated herein, there is provided APPLICATIONS a method for improving symptoms in a Subject with a neurodegenerative disorder including administering to the 0001. This application is a Continuation of and claims the Subject an effective amount of an isolated binding molecule benefit of both U.S. Non-Provisional patent application Ser. which specifically binds to semaphorin 4D (SEMA4D) and No. 15/420,662, filed on Jan. 31, 2017 and U.S. Non inhibits, suppresses, prevents, reverses or slows the effect of Provisional patent application Ser. No. 14/519,965, filed on SEMA4D. Oct. 21, 2014, now U.S. Pat. No. 9,598,495, issued Mar. 21, 0007 According to aspects illustrated herein, there is 2017, and also claims benefit to U.S. Provisional application provided a method of treating a subject with a neurodegen No. 62/012,805, filed on Jun. 16, 2014, U.S. Provisional erative disorder including administering to the Subject an Appl. No. 61/979,384, filed on Apr. 14, 2014, and U.S. effective amount of an isolated binding molecule which Provisional Appl. No. 61/893,814, filed on Oct. 21, 2013, the specifically binds to semaphorin 4D (SEMA4D), wherein contents of which are each hereby incorporated by reference the binding to SEMA4D acts to improve symptoms associ in their entireties. ated with the disorder. 0008 Methods of alleviating symptoms in a subject hav REFERENCE TO SEQUENCE LISTING ing a neurodegenerative disorder are provided, comprising SUBMITTED ELECTRONICALLY administering to that Subject an effective amount of an isolated binding molecule which specifically binds to Sema 0002 The content of the electronically submitted phorin-4D (SEMA4D). In certain embodiments of the meth sequence listing in ASCII text file (Name 58008-163820seq ods, the binding molecule inhibits SEMA4D interaction 1stg Div ST25.txt; Size: 32,500 bytes; and Date of Cre with its receptor or a portion of its receptor. In certain ation: Mar. 1, 2017) filed with the application is incorporated embodiments of the methods, the receptor is selected from herein by reference in its entirety. the group consisting of Plexin-B1 and Plexin-B2. In certain embodiments of the methods, the binding molecule inhibits BACKGROUND OF THE DISCLOSURE SEMA4D-mediated Plexin-B1 signal transduction. In cer tain embodiments of the methods, the isolated binding 0003. Semaphorin 4D (SEMA4D), also known as molecule specifically binds to the same SEMA4D epitope as CD100, is a transmembrane protein (e.g., SEQ ID NO: 1 a reference monoclonal antibody selected from the group (human): SEQ ID NO: 2 (murine)) that belongs to the consisting of VX15/2503 or 67. In certain embodiments of semaphorin gene family. SEMA4D is expressed on the cell the methods, the isolated binding molecule competitively surface as a homodimer, but upon cell activation SEMA4D inhibits a reference monoclonal antibody selected from the can be released from the cell Surface via proteolytic cleavage group consisting of VX15/2503 or 67 from specifically to generatesSEMA4D, a soluble form of the protein, which binding to SEMA4D. In certain embodiments of the meth is also biologically active. See Suzuki et al., Nature Rev. ods, the isolated binding molecule comprises an antibody or Immunol. 3:159-167 (2003); Kikutani et al., Nature Immu antigen-binding fragment thereof. In certain embodiments of mol. 9:17-23 (2008). the methods, the antibody or antigen-binding fragment thereof is monoclonal antibody VX15/2503 or 67. In certain 0004 SEMA4D is expressed at high levels in lymphoid embodiments of the methods, the antibody or antigen organs, including the spleen, thymus, and lymph nodes, and binding fragment thereof comprises a variable heavy chain in non-lymphoid organs, such as the brain, heart, and kidney. (VH) comprising VHCDRs 1-3 comprising SEQID NOS 6, In lymphoid organs, SEMA4D is abundantly expressed on 7, and 8, respectively, and a variable light chain (VL) resting T cells but only weakly expressed on resting B cells comprising VLCDRs 1-3 comprising SEQ ID NOs 14, 15, and antigen-presenting cells (APCs), such as dendritic cells and 16, respectively. In certain embodiments of the methods, (DCs). Its expression, however, is upregulated in these cells the VH and VL comprise, respectively, SEQ ID NO: 9 and following activation by various immunological stimuli. The SEQID NO: 17 or SEQID NO: 10 and SEQID NO: 18. In release of soluble SEMA4D from immune cells is also certain embodiments of any of the aforementioned methods, increased by cell activation. the neurodegenerative disorder is selected from a group 0005 SEMA4D has been implicated in the development consisting of Alzheimer's disease, Parkinson's disease, of neurodegenerative disorders, autoimmune diseases, Huntington's disease, Down syndrome, ataxia, amyotrophic demyelinating diseases, and certain cancers. However, the lateral sclerosis (ALS), frontotemporal dementia (FTD). effect of blocking SEMA4D signaling on the organization HIV-related cognitive impairment, CNS Lupus, mild cog and function of the central nervous system (CNS) including nitive impairment, or a combination thereof. In certain brain and spinal cord and on behaviors controlled by the embodiments of any of the aforementioned methods, the CNS remains to be elucidated. This is important because neurodegenerative disorder is Alzheimer's disease or Hun changes in the CNS have a profound influence on a subjects tington's disease. In certain embodiments of any one of the behavior and quality of life. In particular, Such changes can aforementioned methods, the symptoms are selected from a impact a subject's neuropsychiatric behavior, cognitive group consisting of neuropsychiatric symptoms, cognitive behavior, and motor skills. There remains, therefore, a need symptoms, motor dysfunction, and any combination thereof. for treatments for neurodegenerative disorders that alleviate In certain embodiments of any of the aforementioned meth the symptoms associated with the disorder.
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