Methods for treating neurological disorders using Anti-NOGO-a antibodies

Abstract

The present disclosure provides methods for treating neurological disorders (e.g., trauma of peripheral nervous system (PNS) or central nervous system (CNS)) using anti- Nogo-A antibodies or antigen-binding fragments thereof.

Description

New PCT application August 21, 2025Applicant: NovaGo Therapeutics AG WJS Reference: NO48A09 / P-WO METHODS FOR TREATING NEUROLOGICAL DISORDERS USING ANTI-NOGO-A ANTIBODIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No.63 / 685,907 filed August 22, 2024 and United States Provisional Application No. 63 / 709,585filed October 21, 2024, the content of each of which is incorporated by reference in itsentirety herein.SEQUENCE LISTING

[0002] This application contains an electronic Sequence Listing which has been submitted inXML file format with this application, the entire content of which is incorporated byreference herein in its entirety. The Sequence Listing XML file submitted with thisapplication is entitled “14866-038-228_SEQ_LISTING.xml”, was created on August 18, 2025, and is 34,841 bytes in size.1. FIELD

[0003] The present disclosure provides methods for treating neurological disorders (e.g.,trauma of peripheral nervous system (PNS) or central nervous system (CNS)) using anti- Nogo-A antibodies or antigen-binding fragments thereof.2. BACKGROUND

[0004] Central nervous system (CNS) regeneration is prevented by various cell-intrinsicsuppressors of growth signaling as well as by cell-extrinsic mechanisms. The latter include growth inhibitory factors enriched in the glial scar and in myelin. Nogo-A has been identified as one of the myelin-associated factors limiting the amount of recovery andplasticity in damaged central nervous system of both vasculature and neuronal cells. It is amember of the reticulon protein family and has at least two biologically active andpharmacologically distinct domains, Nogo-66 and Nogo-inhibitory activity for neurite growth. Thus, blocking the inhibitory activity of Nogo-A canbe useful in treating conditions accompanied by injury or degeneration of vascular orneuronal elements of CNS tissues, by ameliorating and promoting vascular and neuronalrepair and growth.

[0005] WO2004052932A2 describes murine anti-Nogo-A antibody 11C7, which efficientlyblocks Nogo-A-induced inhibition. Studies examined the activities of 11C7 are described inOertle et al., J. Neurosci. (2003);23:5393-5406; Liebscher et al, Annals of Neurology(2005);58:706-719; Joly et al., Glia 66 (2018), 2079-2093; Rust et al., PNAS 116 (2019),14270-14279; Wahl et al., Science 344 (2014), 1250-5; Freund et al., Nat Med. 12 (2006),790-2; Hamadjida et al., Exp Brain Res. 223 (2012), 321-40; and Mdzomba et al., Cell Deathand Disease (2018) 9:727.

[0006] Additional monoclonal anti-Nogo-A antibodies are disclosed in WO2005061544A2(murine antibody 2A10 and the humanized version thereof H1 L11), WO2007068750A2 and WO2009056509A1 (ATI355, derived from monoclonal antibody 6A3 generated inHuMabmouse™; this genetically reconstituted mouse had human immunoglobulin genes toreplace their murine counterparts). Several of these antibodies are in clinical trials for treatingspinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS);see Schmandke et al., Neuroscience (2014);20:372-386 (2014), and Kucher et al.,Neurorehabil. Neural Repair. (2018), 578-589. ATI355, also designated as NG-101, is beinginvestigated in a multicenter, multinational, placebo-controlled phase-II study for the safety and preliminary efficacy in patients with acute cervical SCI, wherein the antibody isadministered by intrathecal bolus injections of 45 mg; see, e.g., ClinicalTrials.gov Identifier:NCT03935321. WO2021079002A2 discloses novel human-derived antibodies as well asfragments, derivatives and biotechnological variants thereof specifically binding to and neutralizing Nogo-A.

[0007] There remain needs for novel and effective therapeutics and dosing regimen fortreating Nogo-A associated neurological disorders.3. SUMMARY

[0008] The present disclosure provides methods for treating neurological disorders usinganti-Nogo-A antibodies or antigen-binding fragments thereof and pharmaceutical compositions comprising thereof, where at least two doses of the anti-Nogo-A antibodies orantigen-binding fragments thereof are administered sequentially to a subject in need thereof,and each dose is between about 50 mg and about 450 mg (e.g., about 50 mg, about 150 mg, about 450 mg).

[0009] In one aspect, the present disclosure provides a method for treating a neurologicaldisease in a subject in need thereof, the method comprising sequentially administering to thesubject at least two doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof, wherein each of the at least two doses is between about 50 mg and about 450 mg.

[0010] In certain embodiments, each dose is about 50 mg. In certain embodiments, eachdose is about 100 mg. In certain embodiments, each dose is about 150 mg. In certainembodiments, each dose is about 200 mg. In certain embodiments, each dose is about 400mg. In certain embodiments, each dose is about 450 mg.

[0011] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof is administered at an interval of from 3 days to 7 days between two consecutively administered doses. In certain embodiments, the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28. In certain embodiments, the method comprises sequentially administering to the subject 6 doses of the anti-Nogo-A antibody or antigen-binding fragment thereof within 4 weeks.

[0012] In certain embodiments, each dose is administered as a single-dose injection. Incertain embodiments, each dose is administered via slow bolus, optionally wherein each dose is administered via slow bolus over about 100 seconds. In certain embodiments, the anti- Nogo-A antibody or antigen-binding fragment thereof is administered via intrathecal injection. In certain embodiments, the intrathecal injection is administered at the lumbar level.

[0013] In another aspect, the present disclosure provides a method for treating aneurological disease in a subject in need thereof, the method comprising sequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof within 4 weeks, wherein each dose is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, or about 450 mg; and wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection, optionally wherein the intrathecal injection is administeredat the lumbar level. In certain embodiments, each dose is about 50 mg. In certainembodiments, each dose is about 100 mg. In certain embodiments, each dose is about 150mg. In certain embodiments, each dose is about 200 mg. In certain embodiments, each doseis about 400 mg. In certain embodiments, each dose is about 450 mg.

[0014] A method for treating a neurological disorder in a subject in need thereof, themethod comprising sequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof within 4 weeks, wherein each dose is about50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, or about 450 mg; whereinthe first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection, optionally wherein theintrathecal injection is administered at the lumbar level; wherein the anti-Nogo-A antibody orantigen-binding fragment thereof comprises a VH and a VL, wherein (a) the VH comprises aVH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, a VH-CDR2 comprisingthe amino acid sequence of SEQ ID NO:4, the VH-CDR3 comprising the amino acidsequence of SEQ ID NO:5; and (b) the VL comprises a VL-CDR1 comprising the amino acidsequence of SEQ ID NO:8, a VL-CDR2 comprising the amino acid sequence of SEQ IDNO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:10, wherein theamino acid sequences of the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition. In certain embodiments, the neurologicaldisorder is spinal cord injury.

[0015] In another aspect, the present disclosure provides an anti-Nogo-A antibody or anantigen-binding fragment thereof for use in treating a neurological disorder in a subject inneed thereof, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is to beadministered to the subject in at least two doses sequentially, wherein each of the at least two doses is between about 50 mg and about 450 mg.

[0016] In another aspect, the present disclosure provides an antigen-binding fragment thereofin the manufacture of a medicament for the treatment of a neurological disorder in a subject in need thereof, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is to be administered to the subject in at least two doses sequentially, wherein each of the at least two doses is between about 50 mg and about 450 mg.

[0017] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof for use with the methods, uses, or medicament herein is administered to the subject in a pharmaceutical composition, wherein the pharmaceutical composition comprises:(i) the anti-Nogo-A antibody or antigen-binding fragment thereof, optionallywherein the anti-Nogo-A antibody or antigen-binding fragment thereof is at a concentration of between about 50 mg / ml and about 150 mg / ml; (ii) a buffer, optionally wherein the buffer is at a concentration of between about 1mM and about 50 mM; (iii) a carbohydrate, optionally wherein the carbohydrate is at a concentration ofbetween about 1.0% (w / v) and about 10% (w / v); (iv) a salt, optionally wherein the salt is at a concentration of between about 10mM and about 200 mM; and (v) a surfactant, optionally wherein the surfactant is at a concentration of betweenabout 0.002% (w / v) and about 0.05% (w / v); wherein the pharmaceutical composition has a pH of between about 5.0 and about 7.0.

[0018] In certain embodiments, the pharmaceutical composition comprises:(i) the anti-Nogo-A antibody or antigen-binding fragment thereof at aconcentration of about 100 mg / ml; (ii) phosphate buffer at a concentration of about 5 mM;(iii) sucrose at a concentration of about 4.2% (w / v);(iv) sodium chloride at a concentration of about 50 mM; and(v) polysorbate 80 at a concentration of about 0.01% (w / v);wherein the pharmaceutical composition has a pH of about 5.8.

[0019] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof used in the methods, uses, and medicaments disclosed herein: (i) binds Nogo-A-(ii) recognizes an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355; (iii) does not compete with 11C7 and / or Ozanezumab for binding to Nogo-A;and / or (iv) binds a Nogo-A epitope comprising the amino acid sequence of SEQ IDNO:21 or SEQ ID NO:28.

[0020] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof is a recombinant human antibody or an antigen-binding fragment thereof.

[0021] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof is capable of neutralizing the biological activity of Nogo-A. In certain embodiments,the anti-Nogo-A antibody or antigen-binding fragment thereof is capable of neutralizing thebiological activity of Nogo-A by inducing neurite outgrowth and / or angiogenesis in stroke penumbra.

[0022] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises a heavy chain variable region (VH) comprising a heavy chain variable region complementarity determining region 1 (VH-CDR1), a heavy chain variable region complementarity determining region 2 (VH-CDR2), and a heavy chain variable region complementarity determining region 3 (VH-CDR3) as set forth in a VH comprising the amino acid sequence of SEQ ID NO:2; and a light chain variable region (VL) comprising a light chain variable region complementarity determining region 1 (VL-CDR1), a light chain variable region complementarity determining region 2 (VL-CDR2), and a light chain variable region complementarity determining region 3 (VL-CDR3) as set forth in a VL comprising theamino acid sequence of SEQ ID NO:7.

[0023] In certain embodiments, the VH-CDR1 comprises the amino acid sequence of SEQID NO:3, the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:4, the VH-CDR3 comprises the amino acid sequence of SEQ ID NO:5, the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:8, the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:9, and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO:10, and wherein the amino acid sequences of the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL- CDR2, and VL-CDR3 are determined by Kabat definition.

[0024] In certain embodiments,(i) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:2, or the VL comprises an amino acid sequence at least 80% or at least 90% identical to the amino acidsequence of SEQ ID NO:7; (ii) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:2, and the VL comprises an amino acid sequence at least 80% or at least 90% identical to the aminoacid sequence of SEQ ID NO:7; (iii) the VH comprises the amino acid sequence of SEQ ID NO:2 or the VLcomprises the amino acid sequence of SEQ ID NO:7.

[0025] In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:2and the VL comprises the amino acid sequence of SEQ ID NO:7.

[0026] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forthin a VH comprising the amino acid sequence of SEQ ID NO:12; and a VL comprising a VL- CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:17.

[0027] In certain embodiments, the VH-CDR1 comprises the amino acid sequence of SEQID NO:13, the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:14, the VH- CDR3 comprises the amino acid sequence of SEQ ID NO:15, the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:18, the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:19, and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO:20, wherein the amino acid sequences of the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL- CDR2, and VL-CDR3 are determined by Kabat definition.

[0028] In certain embodiments,(i) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, or the VL comprises an amino acid sequence at least 80% or at least 90% identical to the aminoacid sequence of SEQ ID NO:17; (ii) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, and the VL comprises an amino acid sequence at least 80% or at least 90% identical to the aminoacid sequence of SEQ ID NO:17; (iii) the VH comprises the amino acid sequence of SEQ ID NO:12 or the VLcomprises the amino acid sequence of SEQ ID NO:17.

[0029] In certain embodiments, the VH comprises the amino acid sequence of SEQ IDNO:12 and the VL comprises the amino acid sequence of SEQ ID NO:17.

[0030] In certain embodiments, the anti-Nogo-A antibody comprises a heavy chain constantregion, wherein the heavy chain constant region is of human IgG4 type. In certainembodiments, the heavy chain constant region comprises an amino acid substitution S228P (numbering according to EU numbering) relative to the amino acid sequence of SEQ ID NO:26.

[0031] In certain embodiments, the anti-Nogo-A antibody comprises a human kappa lightchain constant region.

[0032] In certain embodiments, the anti-Nogo-A antibody comprises(i) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 or a light chaincomprising an amino acid sequence at least 80% or at least 90% identical tothe amino acid sequence of SEQ ID NO:25; (ii) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 and a light chain comprising an amino acid sequence at least 80% or at least 90% identical tothe amino acid sequence of SEQ ID NO:25.; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:23 or alight chain comprising the amino acid sequence of SEQ ID NO:25.

[0033] In certain embodiments, the heavy chain comprises the amino acid sequence of SEQID NO:23 and the light chain comprises the amino acid sequence of SEQ ID NO:25.

[0034] In certain embodiments, the anti-Nogo-A antibody comprises a first and a secondheavy chain each comprising the amino acid sequence of SEQ ID NO:23 and a first and a second light chains each comprising the amino acid sequence of SEQ ID NO:25.

[0035] In certain embodiments, disulfide bridges are formed(i) between C134 of the first heavy chain and C220 of the first light chain,between C134 of the second heavy chain and C220 of the second light chain, between C226 of the first heavy chain and C226 of the second heavy chain, and between C229 of the first heavy chain and C229 of the second heavy chain; or (ii) between C134 of the first heavy chain and C220 of the first light chain,between C134 of the second heavy chain and C220 of the second light chain, between C226 of the first heavy chain and C229 of the second heavy chain, and between C229 of the first heavy chain and C226 of the second heavy chain, wherein the amino acid numberings are based on EU numbering.

[0036] In certain embodiments, the heavy chain comprises an N-linked glycan site at aminoacid residue N297 (numbering according to EU numbering).

[0037] In certain embodiments, the neurological disorder is a trauma of peripheral nervoussystem (PNS) or central nervous system (CNS). In certain embodiments, the neurologicaldisorder is a cranial trauma, a cerebral trauma, a spinal trauma, a brain trauma, or a stroke. Incertain embodiments, the neurological disorder is a spinal cord injury (SCI). In certainembodiments, the SCI is an acute SCI. In certain embodiments, the SCI is not at the lumbar level. In certain embodiments, the SCI is a cervical SCI. In certain embodiments, the SCI isan acute cervical SCI. In certain embodiments, the SCI is an incomplete cervical SCI. In certain embodiments, the SCI is an acute incomplete cervical SCI.

[0038] In certain embodiments, the neurological disorder is a neurodegenerative disease,optionally wherein the neurodegenerative disease is selected from the group consisting of Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (ALS), Lewy like pathologies, and dementia.

[0039] In certain embodiments, the neurological disorder is a demyelinating disease or anophthalmologic disease, optionally wherein the ophthalmologic disease is selected from the group consisting of diabetic retinopathy, diabetic macular edema, and wet and dry age-related macular degeneration (AMD).

[0040] In certain embodiments, the neurological disease is a SCI not at the lumbar level andthe anti-Nogo-A antibody or antigen-binding fragment thereof is administered to the subjectvia intrathecal injection at the lumbar level. In certain embodiments, the SCI is an injury atC1-C8 level and the anti-Nogo-A antibody or antigen-binding fragment thereof isadministered to the subject via intrathecal injection at L1-L5 level.3.1 Illustrative Embodiments

[0041] The present disclosure provides the following non-limiting embodiments:1. A method for treating a neurological disease in a subject in need thereof, the methodcomprising sequentially administering to the subject at least two doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof, wherein each of the at least two doses is between about 50 mg and about 450 mg.2. The method of embodiment 1, wherein the anti-Nogo-A antibody or antigen-bindingfragment thereof binds Nogo-A- .3. The method of embodiment 1 or 2, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof recognizes an epitope that is different from the binding epitope ofanti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355.4. The method of any one of embodiments 1-3, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof does not compete with 11C7 and / or Ozanezumab forbinding to Nogo-A.5. The method of any one of embodiments 1-4, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof binds a Nogo-A epitope comprising the amino acidsequence of SEQ ID NO:21 or SEQ ID NO:28.6. The method of any one of embodiments 1-5, wherein each dose is about 50 mg.7. The method of any one of embodiments 1-5, wherein each dose is about 100 mg.8. The method of any one of embodiments 1-5, wherein each dose is about 150 mg.9. The method of any one of embodiments 1-5, wherein each dose is about 200 mg.10. The method of any one of embodiments 1-5, wherein each dose is about 400 mg.11. The method of any one of embodiments 1-5, wherein each dose is about 450 mg.12. The method of any one of embodiments 1-11, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof is administered at an interval of from 3 days to 7 days between two consecutively administered doses.13. The method of any one of embodiments 1-12, wherein the first dose is administeredon day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28.14. The method of any one of embodiments 1-13, wherein the method comprisessequentially administering to the subject 6 doses of the anti-Nogo-A antibody or antigen- binding fragment thereof within 4 weeks.15. The method of any one of embodiments 1-14, wherein each dose is administered as asingle-dose injection.16. The method of any one of embodiments 1-15, wherein each dose is administered viaslow bolus, optionally wherein each dose is administered via slow bolus over about 100 seconds.17. The method of any one of embodiments 1-16, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof is administered via intrathecal injection.18. The method of embodiment 17, wherein the intrathecal injection is administered at thelumbar level.19. A method for treating a neurological disease in a subject in need thereof, the methodcomprising sequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof within 4 weeks, wherein each dose is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, or about 450 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each doseis administered as a single-dose injection via intrathecal injection, optionally wherein the intrathecal injection is administered at the lumbar level.20. The method of embodiment 19, wherein the anti-Nogo-A antibody or antigen-bindingfragment thereof binds Nogo-A- .21. The method of embodiment 19 or 20, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof recognizes an epitope that is different from the binding epitope ofanti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355.22. The method of any one of embodiments 19-21, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof does not compete with 11C7 and / or Ozanezumab forbinding to Nogo-A.23. The method of any one of embodiments 19-22, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof binds a Nogo-A epitope comprising the amino acidsequence of SEQ ID NO:21 or SEQ ID NO:28.24. The method of any one of embodiments 19-23, wherein each dose is about 50 mg.25. The method of any one of embodiments 19-23, wherein each dose is about 100 mg.26. The method of any one of embodiments 19-23, wherein each dose is about 150 mg.27. The method of any one of embodiments 19-23, wherein each dose is about 200 mg.28. The method of any one of embodiments 19-23, wherein each dose is about 400 mg.29. The method of any one of embodiments 19-23, wherein each dose is about 450 mg.30. The method of any one of embodiments 1-29, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof is administered to the subject in a pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) the anti-Nogo-A antibody or antigen-binding fragment thereof, optionallywherein the anti-Nogo-A antibody or antigen-binding fragment thereof is at a concentration of between about 50 mg / ml and about 150 mg / ml; (ii) a buffer, optionally wherein the buffer is at a concentration of between about 1mM and about 50 mM; (iii) a carbohydrate, optionally wherein the carbohydrate is at a concentration ofbetween about 1.0% (w / v) and about 10% (w / v); (iv) a salt, optionally wherein the salt is at a concentration of between about 10mM and about 200 mM; and (v) a surfactant, optionally wherein the surfactant is at a concentration of betweenabout 0.002% (w / v) and about 0.05% (w / v); wherein the pharmaceutical composition has a pH of between about 5.0 and about 7.0.31. The method of embodiment 30, wherein the pharmaceutical composition comprises:(i) the anti-Nogo-A antibody or antigen-binding fragment thereof at aconcentration of about 100 mg / ml; (ii) phosphate buffer at a concentration of about 5 mM;(iii) sucrose at a concentration of about 4.2% (w / v);(iv) sodium chloride at a concentration of about 50 mM; and(v) polysorbate 80 at a concentration of about 0.01% (w / v);wherein the pharmaceutical composition has a pH of about 5.8.32. The method of any one of embodiments 1-31, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof is a recombinant human antibody or an antigen-binding fragment thereof.33. The method of any one of embodiments 1-32, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof is capable of neutralizing the biological activity of Nogo-A.34. The method of embodiment 33, wherein the anti-Nogo-A antibody or antigen-bindingfragment thereof is capable of neutralizing the biological activity of Nogo-A by inducing neurite outgrowth and / or angiogenesis in stroke penumbra.35. The method of any one of embodiments 1-34, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a heavy chain variable region complementarity determining region 1 (VH-CDR1), a heavy chain variable region complementarity determining region 2 (VH-CDR2), and a heavy chain variable region complementarity determining region 3 (VH-CDR3) as set forth in a VH comprising the amino acid sequence of SEQ ID NO:2; and a light chain variable region (VL) comprising a light chain variable region complementarity determining region 1 (VL-CDR1), a light chain variable region complementarity determining region 2 (VL-CDR2), and a light chain variable region complementarity determining region 3 (VL-CDR3) as set forth in a VLcomprising the amino acid sequence of SEQ ID NO:7.36. The method of embodiment 35, wherein the VH-CDR1 comprises the amino acidsequence of SEQ ID NO:3, the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:4, the VH-CDR3 comprises the amino acid sequence of SEQ ID NO:5, the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:8, the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:9, and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO:10, and wherein the amino acid sequences of the VH-CDR1, VH-CDR2, VH-CDR3, VL- CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition.37. The method of embodiment 35 or 36, wherein(i) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:2, or the VL comprises an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:7; (ii) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:2, and the VL comprises an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:7; or (iii) the VH comprises the amino acid sequence of SEQ ID NO:2 or the VLcomprises the amino acid sequence of SEQ ID NO:7.38. The method of any one of embodiments 35-37, wherein the VH comprises the aminoacid sequence of SEQ ID NO:2 and the VL comprises the amino acid sequence of SEQ ID NO:7.39. The method of any one of embodiments 1-34, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:12; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:17.40. The method of embodiment 39, wherein the VH-CDR1 comprises the amino acidsequence of SEQ ID NO:13, the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:14, the VH-CDR3 comprises the amino acid sequence of SEQ ID NO:15, the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:18, the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:19, and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO:20, wherein the amino acid sequences of the VH-CDR1, VH-CDR2, VH-CDR3,VL-CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition.41. The method of embodiment 39 or 40, wherein(i) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, or the VL comprises an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:17; (ii) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, and the VL comprisesan amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:17; or (iii) the VH comprises the amino acid sequence of SEQ ID NO:12 or the VLcomprises the amino acid sequence of SEQ ID NO:17.42. The method of any one of embodiments 39-41, wherein the VH comprises the aminoacid sequence of SEQ ID NO:12 and the VL comprises the amino acid sequence of SEQ ID NO:17.43. The method of any one of embodiments 1-42, wherein the anti-Nogo-A antibodycomprises a heavy chain constant region, wherein the heavy chain constant region is of human IgG4 type.44. The method of embodiment 43, wherein the heavy chain constant region comprises anamino acid substitution S228P (numbering according to EU numbering) relative to the amino acid sequence of SEQ ID NO:26.45. The method of any one of embodiments 1-44, wherein the anti-Nogo-A antibodycomprises a human kappa light chain constant region.46. The method of any one of embodiments 1-38 and 43-45, wherein the anti-Nogo-Aantibody comprises (i) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 or a light chain comprising an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:25;(ii) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 and a light chain comprising an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:25.; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:23 or alight chain comprising the amino acid sequence of SEQ ID NO:25.47. The method of embodiment 46, wherein the heavy chain comprises the amino acidsequence of SEQ ID NO:23 and the light chain comprises the amino acid sequence of SEQ ID NO:25.48. The method of any one of embodiments 1-38 and 43-47, wherein the anti-Nogo-Aantibody comprises a first and a second heavy chain each comprising the amino acid sequence of SEQ ID NO:23 and a first and a second light chains each comprising the amino acid sequence of SEQ ID NO:25.49. The method of embodiment 48, wherein disulfide bridges are formed(i) between C134 of the first heavy chain and C220 of the first light chain,between C134 of the second heavy chain and C220 of the second light chain, between C226 of the first heavy chain and C226 of the second heavy chain, and between C229 of the first heavy chain and C229 of the second heavy chain; or (ii) between C134 of the first heavy chain and C220 of the first light chain,between C134 of the second heavy chain and C220 of the second light chain, between C226 of the first heavy chain and C229 of the second heavy chain, and between C229 of the first heavy chain and C226 of the second heavy chain, wherein the amino acid numberings are based on EU numbering.50. The method of any one of embodiments 46-49, wherein the heavy chain comprises anN-linked glycan site at amino acid residue N297 (numbering according to EU numbering).51. The method of any one of embodiments 1-50, wherein the neurological disorder is atrauma of peripheral nervous system (PNS) or central nervous system (CNS).52. The method of embodiment 51, wherein the neurological disorder is a cranial trauma,a cerebral trauma, a spinal trauma, a brain trauma, or a stroke.53. The method of embodiment 52, wherein the neurological disorder is a spinal cordinjury (SCI).54. The method of embodiment 53, wherein the SCI is an acute SCI, a cervical SCI, anacute cervical SCI, an incomplete cervical SCI, or an acute incomplete cervical SCI.55. The method of any one of embodiments 1-50, wherein the neurological disorder is aneurodegenerative disease, optionally wherein the neurodegenerative disease is selected from the group consisting of Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (ALS), Lewy like pathologies, and dementia.56. The method of any one of embodiments 1-50, wherein the neurological disorder is ademyelinating disease or an ophthalmologic disease, optionally wherein the ophthalmologic disease is selected from the group consisting of diabetic retinopathy, diabetic macular edema, and wet and dry age-related macular degeneration (AMD).57. A method for treating a neurological disorder in a subject in need thereof, the methodcomprising sequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof within 4 weeks, wherein each dose is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about400 mg, or about 450 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection, optionally wherein the intrathecal injection is administered at the lumbar level; wherein the anti-Nogo-A antibody or antigen-binding fragment thereof comprises aVH and a VL, wherein (a) the VH comprises a VH-CDR1 comprising the amino acidsequence of SEQ ID NO:3, a VH-CDR2 comprising the amino acid sequence of SEQ IDNO:4, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:5; and (b) the VLcomprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VL-CDR2comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising theamino acid sequence of SEQ ID NO:10, wherein the amino acid sequences of the VH-CDR1,VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition.58. The method of embodiment 57, wherein the neurological disorder is a spinal cordinjury (SCI).59. The method of embodiment 58, wherein the SCI is an acute SCI, a cervical SCI, anacute cervical SCI, an incomplete cervical SCI, or an acute incomplete cervical SCI.60. The method of any one of embodiments 57-59, wherein(i) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, or the VL comprises an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:17; (ii) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, and the VL comprises an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:17; or (iii) the VH comprises the amino acid sequence of SEQ ID NO:12 or the VLcomprises the amino acid sequence of SEQ ID NO:17.61. The method of any one of embodiments 57-60, wherein the VH comprises the aminoacid sequence of SEQ ID NO:12 and the VL comprises the amino acid sequence of SEQ ID NO:17.62. The method of any one of embodiments 57-61, wherein the anti-Nogo-A antibodycomprises (i) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 or a light chain comprising an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:25;(ii) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 and a light chain comprising an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:25.; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:23 or alight chain comprising the amino acid sequence of SEQ ID NO:25.63. The method of embodiment 62, wherein the heavy chain comprises the amino acidsequence of SEQ ID NO:23 and the light chain comprises the amino acid sequence of SEQ ID NO:25.64. The method of any one of embodiments 57-63, wherein the anti-Nogo-A antibodycomprises a first and a second heavy chain each comprising the amino acid sequence of SEQ ID NO:23 and a first and a second light chains each comprising the amino acid sequence of SEQ ID NO:25.65. The method of any one of embodiments 57-64, wherein each dose is about 50 mg.66. The method of any one of embodiments 57-64, wherein each dose is about 100 mg.67. The method of any one of embodiments 57-64, wherein each dose is about 150 mg.68. The method of any one of embodiments 57-64, wherein each dose is about 200 mg.69. The method of any one of embodiments 57-64, wherein each dose is about 400 mg.70. The method of any one of embodiments 57-64, wherein each dose is about 450 mg.71. The method of any one of embodiments 1-70, wherein the neurological disease is aSCI not at the lumbar level and the anti-Nogo-A antibody or antigen-binding fragmentthereof is administered to the subject via intrathecal injection at the lumbar level.72. The method of any one of embodiments 1-71, wherein the SCI is an injury at C1-C8level and the anti-Nogo-A antibody or antigen-binding fragment thereof is administered tothe subject via intrathecal injection at L1-L5 level.73. An anti-Nogo-A antibody or an antigen-binding fragment thereof for use in treating aneurological disorder in a subject in need thereof, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is to be administered to the subject in at least two dosessequentially, wherein each of the at least two doses is between about 50 mg and about 450 mg; optionally wherein the anti-Nogo-A antibody or antigen-binding fragment thereof: (i) binds Nogo-A-(ii) recognizes an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355; (iii) does not compete with 11C7 and / or Ozanezumab for binding to Nogo-A;and / or (iv) binds a Nogo-A epitope comprising the amino acid sequence of SEQ IDNO:21 or SEQ ID NO:28.74. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toembodiment 73, wherein administration is performed as defined in any one of embodiments 12-18.75. An anti-Nogo-A antibody or an antigen-binding fragment thereof for use in a methodof treating a neurological disease in a subject in need thereof, wherein the method comprisessequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof within 4 weeks, wherein each dose is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, or about 450 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection, optionally wherein the intrathecal injection is administered at the lumbar level; optionally wherein the anti-Nogo-A antibody or antigen-binding fragment thereof: (i) binds Nogo-A-(ii) recognizes an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355; (iii) does not compete with 11C7 and / or Ozanezumab for binding to Nogo-A; and / or (iv) binds a Nogo-A epitope comprising the amino acid sequence of SEQ ID NO:21 or SEQ ID NO:28.76. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toany one of embodiments 73-75, wherein each dose is the dose as defined in any one of embodiments 6-11.77. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toany one of embodiments 73-76, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is administered to the subject in a pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) the anti-Nogo-A antibody or antigen-binding fragment thereof, optionally wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is at a concentration of between about 50 mg / ml and about 150 mg / ml; (ii) a buffer, optionally wherein the buffer is at a concentration of between about 1 mM and about 50 mM; (iii) a carbohydrate, optionally wherein the carbohydrate is at a concentration of between about 1.0% (w / v) and about 10% (w / v); (iv) a salt, optionally wherein the salt is at a concentration of between about 10 mM and about 200 mM; and (v) a surfactant, optionally wherein the surfactant is at a concentration of between about 0.002% (w / v) and about 0.05% (w / v); wherein the pharmaceutical composition has a pH of between about 5.0 and about 7.0.78. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toembodiment 77, wherein the pharmaceutical composition comprises: (i) the anti-Nogo-A antibody or antigen-binding fragment thereof at a concentration of about 100 mg / ml; (ii) phosphate buffer at a concentration of about 5 mM; (iii) sucrose at a concentration of about 4.2% (w / v); (iv) sodium chloride at a concentration of about 50 mM; and (v) polysorbate 80 at a concentration of about 0.01% (w / v); wherein the pharmaceutical composition has a pH of about 5.8.79. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toany one of embodiments 73-78, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is the antibody or antigen-binding fragment thereof as defined in any one of embodiments 32-50.80. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toany one of embodiments 73-79, wherein the neurological disease or disorder is a disease or disorder as defined in any one of embodiments 51-56.81. An anti-Nogo-A antibody or an antigen-binding fragment thereof for use in a methodof treating a neurological disorder in a subject in need thereof, the method comprisingsequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen- binding fragment thereof within 4 weeks, wherein each dose is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, or about 450 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day19 and day 23, and the sixth dose is administered between day 24 and day 28, and each doseis administered as a single-dose injection via intrathecal injection, optionally wherein the intrathecal injection is administered at the lumbar level; wherein the anti-Nogo-A antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein (a) the VH comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:4, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:5; and (b) the VL comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:10, wherein the amino acid sequences of the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition.82. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toembodiment 81, wherein the neurological disorder is a spinal cord injury (SCI), optionallywherein the SCI is an acute SCI, an incomplete cervical SCI, or an acute incomplete cervical SCI.83. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toembodiment 81 or 82, wherein the antibody or antigen-binding fragment thereof is theantibody or antigen-binding fragment thereof as defined in any one of embodiments 60-64.84. Use of an anti-Nogo-A antibody or an antigen-binding fragment thereof in themanufacture of a medicament for the treatment of a neurological disorder in a subject in need thereof, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is to be administered to the subject in at least two doses sequentially, wherein each of the at least two doses is between about 50 mg and about 450 mg; optionally wherein the anti-Nogo-A antibody or antigen-binding fragment thereof: (i) binds Nogo-A-(ii) recognizes an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355; (iii) does not compete with 11C7 and / or Ozanezumab for binding to Nogo-A;and / or (iv) binds a Nogo-A epitope comprising the amino acid sequence of SEQ IDNO:21 or SEQ ID NO:28.4. BRIEF DESCRIPTION OF THE FIGURES

[0042] FIGS. 1A & 1B provide amino acid sequences of VH and VL of human anti-Nogo-Aantibodies Ab1 (FIG. 1A) and Ab2 (FIG. 1B). Framework (FR) and CDRs regions areindicated with CDRs being underlined. Kabat definition was used to identify CDRsequences.

[0043] FIG. 2 is a schematic showing of Ab1. The N-link Glycan is on Asparagine 297 ofthe heavy chains as shown in oval dots. The S to P mutation is on Proline 228 of the heavychains indicated by arrows. The 4 inter-chain disulfide bonds are indicated by dark linesbetween chains.

[0044] FIG. 3 is a flow chart showing the clinical trial schedule of Example 1 and Example2.5. DETAILED DESCRIPTION

[0045] The present disclosure provides methods for treating neurological disorders (Section5.4). In certain embodiments, the neurological disorders to be treated are selected from the ones disclosed in Section 5.4.1. In certain embodiments, the methods comprise administeringto a subject in need thereof an anti-Nogo-A antibody or an antigen-binding fragment thereof(e.g., an anti-Nogo-A antibody or an antigen-binding fragment thereof disclosed in Section5.2) or a pharmaceutical composition comprising thereof (e.g., a pharmaceutical compositiondisclosed in Section 5.3). In certain embodiments, the methods comprise administering theanti-Nogo-A antibody or antigen-binding fragment thereof or the pharmaceutical compositioncomprising thereof according to a dosing regimen of Section 5.4.2.

[0046] In certain embodiments, a method disclosed herein for treating a neurologicaldisorder comprises administering to a subject in need thereof an anti-Nogo-A antibody or an antigen-binding fragment thereof (e.g., an anti-Nogo-A antibody or an antigen-binding fragment thereof disclosed in Section 5.2) or a pharmaceutical composition comprisingthereof (e.g., a pharmaceutical composition disclosed in Section 5.3), where least two dosesof the anti-Nogo-A antibody or antigen-binding fragment thereof are administeredsequentially to the subject, and each dose is between about 50 mg and about 450 mg (e.g.,about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, about 450 mg). Incertain embodiments, 6 doses of the anti-Nogo-A antibody or antigen-binding fragment thereof are administered within 4 weeks. In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragment thereof has the properties of (i) binding Nogo-A- (ii) recognizing an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355; (iii) not competing with 11C7 and / or Ozanezumab, for binding to Nogo-A; and / or (iv) binding a Nogo-A epitope comprising theamino acid sequence of SEQ ID NO:21 or SEQ ID NO:28.5.1 Definitions

[0047] Unless otherwise stated, a term as used herein is given the definition as provided inthe Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, 1997, revised 2000 and reprinted 2003, ISBN 0198506732; Second edition published 2006,ISBN 0-19-852917-1978-0-19852917-0. Furthermore, unless stated otherwise, terms andexpressions used herein in order to characterize the present disclosure are given thedefinitions as provided in WO2015092077A1, in particular in subsection “I. Definitions” at pages 16 to 42, the disclosure content of which is explicitly incorporated herein by reference.

[0048] “Antibody” as used herein also includes antibody fragments (and / or polypeptides thatcomprise antibody fragments) that are derived from the full-length antibody and retainantigen (e.g., Nogo-A) binding characteristics of the antibody from which the respectivefragment was derived. Non-limiting examples of antibody fragments include Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable domain antibody,single variable domain, linear antibody, V region, multispecific antibodies formed fromantibody fragments, F(ab)2, Fd, Fc, diabody, disulfide-linked Fvs (dsFv), and single-domain antibody (e.g., nanobody). As used herein, the term “anti-Nogo-A antibody” also includes antigen-binding (i.e., Nogo-A-binding) fragments of the full-length anti-Nogo-A antibody.

[0049] The term “human antibody” as used herein refers to an antibody that possesses anamino acid sequence that corresponds to an antibody produced by a human and / or an antibody that has been made using any of the techniques that are known to those of skill in the art for making human antibodies. These techniques include, but not limited to, phage display libraries, yeast display libraries, transgenic animals, recombinant protein production, and B-cell hybridoma technology.

[0050] The term “complementarity determining region,” or “CDR” as used herein refers tothe regions of an antibody variable region that are hypervariable in sequence and / or formstructurally defined loops. Herein, the CDRs are referred to in terms of both the amino acidsequence and the location within the light or heavy chain. As the location of the CDRswithin the structure of the immunoglobulin variable domain is conserved between species andpresent in structures called loops, by using numbering systems that align variable domainsequences according to structural features, CDR and framework residues and are readilyidentified by one skilled in the art. Various systems known in the art or disclosed hereinrepresent different ways of delineating CDRs, and when they are used to define the same antibody, they are considered equivalent. The residues from each of these CDRs are exemplified in the table below. Exemplary CDRs According to Various Numbering Systems IMGT Kabat AbM Chothia ContactVH-CDR1 27-38 31-35 26-35 26-32 30-35VH-CDR2 56-65 50-65 50-58 53-55 47-58VH-CDR3 105-117 95-102 95-102 96-101 93-101VL-CDR1 27-38 24-34 24-34 26-32 30-36VL-CDR2 56-65 50-56 50-56 50-52 46-55VL-CDR3 105-117 89-97 89-97 91-96 89-96

[0051] The specific CDR sequences defined in the anti-Nogo-A antibodies herein (e.g., Ab1and Ab2) are based on Kabat definition. However, it will be understood that reference to a heavy chain variable region CDR or CDRs and / or a light chain variable region CDR or CDRs of a specific antibody will encompass all CDR definitions as known to those of skill in the art. For example, depending on the position of the first CDR the following CDRs might be shifted in either direction. Accordingly, in case of any inadvertent errors or inconsistenciesregarding indication of CDRs in FIGS. 1A-1B and / or the sequence listing, the person skilledin the art on the basis of the disclosure content of the present application is well in theposition to determine the correct CDR sequences in accordance with various definitions known in the art.

[0052] As used herein, reference to “about” of a given value includes (and describes)embodiments that are directed to the given value and embodiments with 10% or less variationof the given value.5.2 Anti-Nogo-A Antibodies and Antigen-Binding Fragments Thereof

[0053] The present disclosure provides anti-Nogo-A antibodies and antigen-binding (i.e.,Nogo-A binding) fragment thereof to be used in the therapeutic methods disclosed herein(e.g., methods disclosed in Section 5.4). As used herein, the term “anti-Nogo-A antibody” also includes antigen-binding (i.e., Nogo-A-binding) fragments of the full-length anti-Nogo- A antibody.

[0054] In certain embodiments, the anti-Nogo-A antibody is a neutralizing antibody. Aneutralizing antibody, as commonly understood in the art, refers to an antibody that reduces or abolishes at least some biological activity of an antigen or a living microorganism. Neutralization is commonly defined by 50% inhibitory concentrations (IC50) and can bestatistically assessed based on the area under the neutralization titration curves (AUC). Incertain embodiments, the anti-Nogo-A antibody can downregulate the level of endogenousNogo-A in vivo in CNS as determined by immunohistochemistry, increase long-term synapticplasticity (long-term potentiation, LTP) as determined in LTP assay in mouse hippocampi,and / or stimulate neurite outgrowth in in vitro neurite outgrowth assay, and induceangiogenesis in the penumbra of in vivo mouse stroke model. In certain embodiments, theanti-Nogo-A antibody can neutralize the biological activity of Nogo-A by inducing dose dependent neurite outgrowth in the presence of outgrowth inhibitory CNS extract.

[0055] In certain embodiments, the anti-Nogo-A antibody can downregulate the level ofNogo-A level in CNS. In certain embodiments, the anti-Nogo-A antibody is derived from ananti-Nogo-A antibody designated as Ab1 disclosed herein and can recognize the humanNogo-A d20plus peptide preferentially over the corresponding antigen from other species such as rats or mice.

[0056] In certain embodiments, the anti-Nogo-A antibody has an IC50 value for inducingneurite outgrowth in a neurite outgrowth inhibition assay less than about 15 nM, less thanabout 12 nM, or less than about 11 nM. In certain embodiments, the anti-Nogo-A antibody has an EC50 value for binding the human or rat Nogo-A d20plus region of less than about 0.5nM, less than about 0.4 nM, or less than about 0.3 nM. However, also depending on theantibody format, for example whether an IgG1, IgG4 or antibody fragment is used, like Fabfragments, the IC50 and EC50 values may deviate and may be higher or lower than the valuesdisclosed herein. Accordingly, in this context, the term “about” means within one order ofmagnitude and or within the same order of magnitude variation of a given value, for example,the IC50 may be ±10 nM and the EC50 may be ± 0.3 nM of a given value.

[0057] In certain embodiments, the anti-Nogo-A antibody does not compete with anti-Nogo-A antibody 11C7 for binding to Nogo-A. In certain embodiments, the anti-Nogo-A antibodydoes not compete with Ozanezumab for binding to Nogo-A. Competition between antibodiesis determined by an assay in which the immunoglobulin under test is inhibited by specificbinding of a reference antibody to a common antigen, such as Nogo-A. Types of competitivebinding assays are known in the art; see Harlow and Lane, Antibodies, A Laboratory Manual,Cold Spring Harbor Press (1988), (2014).

[0058] Nogo-A protein contains 3 inhibitory regions. Two are shared with the splice variantNogo-B (Nogo-66 located between the two transmembrane regions and the NIR domain at the tip of the N-terminus) and one is shared with the splice variant Nogo-C (Nogo-66). Delta 20 region (d20; amino acid position 566-748 of human Nogo-A (NCBI Reference Sequence: NP_065393.1)) is the unique, highly inhibitory domain for neurite outgrowth of Nogo-A, andis located in the exon 3 of Nogo-A. In certain embodiments, the anti-Nogo-A antibody bindsto Nogo-A within the region between amino acid positions 543-866 of human Nogo-A. In certain embodiments, the anti-Nogo-A antibody binds an epitope and / or a peptide comprising or consisting of the amino acid sequence 141-INAALQE-147 (SEQ ID NO:21)corresponding amino acids 683-689 of human Nogo-A. In certain embodiments, the anti-Nogo-A antibody binds an epitope and / or a peptide comprising or consisting of the amino acid sequence of SEQ ID NO:28. In certain embodiments, the anti-Nogo-A antibodycomprising the six CDRs of Ab1 binds to an epitope comprising the amino acid sequence ofSEQ ID NO:21. In certain embodiments, the anti-Nogo-A antibody comprising the six CDRsof Ab2 binds to an epitope comprising the amino acid sequence of SEQ ID NO:28.

[0059] In certain embodiments, anti-Nogo-A antibodies disclosed herein include humanmonoclonal anti-Nogo-A antibodies, antigen-binding (i.e., Nogo-A binding) fragmentsderived from such antibodies, and synthetic derivative or biotechnological derivative derivedfrom such antibodies.

[0060] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3, and a VLcomprising a VL-CDR1, a VL-CDR2, and a VL-CDR3, wherein the amino acid sequences ofthe VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition, and: (a) the VH-CDR1 comprises the amino acid sequence of SEQ ID NO:3 or a variantthereof, wherein the variant comprises one or two amino acid substitutions, (b) the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:4 or a variantthereof, wherein the variant comprises one or two amino acid substitutions, (c) the VH-CDR3 comprises the amino acid sequence of SEQ ID NO:5 or a variantthereof, wherein the variant comprises one or two amino acid substitutions,(d) the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:8 or a variantthereof, wherein the variant comprises one or two amino acid substitutions, (e) the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:9 or a variantthereof, wherein the variant comprises one or two amino acid substitutions, and (f) the VL-CDR3 comprises the amino acid sequence of SEQ ID NO:10 or a variantthereof, wherein the variant comprises one or two amino acid substitutions.

[0061] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3, and a VLcomprising a VL-CDR1, a VL-CDR2, and a VL-CDR3, wherein the amino acid sequences ofthe VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition, and: (a) the VH-CDR1 comprises the amino acid sequence of SEQ ID NO:13 or a variantthereof, wherein the variant comprises one or two amino acid substitutions, (b) the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:14 or a variantthereof, wherein the variant comprises one or two amino acid substitutions, (c) the VH-CDR3 comprises the amino acid sequence of SEQ ID NO:15 or a variantthereof, wherein the variant comprises one or two amino acid substitutions, (d) the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:18 or a variantthereof, wherein the variant comprises one or two amino acid substitutions, (e) the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:19 or a variantthereof, wherein the variant comprises one or two amino acid substitutions, and (f) the VL-CDR3 comprises the amino acid sequence of SEQ ID NO:20 or a variantthereof, wherein the variant comprises one or two amino acid substitutions.

[0062] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises: (a) a VH chain comprises the amino acid sequence of SEQ ID NO:2 or a variantthereof, wherein the variant comprises one or more amino acid substitutions; and (b) a VL comprises the amino acid sequence of SEQ ID NO:7, or a variantthereof, wherein the variant comprises one or more amino acid substitutions.

[0063] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises: (a) a VH comprises the amino acid sequence of SEQ ID NO:12 or a variantthereof, wherein the variant comprises one or more amino acid substitutions; and(b) a VL comprises the amino acid sequence of SEQ ID NO:17, or a variantthereof, wherein the variant comprises one or more amino acid substitutions.

[0064] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises six CDRs of an antibody designated as Ab1 or Ab2 based on the Kabatdefinition as set forth in Tables 1 and 2 and FIGS. 1A-1B.Table 1: Antibody Ab1 VH-CDR1 VH-CDR2 VH-CDR3SHAMH (SEQ ID NO:3) VTSYDGTNKYYADSVKG (SEQ GRAVAGTREDY (SEQID NO:4) ID NO:5) Heavy chain variable region (VH) EVQLVESGGGVVQPGRSLRLSCAASGFTFRSHAMHWVRQAPGKGLEWVAVTSYDGTNKYYADSVKG RFTISKDNSKNTLYLQMDSLRVEDTAVYYCARGRAVAGTREDYWGQGTLVTVSS (SEQ IDNO:2) Exemplary nucleotide sequence encoding VH gaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgt gcagcctctggattcaccttcaggagccatgctatgcactgggtccgccaggctccaggcaagggg ctggagtgggtggcagttacatcatatgatggaaccaataaatactacgcagactccgtgaagggc cgattcaccatctccaaagacaattccaagaacacgctgtatctgcaaatggacagcctcagagtt gaggacacggctgtgtattactgtgcgagaggccgagcagtggctggtacgagggaagattattgg ggccagggaaccctggtcaccgtctcctcg (SEQ ID NO:1) VL-CDR1 VL-CDR2 VL-CDR3KSSQSVLFSSNSKNYLA (SEQ WASTRES (SEQ ID NO:9) QQYYTTRPT (SEQID NO:8) ID NO:10) Light chain variable region (VL) DIQMTQSPDSLAVSLGERATINCKSSQSVLFSSNSKNYLAWYQQKPGQPPKVLIYWASTRESGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTRPTFGLGTKVDIK (SEQ ID NO:7)Exemplary nucleotide sequence encoding VL Gacatccagatgacccagtctccagactccctggctgtgtctctgggcgagagggccaccatcaac tgcaagtccagccagagtgttttattcagctccaacagtaagaactacttagcttggtaccagcag aaaccaggacagcctcctaaggtgctcatttactgggcatctacccgggaatccggggtccctgac cgattcagtggcagcgggtctgggacagatttcactctcaccatcagcagcctgcaggctgaagat gtggcagtttattactgtcagcaatattatactactcgccctacgttcggcctagggaccaaagtg gatatcaaa (SEQ ID NO:6) Heavy chain EVQLVESGGGVVQPGRSLRLSCAASGFTFRSHAMHWVRQAPGKGLEWVAVTSYDGTNKYYADSVKG RFTISKDNSKNTLYLQMDSLRVEDTAVYYCARGRAVAGTREDYWGQGTLVTVSSASTKGPSVFPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO:23] Light chain DIQMTQSPDSLAVSLGERATINCKSSQSVLFSSNSKNYLAWYQQKPGQPPKVLIYWASTRESGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTRPTFGLGTKVDIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO:25] *CDR sequences are determined based on Kabat definitionTable 2: Antibody Ab2 VH-CDR1 VH-CDR2 VH-CDR3NYSMH (SEQ ID NO:13) AISSDGGDPFYASSVKG (SEQ DAFDV (SEQ IDID NO:14) NO:15) Heavy chain variable region (VH) EVQLVETGGGLVPPGGSLRLSCAASGFTFTNYSMHWVRLAPGKRLEYISAISSDGGDPFYASSVKG RVAISRDNSKKTLYLQMGRLRPEDTAVYYCVSDAFDVWGQGTMVTVSS (SEQ ID NO:12) Exemplary nucleotide sequence encoding VH gaggtgcagctggtggagactgggggaggcttggtcccaccgggggggtccctgagactctcctgt gcagcctctggattcaccttcaccaactattctatgcactgggtccgcctggctccagggaagaga ctggaatatatttcagctattagtagtgatggcggtgacccattttatgcaagctctgtgaagggc agagtcgccatctccagagacaattccaagaagacgttgtatcttcaaatgggcagactgagacct gaggacacggctgtatattattgtgtgagtgatgcttttgatgtctggggccaggggacaatggtc accgtctcttcg (SEQ ID NO:11) VL-CDR1 VL-CDR2 VL-CDR3RSSQSLLYSNGNTYLN (SEQ RVSNRDS (SEQ ID NO:19) MQGTHWPRT (SEQID NO:18) ID NO:20) Light chain variable region (VL) EIVLTQSPLSLSVTLGQPASISCRSSQSLLYSNGNTYLNWFQQRPGQSPRRLLYRVSNRDSGVPDR FSGSGSGTHFTLKISRVEAEDVGVYYCMQGTHWPRTFGQGTKVEIK (SEQ ID NO:17)Exemplary nucleotide sequence encoding VL gaaattgtgctgacccagtctccactctccctgtccgtcacccttggacagccggcctccatctcc tgcaggtctagtcaaagcctcctatacagtaatggcaacacctacttgaattggtttcagcagagg ccaggccaatctccaaggcgcctactttatagggtttctaaccgggactctggggtcccagacaga ttcagcggcagtgggtcaggcactcatttcacactgaaaattagtagggtggaggctgaggatgtt ggagtttattactgcatgcaaggtacacactggcctcgcacgttcggccaagggaccaaggtggag atcaaa (SEQ ID NO:16)* CDR sequences are determined based on Kabat definition

[0065] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises (a) a VH-CDR1, a VH-CDR2, and a VH-CDR3 from antibody Ab1 (Table1); or (b) a VL-CDR1, a VL-CDR2, and a VL-CDR3 from antibody Ab1 (Table 1). Incertain embodiments, the anti-Nogo-A antibody or antigen-binding fragment thereofcomprises (a) a VH-CDR1, a VH-CDR2, and a VH-CDR3 from antibody Ab1 (Table 1); and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3 from antibody Ab1 (Table 1).

[0066] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises (a) a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO:2; or (b) a VL-CDR1, a VL-CDR2, and aVL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:7. Incertain embodiments, the anti-Nogo-A antibody or antigen-binding fragment thereofcomprises (a) a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprisingthe amino acid sequence of SEQ ID NO:2; and (b) a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:7.

[0067] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises (a) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:4, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:5; or (b) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VL-CDR2 comprising the amino acid sequence ofSEQ ID NO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:10. Incertain embodiments, the anti-Nogo-A antibody or antigen-binding fragment thereof comprises (a) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO:4, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:5; and (b) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:10.

[0068] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3disclosed herein, or (b) a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3disclosed herein. In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof comprises (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3disclosed herein, and (b) a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3disclosed herein. In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof comprises a VH at least 75%, at least 80%, at least 85%, at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:2; and / or a VLat least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identicalto the amino acid sequence of SEQ ID NO:7. In certain embodiments, the anti-Nogo-Aantibody or antigen-binding fragment thereof comprises a VH comprising the amino acidsequence of SEQ ID NO:2, or a VL comprising the amino acid sequence of SEQ ID NO:7.In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragment thereofcomprises a VH comprising the amino acid sequence of SEQ ID NO:2, and a VL comprisingthe amino acid sequence of SEQ ID NO:7.

[0069] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises a VH at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQID NO:1; and / or a VL at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:6. In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises a VH comprising the amino acid sequence encoded by the nucleotidesequence of SEQ ID NO:1, or a VL comprising the amino acid sequence encoded by thenucleotide sequence of SEQ ID NO:6. In certain embodiments, the anti-Nogo-A antibody orantigen-binding fragment thereof comprises a VH comprising the amino acid sequenceencoded by the nucleotide sequence of SEQ ID NO:1, and a VL comprising the amino acidsequence encoded by the nucleotide sequence of SEQ ID NO:6.

[0070] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises (a) a VH-CDR1, a VH-CDR2, and a VH-CDR3 from antibody Ab2 (Table2); or (b) a VL-CDR1, a VL-CDR2, and a VL-CDR3 from antibody Ab2 (Table 2). Incertain embodiments, the anti-Nogo-A antibody or antigen-binding fragment thereofcomprises (a) a VH-CDR1, a VH-CDR2, and a VH-CDR3 from antibody Ab2 (Table 2); and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3 from antibody Ab2 (Table 2).

[0071] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises (a) a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO:12; or (b) a VL-CDR1, a VL-CDR2, anda VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:17. Incertain embodiments, the anti-Nogo-A antibody or antigen-binding fragment thereofcomprises (a) a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprisingthe amino acid sequence of SEQ ID NO:12; and (b) a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:17.

[0072] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises (a) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:13, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:14, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:15; or (b) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VL-CDR2 comprising the amino acid sequence ofSEQ ID NO:19, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:20. Incertain embodiments, the anti-Nogo-A antibody or antigen-binding fragment thereof comprises (a) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:13, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO:14, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL-CDR1 comprising the amino acidsequence of SEQ ID NO:18, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:19, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:20.

[0073] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3disclosed herein, or (b) a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3disclosed herein. In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof comprises (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3disclosed herein, and (b) a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3disclosed herein. In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof comprises a VH at least 75%, at least 80%, at least 85%, at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:12; and / or a VL at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%identical to the amino acid sequence of SEQ ID NO:17. In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragment thereof comprises a VH comprising the aminoacid sequence of SEQ ID NO:12, or a VL comprising the amino acid sequence of SEQ IDNO:17. In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises a VH comprising the amino acid sequence of SEQ ID NO:12, and a VLcomprising the amino acid sequence of SEQ ID NO:17.

[0074] In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises a VH at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQID NO:11; and / or a VL at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQID NO:16. In certain embodiments, the anti-Nogo-A antibody or antigen-binding fragmentthereof comprises a VH comprising the amino acid sequence encoded by the nucleotidesequence of SEQ ID NO:11, or a VL comprising the amino acid sequence encoded by thenucleotide sequence of SEQ ID NO:16. In certain embodiments, the anti-Nogo-A antibodyor antigen-binding fragment thereof comprises a VH comprising the amino acid sequenceencoded by the nucleotide sequence of SEQ ID NO:11, and a VL comprising the amino acidsequence encoded by the nucleotide sequence of SEQ ID NO:16.

[0075] In certain embodiments, preferably one or more of the CDRs according to the Kabatdefinition are maintained substantially unchanged. However, under the simplified assumption that the paratope corresponds to the CDRs, the Chothia definition of the CDRs may be usedin addition or alternatively as they correlate very well with the structural loops present in thevariable regions. Thus, in order to provide anti-Nogo-A antibodies equivalent to subjectantibodies Ab1 and Ab2, preferably at least one or two of said one or more, preferably notmore than two amino acid substitutions if made in the CDRs as defined according to Kabat are made outside the CDRs as defined by Chothia and / or IMGT and most preferably outside the overlap of the CDRs as defined according to Kabat and Chothia.

[0076] For example, regarding amino acid substitutions within the CDRs, variable heavy andlight chain and framework amino acid sequences, respectively, preferably conservative amino acid substitutions are performed for example in accordance with the most frequently exchanged amino acids as analyzed and described by Mirsky et al., Mol. Biol. Evol. 32(2014), 806-819; see Figure 6 at page 813 of Mirsky et al. In particular, within VH-CDR1, Smay be substituted with T; within VH-CDR3, V may be substituted with E, T may be substituted with S and / or M may be substituted with V; within VL-CDR1, R may be substituted with K, R may be substituted with E, and / or T may be substituted; within VL- CDR2, S may be substituted with A and / or A may be substituted with G; and in VL-CDR3, P may be substituted with S. As mentioned, preferably amino acid substitutions are selected which belong to the same category in either or preferably both models LG and AB shown inFigure 6 of Mirsky et al. (2014), supra, with the LG model being preferred for the tendencyto keep amino acid properties, and wherein the amino acid substitutions are selected preferably such that the physiochemical properties of the original amino acid is substantiallymaintained, i.e., hydrophobic, polar or charged property or for example that in case two ormore amino acid substitutions are performed, they compensate each other so as to provide the physicochemical property of the surface all together. In a preferred embodiment, the antibodyof the present disclosure comprises a variant of the amino acid sequence of the VH and / or VLregion which is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the VH andVL regions depicted in FIGS. 1A and 1B.

[0077] Of course, besides theoretical considerations also experimental approaches exist foridentifying CDR variants within a reasonable time and undue burden. For example, Tiller et al., in Front Immunol. 8 (2017), 986 describe facile affinity maturation of antibody variable domains using natural diversity mutagenesis. Indeed, already a few years earlier Rajpal et al., in PNAS 102 (2005), 8466–8471 reported a general method for greatly improving the affinityof antibodies by using combinatorial libraries and illustrated their method with anti-TNF- antibody D2E7 (HUMIRA©) identifying 38 substitutions in 21 CDR positions that resultedin higher affinity binding to TNF- et al., in PLOS ComputationalBiology, https: / / doi.org / 10.1371 / journal.pcbi.1006980 May 1, 2019 described experimentallyguided computational antibody affinity maturation with de novo docking, modelling andrational design in silico affinity maturation, together with alanine scanning, that allowed fine-tuning the protein-protein docking model to subsequently enable the identification of two single-point mutations that increase the affinity of a hybridoma-derived antibody, AB1 for its antigen murine CCL20.

[0078] Accordingly, though each antibody is unique and may have distinct features,nevertheless once a lead candidate has been provided the person skilled in the art inconsideration of the teaching of the present disclosure as disclosed in the present application,as well as in view of the computational design and experimental approaches developed so far is able to arrive at equivalent anti-Nogo-A antibodies which keep the desired features of the antibody disclosed herein and specifically defined in the claims. In this context, it is well understood that the variant antibody substantially maintains the binding specificity of the parent antibody, for example competing with the parent antibody for binding Nogo-A whilenot competing with one or more, preferably all of the mentioned prior art antibodies, i.e., atleast not with 11C7, preferably also not with Ozanezumab, which can be assessed in accordance with the competition assay disclosed herein. In particular, an antibody of thepresent disclosure derived from antibody Ab1 does not compete with antibody 11C7 andOzanezumab. Preferably however, the antibody of the present disclosure comprises in one orboth of its immunoglobulin chains one, two or all three CDRs of the variable regions as setforth in FIGS. 1A-1B or one, two or all three CDRs which are 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98% or 99% identical to the CDRs of the variable regions as set forth in FIGS. 1A-1B. In addition or alternatively, one or more framework regions (FRs) from the FRs are 80% identical to the corresponding FRs depicted in FIGS. 1A-1B, preferably 85%, 90%, 95%, 96, 97%, 98%, 99% or 100% identical to the framework regions depicted in FIGS. 1A-1B. In some embodiments, 1, 2, 3, or all 4 FRs (each being at least 90%, 90-95%, and / or 95-99% identical to the FRs shown in FIGS. 1A-1B, respectively) are present.

[0079] As known in the art, CDR3 of the variable heavy chain (VH-CDR3) seems to mainlydetermine antigen specificity; see, e.g., Xu and Davis, Immunity 13 (2000), 37-45. In this context, it was noted that it is the diversity of heavy-chain CDR3s that drive specificity, whereas VH-CDR1 and VH-CDR2 residues are broadly cross-reactive and subject toimprovement by somatic hypermutation; see Davis, Semin. Immunol. 16 (2004), 239-243.Accordingly, in certain embodiments of the antibodies of the present disclosure, which hasthe immunological characteristics of the reference antibody Ab1 and being capable ofcompeting with its binding Nogo-A at the respective epitope comprise in their variable region at least VH-CDR3 of the corresponding reference antibody or a VH-CDR3 which amino acid sequence is at least 90% identical to the reference VH-CDR3, preferably 95% identical and, more 96%, 97%, 98%, 99% or 100% identity. For example, a variant antibody of a reference antibody may retain VH-CDR3 of the reference (parent) antibody while VH-CDR1 and / orVH-CDR2 may contain one or more amino acid substitutions; see supra.

[0080] In a further additional or alternative embodiment of the present disclosure the anti-Nogo-A antibody, antigen-binding fragment, synthetic or biotechnological variant thereof can be optimized to have appropriate binding affinity to the target and pharmacokinetic and stability properties. Therefore, at least one amino acid in the CDR or variable region, which is prone to modifications selected from the group consisting of glycosylation, oxidation, deamination, peptide bond cleavage, iso-aspartate formation and / or unpaired cysteine is substituted by a mutated amino acid that lack such alteration or wherein at least one carbohydrate moiety is deleted or added chemically or enzymatically to the antibody, see, e.g. Liu et al., J. Pharm. Sci. 97 (2008), 2426-2447; Beck et al., Nat. Rev. Immunol. 10 (2010),345-352; Haberger et al., MAbs. 6 (2014), 327-339.

[0081] An immunoglobulin or its encoding cDNA may be further modified. Thus, in afurther embodiment, the method of the present disclosure comprises any one of the step(s) ofproducing a chimeric antibody, murinized antibody, single-chain antibody, Fab-fragment, bi- specific antibody, fusion antibody, labeled antibody or an analog of any one of those. Corresponding methods are known to the person skilled in the art and are described, e.g., inHarlow and Lane “Antibodies, A Laboratory Manual”, CSH Press, Cold Spring Harbor(1988) First edition; Second edition by Edward A. Greenfield, Dana-Farber Cancer Institute© 2014, ISBN 978-1-936113-81-1. For example, Fab and F(ab’)2 fragments may be produced recombinantly or by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab’)2fragments). F(ab’)2fragments contain the variable region, the light chain constant region and the CH1 domain of the heavy chain. Such fragments are sufficient for use, for example, in immunodiagnostic procedures involving coupling the immunospecific portions of immunoglobulins to detecting reagents such as radioisotopes.

[0082] In certain embodiments, the antibody of the present disclosure may thus be providedin a format selected from the group consisting of a single chain Fv fragment (scFv), an F(ab’) fragment, an F(ab) fragment, and an F(ab’)2fragment, an Fd, an Fv, a single-chain antibody, and a disulfide-linked Fv (sdFv) and / or which is a chimeric murine-human or a murinized antibody.

[0083] In certain embodiments, the anti-Nogo-A antibody disclosed herein is a complete IgGantibody, wherein the antibody comprises a constant domain. The constant domain may benative, i.e., originally cloned together with the variable domain or heterologous, for example,a murine constant in case animal studies are envisaged. Preferably, the constant domain is ofhuman origin with a different IgG subtype, e.g. IgG1 versus IgG4 or a different allotype andallele, respectively, compared to the constant domain of the antibody as naturally occurred in human. The definition of “allotypes” requires that antibody reagents are available to determine the allotypes serologically. If the determination is only done at the sequence level, the polymorphisms have to be described as “alleles”. This does not hinder to establish a correspondence with allotypes if the correspondence allele-allotype has been experimentally proven, or if the individual sequence is identical to a sequence for which it has been demonstrated.

[0084] In a preferred embodiment of the present disclosure, the constant domain isheterologous to at least one of the CDRs and the VH and VL chains, respectively, e.g. animmunoglobulin heavy chain constant domain and / or immunoglobulin light chain constant domain, preferably of the IgG type. In addition, or alternatively, the heterologous part of the antibody may be a mammalian secretory signal peptide. Put in other words, in certainembodiments the anti-Nogo-A antibodies and Nogo-A binding fragments, syntheticderivative, and biotechnological derivative thereof of the present disclosure is a (i) fusionprotein comprising a polypeptide sequence which is heterologous to the VH region and / or VLregion, or at least one CDR; and / or (ii) a non-natural variant of a polypeptide derived from an immunoglobulin, said non-natural variant comprising a heavy chain constant region that comprises one or more amino acid deletions, substitutions, and / or additions relative to a wild type polypeptide.

[0085] As mentioned, five immunoglobulin isotypes exist, of which immunoglobulin G (IgG)is most abundant in human serum. The four subclasses, IgG1, IgG2, IgG3, and IgG4, which are highly conserved, differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptors (FcgR) and C1q. As a result, the different subclasses have different effector functions, both in terms oftriggering FcgR-expressing cells, resulting in phagocytosis or antibody-dependent cell- mediated cytotoxicity, and activating complement. The Fc regions also contain a binding epitope for the neonatal Fc receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG through mucosal surfaces. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcgR and complement. How these properties, IgG- polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function is described in Vidarsson et al., (2014) IgG subclasses and allotypes: from structure to effector function. Front. Immunol. 5:520. doi: 10.3389 / fimmu.2014.00520 and de Taeye et al., Antibodies 2019, 8, 30; doi:10.3390 / antib8020030. Preferably, the immunoglobulin heavy and / or light chain constantdomain present in the antibody of the present disclosure is of the IgG type, most preferably ofthe IgG4 class or isotype. Human immunoglobulin G isotype 4 (IgG4) antibodies are potential candidates for antibody therapy when reduced immune effector functions are desirable.

[0086] In certain embodiments of the antibodies of the present disclosure, the Fc portion maybe mutated to decrease immune effector function using techniques known in the art. For example, the deletion or inactivation (through point mutations or other means) of a constant region domain may reduce Fc receptor binding of the modified antibody applied into the cerebrospinal fluid / CNS compartment to the transepithelial transporters of the blood-brain- barrier thereby increasing its Nogo-A protein binding. In other cases, it may be that constantregion modifications consistent with the present disclosure moderate complement bindingand thus reduce the serum half-life and nonspecific association of a conjugated cytotoxin. Yet other modifications of the constant region may be used to modify disulfide linkages or oligosaccharide moieties that allow for enhanced tissue antigen interaction due to increased antigen specificity or antibody flexibility. The resulting physiological profile, bioavailability and other biochemical effects of the modifications, such as Nogo-A protein binding and neutralization, biodistribution and serum half-life, may easily be measured and quantified using well know immunological techniques without undue experimentation. Recombinant human IgG antibod complement protein C1q, and thus with abolished immune effector functions, are of use for various therapeutic applications. It was found that the combination of Leu234Ala and Leu235Ala (LALA-PG mutation was an improvement over LALA mutations alone in that they nullified Fc function in mouse and human IgG; for corresponding review see, e.g., Saunders (2019) Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half- Life. Front. Immunol. 10:1296.doi: 10.3389 / fimmu.2019.01296 and Schlothauer et al., Protein Engineering, Design and Selection 29 (2016), 457-466,

[0087] IgG4 antibodies are dynamic molecules able to undergo a process known as Fab armexchange (FAE). This results in functionally monovalent, bispecific antibodies (bsAbs) withunknown specificity and hence, potentially, reduced therapeutic efficacy. In a particularpreferred embodiment the antibody of the present disclosure is of the IgG4 class or isotypeincluding the S228P mutation. The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays andphysiological matrix preparation; see Silva et al., J. Biol. Chem. 290 (2015), 5462–5469. Ab1IgG4 S228P indeed shows a reduced reactivity to C1q and behaves similar to other IgG4 antibodies, like Natalizumab.

[0088] In certain embodiments, the anti-Nogo-A antibody comprises a heavy chain constantregion, wherein the heavy chain constant region is of IgG1, IgG2, IgG3, or IgG4 type. In certain embodiments, the anti-Nogo-A antibody comprises a heavy chain constant region, wherein the heavy chain constant region is of human IgG1, IgG2, IgG3, or IgG4 type. In certain embodiments, the heavy chain constant region is of human IgG4 type. In certain embodiments, the heavy chain constant region comprises an amino acid substitution S228P (numbering according to EU numbering) relative to the wildtype human IgG4 heavy chainconstant region. In certain embodiments, the wildtype human IgG4 heavy chain constantregion comprises CH1, hinge, CH2 and CH3 regions. In certain embodiments, the wildtype human IgG4 heavy chain constant region comprises the amino acid sequence of SEQ ID NO:26. In certain embodiments, the heavy chain constant region comprises an amino acidsubstitution S228P (numbering according to EU numbering) relative to the amino acidsequence of SEQ ID NO:26.

[0089] In certain embodiments, the anti-Nogo-A antibody comprises a kappa or a lambdalight chain constant region. In certain embodiments, the anti-Nogo-A antibody comprises ahuman kappa or a human lambda light chain constant region. In certain embodiments, the anti-Nogo-A antibody comprises a human kappa light chain constant region.

[0090] In certain embodiments, the anti-Nogo-A antibody comprises a human IgG4 heavychain constant region and a human kappa light chain constant region.

[0091] In certain embodiments, the anti-Nogo-A antibody comprises a heavy chain at least75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:23; and / or a light chain at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:25. In certain embodiments, the anti-Nogo-A antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:23, or a light chain comprising the aminoacid sequence of SEQ ID NO:25. In certain embodiments, the anti-Nogo-A antibodycomprises a heavy chain comprising the amino acid sequence of SEQ ID NO:23, and a light chain comprising the amino acid sequence of SEQ ID NO:25.

[0092] In certain embodiments, the anti-Nogo-A antibody comprises two heavy chains andtwo light chains. In certain embodiments, the anti-Nogo-A antibody comprises two identical heavy chains and two identical light chains. In certain embodiments, the anti-Nogo-A antibody comprises a first and a second heavy chain each comprising the amino acidsequence of SEQ ID NO:23, and a first and a second light chains each comprising the aminoacid sequence of SEQ ID NO:25. In certain embodiments, disulfide bridges are formed (i)between C134 of the first heavy chain and C220 of the first light chain, between C134 of the second heavy chain and C220 of the second light chain, between C226 of the first heavy chain and C226 of the second heavy chain, and between C229 of the first heavy chain andC229 of the second heavy chain; or (ii) between C134 of the first heavy chain and C220 ofthe first light chain, between C134 of the second heavy chain and C220 of the second light chain, between C226 of the first heavy chain and C229 of the second heavy chain, and between C229 of the first heavy chain and C226 of the second heavy chain, wherein the amino acid numberings are based on EU numbering.

[0093] In certain embodiments, the heavy chain of the anti-Nogo-A antibody comprises anN-linked glycan site at amino acid residue N297 (numbering according to EU numbering). Incertain embodiments, each of the two heavy chains of the anti-Nogo-A antibody comprises an N-linked glycan site at amino acid residue N297 (numbering according to EU numbering).

[0094] The present disclosure also relates to one or more polynucleotide(s) encoding theantibody or antigen-binding fragment thereof of the present disclosure or an immunoglobulinVH and VL thereof, preferably wherein the polynucleotide(s) are cDNA.

[0095] In a preferred embodiment of the present disclosure, the polynucleotide comprises,consists essentially of, or consists of a nucleic acid having a polynucleotide sequenceencoding the VH or VL chain of an anti-Nogo-A antibody as depicted in Table 1 or Table 2.In this respect, the person skilled in the art will readily appreciate that the polynucleotides encoding the light and / or heavy chain may be encoded by one or more polynucleotides. Incertain embodiments therefore, the polynucleotide comprises, consists essentially of, orconsists of a nucleic acid having a polynucleotide sequence of the VH and the VL chain of ananti-Nogo-A antibody as depicted in Table 1 or Table 2.

[0096] In certain embodiments of the present disclosure, the polynucleotide(s) are linked to aheterologous nucleic acid, for example expression control sequences such as a promoter, transcription and / or translation enhancer sequences, internal ribosome binding sites, nucleic acids encoding a peptide leader sequence for recombinant expression in a host and the like.Accordingly, the present disclosure relates to a polynucleotide encoding a human-derivedrecombinant anti-Nogo-A antibody or Nogo-A binding fragment, synthetic derivative, or biotechnological derivative thereof, wherein the polynucleotide encodes (i) a VH chain comprising CDRs 1, 2, and 3, and / or a VL chain comprising VLCDRs 1, 2, and 3 as defined by Kabat, wherein (a) the VH-CDR1 comprises the amino acid sequence of SEQ ID NO:3 ora variant thereof, wherein the variant comprises one or two amino acid substitutions, (b) the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:4 ora variant thereof, wherein the variant comprises one or two amino acid substitutions, (c) the VH-CDR3 comprises the amino acid sequence of SEQ ID NO:5 ora variant thereof, wherein the variant comprises one or two amino acid substitutions, (d) the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:8 ora variant thereof, wherein the variant comprises one or two amino acid substitutions, (e) the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:9 ora variant thereof, wherein the variant comprises one or two amino acid substitutions, and (f) the VL-CDR3 comprises the amino acid sequence of SEQ ID NO:10or a variant thereof, wherein the variant comprises one or two amino acid substitutions; and / or (ii) a VH chain and / or a VL chain, wherein(a) the VH chain comprises the amino acid sequence depicted in SEQ IDNO:2 or a variant thereof, wherein the variant comprises one or more amino acid substitutions; and (b) the VL comprises the amino acid sequence depicted in SEQ ID NO:7,or a variant thereof, wherein the variant comprises one or more amino acid substitutions;preferably wherein the VH and VL chain amino acid sequence is at least 90% identical toSEQ ID NO:2 and 7, respectively; or (iii) a VH chain comprising CDRs 1, 2, and 3, and / or a VL chain comprising VLCDRs 1, 2, and 3 as defined by Kabat, wherein (a) the VH-CDR1 comprises the amino acid sequence of SEQ ID NO:13or a variant thereof, wherein the variant comprises one or two amino acid substitutions, (b) the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:14or a variant thereof, wherein the variant comprises one or two amino acid substitutions, (c) the VH-CDR3 comprises the amino acid sequence of SEQ ID NO:15or a variant thereof, wherein the variant comprises one or two amino acid substitutions, (d) the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:18or a variant thereof, wherein the variant comprises one or two amino acid substitutions, (e) the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:19or a variant thereof, wherein the variant comprises one or two amino acid substitutions, and (f) the VL-CDR3 comprises the amino acid sequence of SEQ ID NO:20or a variant thereof, wherein the variant comprises one or two amino acid substitutions; and / or (iv) a VH chain and / or a VL chain, wherein(a) the VH chain comprises the amino acid sequence depicted in SEQ IDNO:12 or a variant thereof, wherein the variant comprises one or more amino acid substitutions; and (b) the VL comprises the amino acid sequence depicted in SEQ ID NO:17,or a variant thereof, wherein the variant comprises one or more amino acid substitutions;preferably wherein the VH and VL chain amino acid sequence is at least 90% identical toSEQ ID NO:12 and 17, respectively.

[0097] In addition, the present disclosure relates to a polynucleotide linked to a heterologousnucleic acid, wherein the polynucleotide is selected from the group consisting of: (a) a polynucleotide encoding an immunoglobulin heavy chain or a fragmentthereof comprising a heavy chain variable region (VH) comprising CDRs 1, 2, and 3 with theamino acid sequences set forth in SEQ ID NOs: 3, 4, and 5, respectively, and wherein the VHwhen paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:7 binds to Nogo-A; (b) a polynucleotide encoding an immunoglobulin light chain or a fragmentthereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences setforth in SEQ ID NOs: 8, 9, and 10, respectively, and wherein the VL when paired with a VHcomprising the amino acid sequence set forth in SEQ ID NO:2 binds to Nogo-A; (c) a polynucleotide encoding(i) an immunoglobulin heavy chain or a fragment thereof comprising aVH comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs: 3,4, and 5, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a VLcomprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs: 8, 9, and 10, respectively; (d) a polynucleotide encoding an immunoglobulin heavy chain or a fragmentthereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:2,wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQID NO:7 binds to Nogo-A; (e) a polynucleotide encoding an immunoglobulin light chain or a fragmentthereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:7,wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQID NO:2 binds to Nogo-A; (f) a polynucleotide encoding an immunoglobulin heavy chain or a fragmentthereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:2 andan immunoglobulin light chain or a fragment thereof comprising a VL comprising the aminoacid sequence set forth in SEQ ID NO:7; (g) a polynucleotide as in any one of (a)-(f), wherein a CDR comprises one ormore, preferably no more than two amino acid substitution and / or the variable region sequence is at least 90% identical to SEQ ID NO:2 or SEQ ID NO:7.

[0098] Alternatively, the present disclosure relates to a polynucleotide linked to aheterologous nucleic acid, wherein the polynucleotide is selected from the group consisting of: (a) a polynucleotide encoding an immunoglobulin heavy chain or a fragmentthereof comprising a heavy chain variable region (VH) comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively, and wherein theVH when paired with a light chain variable region (VL) comprising the amino acid sequenceset forth in SEQ ID NO:17 binds to Nogo-A;(b) a polynucleotide encoding an immunoglobulin light chain or a fragmentthereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences setforth in SEQ ID NOs: 18, 19, and 20, respectively, and wherein the VL when paired with aVH comprising the amino acid sequence set forth in SEQ ID NO:12 binds to Nogo-A;(c) a polynucleotide encoding(i) an immunoglobulin heavy chain or a fragment thereof comprising aVH comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:13, 14, and 15, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a VLcomprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs: 18, 19, and 20, respectively; (d) a polynucleotide encoding an immunoglobulin heavy chain or a fragmentthereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:12,wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQID NO:17 binds to Nogo-A; (e) a polynucleotide encoding an immunoglobulin light chain or a fragmentthereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:17,wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQID NO:12 binds to Nogo-A; (f) a polynucleotide encoding an immunoglobulin heavy chain or a fragmentthereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:12 andan immunoglobulin light chain or a fragment thereof comprising a VL comprising the aminoacid sequence set forth in SEQ ID NO:17; (g) a polynucleotide as in any one of (a)-(f), wherein a CDR comprises one ormore, preferably no more than two amino acid substitution and / or the variable region sequence is at least 90% identical to SEQ ID NO:12 or SEQ ID NO:17.

[0099] Furthermore, the present disclosure relates to a vector and vectors comprising one ormore of those polynucleotides, preferably wherein the vector is an expression vector and the one or more polynucleotides are operably linked to expression control sequences.

[0100] The polynucleotides may be produced and, if desired manipulated usingmethods well known in the art for the manipulation of nucleotide sequences, e.g., recombinant DNA techniques, site directed mutagenesis, PCR, etc. (see, for example, the techniques described in Molecular Cloning: A Laboratory Manual (Fourth Edition): Three- volume set; Green and Sambrook (2012) ISBN 10: 1936113422 / ISBN 13: 9781936113422 Cold Spring Harbor Laboratory Press; update (2014) ISBN 978-1-936113-42-2 and Ausubel et al., eds., Current Protocols in Molecular Biology, John Wiley & Sons, NY (1998) andupdates, which are both incorporated by reference herein in their entireties), to generate antibodies having a different amino acid sequence, for example to create amino acid substitutions, deletions, and / or insertions.

[0101] Once a polynucleotide encoding an antibody molecule or a heavy or lightchain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), has been obtained, the vector for the production of the antibody moleculemay be produced by recombinant DNA technology using techniques well known in the art.Thus, methods for preparing a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methodsinclude, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivogenetic recombination. The present disclosure, thus, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the present disclosure, or a heavy or light chain thereof, or a heavy or light chain variable domain, operable linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of theantibody molecule (see, e.g., international applications WO 86 / 05807 and WO 89 / 01036; andUS patent no. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.

[0102] The term “vector” or “expression vector” is used herein to mean vectors usedin accordance with the present disclosure as a vehicle for introducing into and expressing adesired gene in a host cell. As known to those skilled in the art, such vectors may easily be selected from the group consisting of plasmids, phages, viruses, and retroviruses. In general,vectors compatible with the present disclosure will comprise a selection marker, appropriaterestriction sites to facilitate cloning of the desired gene and the ability to enter and / or replicate in eukaryotic or prokaryotic cells. The marker may provide for prototrophy to an auxotrophic host, biocide resistance (e.g., antibiotics), or resistance to heavy metals such as copper. The selectable marker gene can either be directly linked to the DNA sequences to be expressed, or introduced into the same cell by co-transformation. Additional elements may also be needed for optimal synthesis of mRNA. These elements may include signal sequences, splice signals, as well as transcriptional promoters, enhancers, and termination signals. For the expression of double-chained antibodies, a single vector or vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.

[0103] The host cell may be co-transfected with two expression vectors of the presentdisclosure, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors may contain identical selectable markers which enable equal expression of heavy and light chain polypeptides. Alternatively, a single vector may be used which encodes both heavy and light chain polypeptides. In suchsituations, the light chain is advantageously placed before the heavy chain to avoid an excessof toxic free heavy chain; see Proudfoot, Nature 322 (1986), 52; Kohler, Proc. Natl. Acad.Sci. USA 77 (1980), 2197. The coding sequences for the heavy and light chains may comprise cDNA or genomic DNA. The expression vector(s) is(are) transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody for use in the methods described herein. Accordingly, thepresent disclosure also relates to host cells comprising one or more polynucleotides or avector or vectors of the present disclosure.

[0104] As used herein, “host cells” refers to cells which harbor vectors constructedusing recombinant DNA techniques and encoding at least one heterologous gene. In descriptions of processes for isolation of antibodies from recombinant hosts, the terms “cell” and “cell culture” are used interchangeably to denote the source of antibody unless it is clearly specified otherwise. In other words, recovery of polypeptide from the “cells” may mean either from spun down whole cells, or from the cell culture containing both the medium and the suspended cells.

[0105] Currently, almost all therapeutic antibodies are still produced in mammaliancell lines in order to reduce the risk of immunogenicity due to altered, non-human glycosylation patterns. However, recent developments of glycosylation-engineered yeast, insect cell lines, and transgenic plants are promising to obtain antibodies with “human-like” post-translational modifications. Furthermore, smaller antibody fragments including bispecific antibodies without any glycosylation are successfully produced in bacteria and have advanced to clinical testing. The first therapeutic antibody products from a non- mammalian source can be expected in coming next years. A review on current antibodyproduction systems that can be applied for preparing the human-derived recombinant anti-Nogo-A antibody or Nogo-A binding fragment, synthetic derivative, or biotechnologicalderivative thereof of the present disclosure including their usability for different applicationsis given in Frenzel et al., Front Immunol. 2013; 4: 217, published online on July 29, 2013doi: 10.3389 / fimmu.2013.00217 and transient expression of human antibodies in mammalian cells is described by Vazquez-Lombardi et al., Nature protocols 13 (2018), 99-117; andHunter et al., Optimization of protein expression in mammalian cells. Current Protocols in Protein Science 95 (2019), e77. doi: 10.1002 / cpps.77.

[0106] Once an antibody molecule of the present disclosure has been recombinantlyexpressed, the whole antibodies, their dimers, individual light and heavy chains, or otherimmunoglobulin forms of the present disclosure can be purified according to standardprocedures of the art, including for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing columnchromatography), centrifugation, differential solubility, e.g. ammonium sulfate precipitation,or by any other standard technique for the purification of proteins; see, e.g., Scopes, “Protein Purification”, Springer Verlag, N.Y. (1982) and Antibodies A Laboratory Manual 2nd edition, 2014 by Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA.

[0107] Furthermore, the present disclosure also relates to the anti-Nogo-A antibody,Nogo-A-binding fragment and immunoglobulin chain(s) thereof encoded by a polynucleotide as defined hereinabove and / or obtainable by the method for their recombinant production mentioned above.

[0108] In certain embodiments, the antibody polypeptide comprises an amino acidsequence or one or more moieties not normally associated with an antibody. Exemplary modifications are described in more detail below. For example, the antibody or Nogo-A binding fragment thereof such a single-chain Fv antibody fragment of the present disclosure may comprise a flexible linker sequence, or may be modified to add a functional moiety or detectable label (e.g., PEG, a drug, a toxin, or a label such as a fluorescent, chemiluminescent, radioactive, enzyme, nuclear magnetic, heavy metal, a tag, a flag and the like); see, e.g., Antibodies A Laboratory Manual 2nd edition, 2014 by Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA for general techniques; Dean and Palmer, Nat. Chem. Biol. 10 (2014), 512–523, for advances in fluorescence labeling strategies for dynamic cellular imaging; and Falck and Müller, Antibodies 7 (2018), 4; doi: 10.3390 / antib7010004 for enzyme-based labeling strategies for antibody-drug conjugates and antibody mimetics.

[0109] An antibody polypeptide of the present disclosure may comprise, consistessentially of, or consist of a fusion protein. Fusion proteins are chimeric molecules which comprise, for example, an immunoglobulin Nogo-A-binding domain with at least one targetbinding site, and at least one heterologous portion, i.e., a portion with which it is not naturallylinked in nature. The amino acid sequences may normally exist in separate proteins that arebrought together in the fusion polypeptide or they may normally exist in the same protein but are placed in a new arrangement in the fusion polypeptide. Fusion proteins may be created, for example, by chemical synthesis, or by creating and translating a polynucleotide in which the peptide regions are encoded in the desired relationship.

[0110] The term “heterologous” as applied to a polynucleotide or a polypeptide,means that the polynucleotide or polypeptide is derived from a distinct entity from that of the rest of the entity to which it is being compared. For instance, as used herein, a “heterologous polypeptide” to be fused to an antibody, or an antigen-binding fragment, variant, or analog thereof is derived from a non-immunoglobulin polypeptide of the same species, or an immunoglobulin or non-immunoglobulin polypeptide of a different species.

[0111] The human-derived recombinant anti-Nogo-A antibody or Nogo-A bindingfragment, synthetic derivative, or biotechnological derivative thereof, optionally as fusion protein and / or labeled as described hereinbefore is then provided for various applications in accordance with standard techniques known in the art; see, e.g., Antibodies A Laboratory Manual 2nd edition, 2014 by Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA. Current advancements in therapeutic antibody design, manufacture, and formulation are described in Sifniotis et al., Antibodies 2019, 8(2), 36; https: / / doi.org / 10.3390 / antib8020036, wherein also developments in computational approaches for the strategic design of antibodies with modulated functions are discussed.

[0112] Accordingly, the polynucleotide(s) of the present disclosure include RNA andmay be used for translation in cells for therapeutics. Thus, the polynucleotide(s), in particularRNA(s) of the present disclosure can be used for generating the antibodies of the presentdisclosure in target cells. Various approaches for the production of suitable RNA are knownto the person skilled in the art and are commercially available, e.g., kits for in vitro transcription, capping of RNA and for making poly(A)-tailed mRNA for translation in cells. In WO 2008 / 083949A2 antibody-coding non-modified and modified RNA for expression of the corresponding antibody are described as well as transcription methods and methods for expressing the antibody. In WO 2009 / 127230 A1 modified (m)RNA suitable for suppressing and / or avoiding an innate immunostimulatory response is described. Furthermore, atechnology used by CELLSCRIPT™ has been developed, wherein the RNA contains-methylcytidine (m5C) in place of the corresponding U or C canonical nucleosides. Such RNA has been shown to be less immunogenic and is translated into protein at much higher levels than the corresponding mRNA that does not containmodified nucleosides. The corresponding technology is described e.g. in Karikó et al.,Immunity 23 (2005), 165-175, Karikó et al., Molecular Therapy 16 (2008), 1833-1840 and Anderson et al., Nucleic Acids Res 38 (2010), 5884-5892. Furthermore, EP 1604688 A1 describes stabilized and translation optimized mRNA having an enhanced G / C-content and optimized codon usage. Further approaches for the modification of RNA are described forexample in Kormann et al., Nature Biotechnology 29 (2011), 154-157 and WO 2007 / 024708A2.

[0113] Thus, in certain embodiments the polynucleotide(s) of the present disclosureis / are RNA which can be mRNA or derived thereof either unmodified or modified as described above and suitable for translation into the corresponding antibody.

[0114] As mentioned above, the present disclosure relates to a vector comprising thepolynucleotide of the present disclosure. In certain embodiments, the vector is a gene transfer vector, for example an adeno-associated virus (AAV) vector. Therapeutic approaches for the treatment of neurodegenerative diseases using AAV vectors are for example described in WO 2015 / 035190 A1 and Lui et al., The Journal of Neuroscience 36 (2016), 12425–12435 both which relate to AAV-vectored anti-tau antibodies. Such constructs can be used for delivery of genes encoding the antibodies directly to the brain, thus bypassing the blood: brain barrier. Furthermore, WO 2017 / 189963 A1 describes in general novel AAV particles having viral genomes engineered to encode antibodies and antibody-based compositions and methods of using these constructs (e.g., VAD) for the treatment, prevention, diagnosis and research of diseases, disorders and / or conditions. The progress and clinical applications of AAV in neurodegenerative disease in central nervous system is reviewed in Qu et al., Neural Regen Res 14 (2019), 931-938.

[0115] AAV vectors are widely used in gene therapy approaches due to a number ofadvantageous features. AAVs are non-replicating in infected cells and therefore not associated with any known disease. Furthermore, AAVs may be introduced to a wide variety of host cells, do not integrate into the genome of the host cell, and are capable of infecting both quiescent and dividing cells. AAVs transduce non-replicating and long-lived cells in vivo, resulting in long term expression of the protein of interest. Further, AAVs can be manipulated with cellular and molecular biology techniques to produce non-toxic particles carrying a payload encoded in the AAV viral genome that can be delivered to a target tissue or set of cells with limited or no side-effects. Given the foregoing, the use of AAVs for vectored antibody delivery would allow for longer lasting efficacy, fewer dose treatments, and more consistent levels of the antibody throughout the treatment period.

[0116] AAV is a member of the Parvoviridae family and comprises a linear, single-stranded DNA genome of less than about 5,000 nucleotides. AAV requires co-infection witha helper virus (i.e., an adenovirus or a herpes virus), or expression of helper genes, forefficient replication. AAV vectors used for administration of therapeutic nucleic acids typically have approximately 96% of the parental genome deleted, such that only the terminal repeats (ITRs), which contain recognition signals for DNA replication and packaging, remain. This eliminates immunologic or toxic side effects due to expression of viral genes. In addition, delivering specific AAV proteins to producing cells enables integration of the AAV vector comprising AAV ITRs into a specific region of the cellular genome, if desired (see, e.g., U.S. Patents 6,342,390 and 6,821,511). Host cells comprising an integrated AAV genome show no change in cell growth or morphology (see, for example, U.S. Patent 4,797,368). The AAV vector may be generated using any AAV serotype known in the art. Several AAV serotypes and over 100 AAV variants have been isolated from adenovirus stocks or from human or nonhuman primate tissues (reviewed in, e.g., Wu et al., Molecular Therapy 14(3), (2006), 316).

[0117] In addition to the nucleic acid sequence encoding the antibody of the presentdisclosure, or an antigen-binding fragment thereof, the AAV vector may comprise expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), and the like, that provide for the expression of the nucleic acid sequence in a host cell. Exemplary expression control sequences are known in the art and described in, for example, Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, CA. (1990).

[0118] Thus, the present disclosure relates to a gene transfer vector comprising theisolated nucleic acid sequence which encodes the antibody of the present disclosure. The gene transfer vector may be an adeno-associated virus (AAV) vector as described above. 5.3 Pharmaceutical Compositions

[0119] The present disclosure further provides a pharmaceutical composition to beused with the methods disclosed herein (e.g., a method disclosed in Section 5.4). In certain embodiments, the pharmaceutical compositions comprises an anti-Nogo-A antibody or an antigen-binding fragment thereof, a biotechnological derivative or variant thereof, apolynucleotide, a vector or cell of the present disclosure (e.g., an anti-Nogo-A antibody or anantigen-binding fragment thereof, a biotechnological derivative or variant thereof, a polynucleotide, a vector or cell disclosed in Section 5.2, or an anti-Nogo-A antibody or an antigen-binding fragment thereof, a biotechnological derivative or variant thereof, apolynucleotide, a vector or cell disclosed in WO2021079002A2, which is incorporated herein by reference).

[0120] In certain embodiments, the pharmaceutical composition comprises an anti-Nogo-A antibody or an antigen-binding fragment thereof disclosed herein. In certainembodiments, the pharmaceutical composition comprises Ab1. In certain embodiments, thepharmaceutical composition comprises Ab2. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the anti-Nogo-A antibody or antigen-binding fragment thereof.

[0121] In certain embodiments, the pharmaceutical composition comprises the anti-Nogo-A antibody or antigen-binding fragment thereof at a concentration of between about 50 mg / ml and about 150 mg / ml. In certain embodiments, the pharmaceutical composition comprises the anti-Nogo-A antibody or antigen-binding fragment thereof at a concentration of about 100 mg / ml.

[0122] In certain embodiments, the pharmaceutical composition further comprisesone or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients.

[0123] In certain embodiments, the pharmaceutical composition comprises a buffer.In certain embodiments, the buffer is phosphate buffer. In certain embodiments, thepharmaceutical composition comprises a buffer at a concentration of between about 1 mMand about 50 mM. In certain embodiments, the pharmaceutical composition comprises abuffer at a concentration of about 5 mM. In certain embodiments, the pharmaceuticalcomposition comprises phosphate buffer at a concentration of between about 1 mM and about50 mM. In certain embodiments, the pharmaceutical composition comprises phosphatebuffer at a concentration of about 5 mM.

[0124] In certain embodiments, the pharmaceutical composition comprises acarbohydrate. In certain embodiments, the carbohydrate is sucrose. In certain embodiments,the pharmaceutical composition comprises a carbohydrate at a concentration of betweenabout 1.0% (w / v) and about 10% (w / v). In certain embodiments, the pharmaceuticalcomposition comprises a carbohydrate at a concentration of about 4.2% (w / v). In certainembodiments, the pharmaceutical composition comprises sucrose at a concentration ofbetween about 1.0% (w / v) and about 10% (w / v). In certain embodiments, the pharmaceuticalcomposition comprises sucrose at a concentration of about 4.2% (w / v).

[0125] In certain embodiments, the pharmaceutical composition comprises a salt. Incertain embodiments, the salt is sodium chloride. In certain embodiments, thepharmaceutical composition comprises a salt at a concentration of between about 10 mM andabout 200 mM. In certain embodiments, the pharmaceutical composition comprises a salt ata concentration of about 50 mM. In certain embodiments, the pharmaceutical compositioncomprises sodium chloride at a concentration of between about 10 mM and about 200 mM.In certain embodiments, the pharmaceutical composition comprises sodium chloride at aconcentration of about 50 mM.

[0126] In certain embodiments, the pharmaceutical composition comprises asurfactant. In certain embodiments, the surfactant is polysorbate 80. In certain embodiments,the pharmaceutical composition comprises a surfactant at a concentration of between about0.002% (w / v) and about 0.05% (w / v). In certain embodiments, the pharmaceuticalcomposition comprises a surfactant at a concentration of about 0.01% (w / v). In certainembodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration ofbetween about 0.002% (w / v) and about 0.05% (w / v). In certain embodiments, thepharmaceutical composition comprises polysorbate 80 at a concentration of about 0.01%(w / v).

[0127] In certain embodiments, the pharmaceutical composition has a pH of betweenabout 5.0 and about 7.0. In certain embodiments, the pharmaceutical composition has a pH of about 5.8.

[0128] In certain embodiments, the pharmaceutical composition comprises:(i) the anti-Nogo-A antibody or antigen-binding fragment; (ii) a buffer; (iii) a carbohydrate; (iv) a salt; and (v) a surfactant.

[0129] In certain embodiments, the pharmaceutical composition comprises:(i) the anti-Nogo-A antibody or antigen-binding fragment thereof at a concentration of between about 50 mg / ml and about 150 mg / ml; (ii) a buffer at a concentration of between about 1 mM and about 50 mM; (iii) a carbohydrate at a concentration of between about 1.0% (w / v) and about 10% (w / v); (iv) a salt at a concentration of between about 10 mM and about 200 mM; and (v) a surfactant at a concentration of between about 0.002% (w / v) and about 0.05% (w / v); wherein the pharmaceutical composition has a pH of between about 5.0 and about 7.0.

[0130] In certain embodiments, wherein the pharmaceutical composition comprises:(i) the anti-Nogo-A antibody or antigen-binding fragment thereof at a concentration of about 100 mg / ml; (ii) a buffer at a concentration of about 5 mM; (iii) a carbohydrate at a concentration of about 4.2% (w / v); (iv) a salt at a concentration of about 50 mM; and (v) a surfactant at a concentration of about 0.01% (w / v); wherein the pharmaceutical composition has a pH of about 5.8.

[0131] In certain embodiments, the pharmaceutical composition comprises:(i) the anti-Nogo-A antibody or antigen-binding fragment thereof at a concentration of between about 50 mg / ml and about 150 mg / ml; (ii) phosphate buffer at a concentration of between about 1 mM and about 50 mM; (iii) sucrose at a concentration of between about 1.0% (w / v) and about 10% (w / v); (iv) sodium chloride at a concentration of between about 10 mM and about 200 mM; and (v) polysorbate 80 at a concentration of between about 0.002% (w / v) and about 0.05% (w / v); wherein the pharmaceutical composition has a pH of between about 5.0 and about 7.0.

[0132] In certain embodiments, wherein the pharmaceutical composition comprises:(i) the anti-Nogo-A antibody or antigen-binding fragment thereof at a concentration of about 100 mg / ml; (ii) phosphate buffer at a concentration of about 5 mM; (iii) sucrose at a concentration of about 4.2% (w / v); (iv) sodium chloride at a concentration of about 50 mM; and (v) polysorbate 80 at a concentration of about 0.01% (w / v); wherein the pharmaceutical composition has a pH of about 5.8.

[0133] In certain embodiments, wherein the pharmaceutical composition comprises:(i) an anti-Nogo-A antibody at a concentration of about 100 mg / ml, wherein the anti- Nogo-A antibody comprises two heavy chains each comprising the amino acid sequence of SEQ ID NO:23 and two light chains each comprising the amino acid sequence of SEQ ID NO:25; (ii) phosphate buffer at a concentration of about 5 mM; (iii) sucrose at a concentration of about 4.2% (w / v);(iv) sodium chloride at a concentration of about 50 mM; and (v) polysorbate 80 at a concentration of about 0.01% (w / v); wherein the pharmaceutical composition has a pH of about 5.8. 5.4 Treatment Methods5.4.1 Neurological Disorders

[0134] Due to its growth restricting properties Nogo-A can have negative effects onnervous system injury and disease. Hence, correlating with its various neurobiological roles,Nogo-A is implicated in a range of CNS injuries and diseases. Nogo-A associated diseasesare understood as diseases or trauma of the nervous system associated with nerve and / orvascular repair. Nogo-A inhibition has a beneficial effect in various diseases of the peripheral(PNS) and central (CNS) nervous system, more particularly in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Amyotrophic lateral sclerosis (ALS), Lewy like pathologies or other dementia in general, traumatic brain injury, spinal cord injury,diseases following cranial, cerebral or spinal trauma, stroke or a demyelinating disease. Suchdemyelinating diseases include, but are not limited to, multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalopathy, panencephalitis, Marchiafava-Bignami disease, pontine myelinolysis, adrenoleukodystrophy, Pelizaeus- Merzbacher disease, spongy degeneration, Alexander’s disease, Canavan’s disease, metachromatic leukodystrophy and Krabbe’s disease.

[0135] In addition, degenerative ocular disorders can directly or indirectly involve thedegeneration of retinal or corneal cells including ischemic retinopathies in general, anteriorischemic optic neuropathy, all forms of optic neuritis, wet and dry age-related maculardegeneration (AMD), diabetic retinopathy, diabetic macular edema, cystoid macular edema (CME), retinitis pigmentosa, Stargardt’s disease, Best’s vitelliform retinal degeneration, Leber’s congenital amaurosis and other hereditary retinal degenerations, pathologic myopia, retinopathy of prematurity, and Leber’s hereditary optic neuropathy, the after effects of corneal transplantation or of refractive corneal surgery, and herpes keratitis. Furthermore, it was shown that Nogo-A can play a role in psychiatric conditions, in particular schizophrenia and depression.

[0136] Hence, the present disclosure also relates to a method of treating aneurological disorder associated with Nogo-A including those recited above, preferably adisease of the PNS or CNS, which method comprises administering to a subject in needthereof a therapeutically effective amount of any one of the afore-described Nogo-A-binding molecules, antibodies, polynucleotides, vectors or cells of the present disclosure.

[0137] In certain embodiments, the neurological disorder is a Nogo-A associatedneurological disorder. In certain embodiments, the neurological disease is a trauma of peripheral nervous system (PNS) or central nervous system (CNS). In certain embodiments, the neurological disorder is a cranial trauma, a cerebral trauma, a spinal trauma, a brain trauma, or a stroke. In certain embodiments, the neurological disorder is a spinal cord injury(SCI). In certain embodiments, the neurological disease is a SCI not at the lumbar level. Incertain embodiments, the SCI is a cervical SCI. In certain embodiments, the SCI is an acutecervical SCI. In certain embodiments, the cervical SCI is an injury at C1-C8 level. In certainembodiments, the SCI is an acute SCI. In certain embodiments, the SCI is an incomplete cervical SCI. In certain embodiments, the SCI is an acute incomplete cervical SCI. In certain embodiments, the neurological disorder is a neurodegenerative disease, optionally wherein the neurodegenerative disease is selected from the group consisting of Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (ALS), Lewy like pathologies and dementia. In certain embodiments, the neurological disorder is a demyelinating disease or an ophthalmologic disease, optionally wherein the ophthalmologic disease is selected from the group consisting of diabetic retinopathy, diabetic macular edema, wet and dry age-related macular degeneration (AMD).

[0138] Acute spinal cord injury (SCI) is a traumatic event that results in disturbancesto normal sensory, motor, or autonomic function and ultimately affects a patient’s physical,psychological, and social well-being. SCIs are mainly caused by work, traffic and sportsaccidents and by violence. Paraplegia (leg and autonomic function affected) and tetraplegia (leg, arm and autonomic function affected; potentially combined with need for artificial respiration) impair the quality of life and the ability to work in the majority of patients in a severe and dramatic way. The social and economic burden of life-long care including frequent secondary complications (ie, urinary tract infections, pressure sores, neuropathic pain, spasticity etc.) is enormous. Currently there is no cure for SCI. Steroid drugs such as methylprednisolone reduce swelling, which is a common cause of secondary damage at the time of injury; efficacy of these steroids, however, has not been clearly established. Complications secondary to SCI are often treated with anticholinergic drugs for bladder dysfunction, baclofen for spasticity, and opioids for pain. There is essentially no spontaneous regeneration of the interrupted nerve fiber tracts in the injured spinal cord, which is the main reason for the low level of recovery after SCI or brain injury.5.4.2 Dosing Regimens

[0139] The present disclosure provides methods for treating a neurological disorder(e.g., a neurological disorder disclosed in Section 5.4.1) comprising administering to asubject in need thereof an anti-Nogo-A antibody or an antigen-binding fragment thereof (e.g., an anti-Nogo-A antibody or an antigen-binding fragment thereof disclosed in Section 5.2, or an anti-Nogo-A antibody or an antigen-binding fragment thereof disclosed inWO2021079002A2) or a pharmaceutical composition comprising thereof (e.g., apharmaceutical composition disclosed in Section 5.3), wherein .

[0140] The present disclosure further provides an anti-Nogo-A antibody or anantigen-binding fragment thereof (e.g., an anti-Nogo-A antibody or an antigen-binding fragment thereof disclosed in Section 5.2, or an anti-Nogo-A antibody or an antigen-binding fragment thereof disclosed in WO2021079002A2) or a pharmaceutical compositioncomprising thereof (e.g., a pharmaceutical composition disclosed in Section 5.3) for use intreating a neurological disorder (e.g., a neurological disorder disclosed in Section 5.4.1) in asubject in need thereof.

[0141] The present disclosure further provides use of an anti-Nogo-A antibody or anantigen-binding fragment thereof (e.g., an anti-Nogo-A antibody or an antigen-binding fragment thereof disclosed in Section 5.2, or an anti-Nogo-A antibody or an antigen-binding fragment thereof disclosed in WO2021079002A2) or a pharmaceutical compositioncomprising thereof (e.g., a pharmaceutical composition disclosed in Section 5.3) in themanufacturing of a medicament for the treatment of a neurological disorder (e.g., a neurological disorder disclosed in Section 5.4.1) in a subject in need thereof.

[0142] In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof is administered to the subject in at least two doses sequentially. In certain embodiments, each of the at least two doses is between about 50 mg and about 450 mg. In certain embodiments, each of the at least two doses is between about 50 mg and about 400 mg. In certain embodiments, each of the at least two doses is between about 50 mg and about200 mg. In certain embodiments, each of the at least two doses is between about 50 mg andabout 150 mg. In certain embodiments, each of the at least two doses is between about 50 mgand about 100 mg. In certain embodiments, each of the at least two doses is between about100 mg and about 450 mg. In certain embodiments, each of the at least two doses is betweenabout 100 mg and about 400 mg. In certain embodiments, each of the at least two doses isbetween about 100 mg and about 200 mg. In certain embodiments, each of the at least twodoses is between about 100 mg and about 150 mg. In certain embodiments, each of the atleast two doses is between about 150 mg and about 450 mg. In certain embodiments, each ofthe at least two doses is between about 150 mg and about 400 mg. In certain embodiments,each of the at least two doses is between about 150 mg and about 200 mg. In certainembodiments, each of the at least two doses is between about 200 mg and about 450 mg. Incertain embodiments, each of the at least two doses is between about 200 mg and about 400mg. In certain embodiments, each of the at least two doses is between about 400 mg andabout 450 mg. In certain embodiments, each dose is about 50 mg. In certain embodiments,each dose is about 100 mg. In certain embodiments, each dose is about 150 mg. In certainembodiments, each dose is about 200 mg. In certain embodiments, each dose is about 400mg. In certain embodiments, each dose is about 450 mg.

[0143] In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof is administered at an interval of from 3 days to 7 days between twoconsecutively administered doses. In certain embodiments, the anti-Nogo-A antibody orantigen-binding fragment thereof is administered at an interval of 3 days, 4 days, 5 days, 6 days, or 7 days between two consecutively administered doses.

[0144] In certain embodiments, the method comprises sequentially administering tothe subject at least 2 doses, at least 3 doses, at least 4 doses, at least 5 doses, at least 6 doses or more doses of the anti-Nogo-A antibody or antigen-binding fragment thereof. In certain embodiments, the method comprises sequentially administering to the subject 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more doses of the anti-Nogo-A antibody or antigen- binding fragment thereof. In certain embodiments, the method comprises sequentially administering to the subject at least 6 doses of the anti-Nogo-A antibody or antigen-binding fragment thereof. In certain embodiments, the method comprises sequentially administeringto the subject 6 doses of the anti-Nogo-A antibody or antigen-binding fragment thereof. Incertain embodiments, the method comprises sequentially administering to the subject 6 doses of the anti-Nogo-A antibody or antigen-binding fragment thereof within 4 weeks.

[0145] In certain embodiments, the first dose is administered on day 1. In certainembodiments, the second dose is administered between day 4 and day 8. In certain embodiments, the third dose is administered between day 9 and day 13. In certainembodiments, the fourth dose is administered between day 14 and day 18. In certainembodiments, the fifth dose is administered between day 19 and day 23. In certainembodiments, the sixth dose is administered between day 24 and day 28.

[0146] In certain embodiments, at least 6 doses or 6 doses of the anti-Nogo-Aantibody or antigen-binding fragment thereof are administered to the subject in need thereof,wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose isadministered between day 14 and day 18, the fifth dose is administered between day 19 andday 23, and the sixth dose is administered between day 24 and day 28.

[0147] In certain embodiments, each dose is administered as a single-dose injection.In certain embodiments, each dose is administered via slow bolus. In certain embodiments,each dose is administered via slow bolus over about 100 seconds. In certain embodiments,each dose is administered as a single-dose injection of 4.5 ml. In certain embodiments, each dose is administered as a single-dose injection of 4.5 ml via slow bolus.

[0148] In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof is administered via intrathecal injection. In certain embodiments, theintrathecal injection is administered at the lumbar level. In certain embodiments, theneurological disease is a SCI not at the lumbar level and the anti-Nogo-A antibody orantigen-binding fragment thereof is administered to the subject via intrathecal injection at thelumbar level. In certain embodiments, the SCI is an injury at C1-C8 level and the anti-Nogo-A antibody or antigen-binding fragment thereof is administered to the subject via intrathecalinjection at L1-L5 level.

[0149] In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof is administered sequentially to the subject in 6 doses within 4 weeks, wherein each dose is about 50 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose isadministered between day 19 and day 23, and the sixth dose is administered between day 24and day 28, and each dose is administered as a single-dose injection via intrathecal injection. In certain embodiments, each dose is administered via slow bolus. In certain embodiments, each dose is administered via slow bolus over about 100 seconds. In certain embodiments, the intrathecal injection is administered at the lumbar level.

[0150] In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof is administered sequentially to the subject in 6 doses within 4 weeks,wherein each dose is about 100 mg; wherein the first dose is administered on day 1, thesecond dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection.In certain embodiments, each dose is administered via slow bolus. In certain embodiments, each dose is administered via slow bolus over about 100 seconds. In certain embodiments, the intrathecal injection is administered at the lumbar level.

[0151] In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof is administered sequentially to the subject in 6 doses within 4 weeks, wherein each dose is about 150 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered betweenday 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose isadministered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection. In certain embodiments, each dose is administered via slow bolus. In certain embodiments, each dose is administered via slow bolus over about 100 seconds. In certain embodiments, the intrathecal injection is administered at the lumbar level.

[0152] In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof is administered sequentially to the subject in 6 doses within 4 weeks,wherein each dose is about 200 mg; wherein the first dose is administered on day 1, thesecond dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection. In certain embodiments, each dose is administered via slow bolus. In certain embodiments, each dose is administered via slow bolus over about 100 seconds. In certain embodiments, the intrathecal injection is administered at the lumbar level.

[0153] In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof is administered sequentially to the subject in 6 doses within 4 weeks,wherein each dose is about 400 mg; wherein the first dose is administered on day 1, thesecond dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection. In certain embodiments, each dose is administered via slow bolus. In certain embodiments, each dose is administered via slow bolus over about 100 seconds. In certain embodiments, the intrathecal injection is administered at the lumbar level.

[0154] In certain embodiments, the anti-Nogo-A antibody or antigen-bindingfragment thereof is administered sequentially to the subject in 6 doses within 4 weeks, wherein each dose is about 450 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection. In certain embodiments, each dose is administered via slow bolus. In certain embodiments, each dose is administered via slow bolus over about 100 seconds. In certain embodiments, the intrathecal injection is administered at the lumbar level.

[0155] In a further embodiment, co-administration or sequential administration ofother agents useful for treating a PNS or CNS disease, disorder, or symptoms associated with Nogo-A may be desirable. For example, the antibody, or Nogo-A-binding fragment, variant, or biotechnological derivative thereof of the present disclosure can be administered in combination with anti-inflammatory agents such as but not limited to corticosteroids following stroke or spinal cord injury as a means for blocking further neuronal damage and inhibition of axonal regeneration, neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotropic factor (BDNF) or other drugs for neurodegenerative diseases suchas Exelon™ (Rivastigmine) or Levodopa (L-DOPA (3,4-dihydroxy-L-phenylalanine)). Othersuitable combination partners for the treatment of stroke are alteplase and desmoteplase (DSPA, e.g., disclosed in W090 / 09438). In certain embodiments, the present disclosure provides a combination comprising an antibody or Nogo-A-binding fragment of the present disclosure and desmoteplase, in particular for the treatment of stroke as well as pharmaceutical compositions comprising said combination. As used herein, two agents aresaid to be administered in combination when the two agents are administered simultaneouslyor are administered independently in a fashion such that the agents act at the same time.

[0156] The structure of the active ingredients identified by code numbers, generic ortrade names may be taken from the actual edition of the standard compendium “The MerckIndex” or from databases, e.g. Patents International (e.g. IMS World Publications) or otherdatabases provided by IMS Health.

[0157] In certain embodiments, cells which express the antibody or Nogo-A-bindingfragment, variant, or derivative thereof of the present disclosure may be transplanted to a site of spinal cord injury to facilitate axonal growth throughout the injured site. Such transplanted cells would provide a means for restoring spinal cord function following injury or trauma.Such cells could include olfactory unsheathing cells and stem cells of different lineages of fetal nerve or tissue grafts.6. EXAMPLES

[0158] The following is a description of various methods and materials used in thestudies. They are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the experiments below were performed and are all of the experiments that may be performed. It is to be understood that exemplary descriptions written in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate the data and the like associated with the teachings of the present disclosure. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, percentages, etc.), but some experimental errors and deviations should be accounted for. 6.1 Example 1: A First-In-Human (FIH) Clinical Trial to Investigate the UmanMonoclonal Antibody Ab1, Administrated Intrathecally in Acute Spinal Cord Injury (SCI) Patients 6.1.1 Ab1 Structure, Properties, and Sequences

[0159] Ab1 -light chains of the k chain and 2 in each light chain. Two heavy chains are coupled with 2 inter chain disulfidebonds. Each heavy and light chain is coupled with one disulfide bond. Ab1 is a glycoproteinand the constant region of each heavy chain contains one N-linked glycan site at residue Asparagine (N297). The IgG4 hinge sequence has a Serine to Proline (S228P) substitution toreduce the formation of half-antibodies. A schematic showing of Ab1 is provided in FIG. 2.

[0160] The amino acid sequence of Ab1 is shown below and in Table 1. The N-linkGlycan is on Asparagine 297 of the heavy chain as shown in oval dots in FIG. 2. The S to P mutation is on Proline 228 of the heavy chain pointed by arrows in FIG. 2. The total numberof amino acids, number of amino acids of the heavy chain (without signal peptide), andnumber of amino acids of the light chain (without signal peptide) are 1334, 447, and 220,respectively.

[0161] Heavy chain amino acid sequence of Ab1 (with signal peptide):MEFGLSWLFLVAILKGVQCEVQLVESGGGVVQPGRSLRLSCAASGFTFRSHAMHWVRQAPGK GLEWVAVTSYDGTNKYYADSVKGRFTISKDNSKNTLYLQMDSLRVEDTAVYYCARGRAVAGT REDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO:22]

[0162] Light chain amino acid sequence of Ab1 (with signal peptide):MVLQTQVFISLLLWISGAYGDIQMTQSPDSLAVSLGERATINCKSSQSVLFSSNSKNYLAWY QQKPGQPPKVLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTRPTF GLGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ IDNO:24]

[0163] Signal peptides are underlined. The variable domains are in bold font. Theconstant domains are in normal font. The potential isomerization sites are in bold, italic andunderlined. The potential deamidation sites are bold and underlined. The potential oxidationsite are bold and boxed.

[0164] The physicochemical properties of Ab1 and the formulation being used in theinstant clinical trial are provided in Table 3 below;Table 3. Physical and Chemical Properties of Ab1

[0165] Ab1 binds to human Nogo-A with high affinity and neutralizes the neuritegrowth inhibitory activity of crude monkey spinal cord or CNS extracts. Ab1 enhanced fibertract regeneration and locomotor recovery in a rat SCI model resembling an injury severity ofAIS C according to International Standards for the Neurological Classification of Spinal CordInjury (ISNCSCI) in human SCI. Ab1 is highly stable and has a favorable safety and PKprofile in NHPs. Ab1 manufactured according to current Good Manufacturing Practice(GMP) is available for the use in clinical trials. 6.1.2 Trial Period and Objectives and Endpoints

[0166] The screening phase including baseline is up to 28 days. The treatment phaseis 4 weeks. The follow-up phase is 20 weeks. Objectives and endpoints are provided in the table below.Table 4. Objectives and Endpoints[1] Modified Ashworth Scale is disclosed in Rust R, Grönnert L, Gantner C, Enzler A, Mulders G, Weber RZ, et al. Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke. Proc Natl Acad Sci U S A. 2019;116(28):14270-9. 6.1.3 Methodology

[0167] Without being bound by any theory, Ab1 can stimulate the outgrowth andregeneration of nerve fibers in the injured spinal cord and in the brain by blocking the nerve fiber growth inhibitor Nogo-A to establish novel functional connections following traumatic injury in acute SCI patients.

[0168] The instant clinical trial is a FIH, multicenter, open-label, sequential, multipleascending dose trial of Ab1 in patients with acute incomplete cervical SCI. The trial evaluatesthe safety, tolerability, and PK of Ab1, and determines the maximum tolerated dose (MTD) of Ab1.

[0169] Patients who remain eligible after the Screening visit undergo baselineassessments, receive 6 intrathecal (i.t.) injections of Ab1 (1 injection every 5 days) over aperiod of 4 weeks and are followed up for 20 weeks after the last Ab1 injection. Follow-upvisits are performed after treatment completion at Days 31 (±2), and 43, 57, 71, 85, 127, 169(±7). Safety assessments (safety laboratory, physical and neurological examinations, vitalsigns, ECG evaluations) and clinical examinations (ISNCSCI assessment) are done at regularintervals during the treatment and follow-up phase. CSF samples for Ab1 concentrationmeasurement are taken prior to each i.t. bolus injection. Serum samples for the PK analysesare collected during the treatment and follow-up phase. Daily life functioning is assessedduring the follow-up. A trial completion evaluation is performed at Day 169 (±7) includingspinal magnetic resonance imaging (MRI) scan.

[0170] Patients are treated in 3 partially overlapping sequential cohorts. The planneddose levels for Cohorts 1 to 3 are 50 mg, 150 mg and 450 mg Ab1 per injection. Each cohortcomprise 1 sentinel patient and at least 2 additional patients. In Cohort 3, 2 additional patients are planned to be treated, resulting in a cohort size of 5 patients.

[0171] Ab1 DP (drug product) concentrate for solution for injection (100 mg / mL): 0.5mL in a 2 mL glass vial. The Ab1 DP concentrate are reconstituted with an appropriatevolume of dilution buffer (4.0 mL phosphate buffer in a 10 mL glass vial) as required to prepare injection doses of 50 to 150 mg / injection. A dilution is not required for the dose of 450 mg / injection.

[0172] 1 dose of 50, 150 or 450 mg Ab1 is given as single slow bolus i.t. injection of4.5 mL at the lumbar level at Days 1, 6, 11, 16, 21, and 26 (±2 days).

[0173] Approximately 11 patients are planned to be enrolled and treated, 3 patientseach in Cohorts 1 and 2, and 5 patients in Cohort 3. Additional patients may be enrolled and treated, if replacements are required or if the occurrence of DLTs (dose limiting toxicities) requires an increase in the number of patients in the cohort. If Cohorts 1 and 2 need to be extended to 6 patients, approximately 17 patients are enrolled and treated.

[0174] Adult male and female patients with acute incomplete cervical SCI arerecruited. Inclusion Criteria

[0175] At Screening and Baseline the following inclusion criteria must be met:1. Male or female2. 18 to 70 years of age, inclusive3. a. confirmed classification of American Spinal Injury Association (ASIA)impairment scale (AIS) C-D at Screening and b. Nodes 10 and 16-18 according to the unbiased recursive partitioning (URP)prediction model for predicted mean UEMS recoveryc. UEMS at Screening and Baseline <284. Trial treatment can be initiated by first i.t. bolus injection upon eligibilityconfirmation within 4-28 days post-injury 5. Tetraplegic patients who are allowed to start treatment are those who either do notrequire mechanical ventilation or who do not completely depend on mechanical ventilation but show some degree of spontaneous ventilation. Only those modes of ventilation where the patients show active initiation of breathing are allowed (e.g., continuous positive airway pressure) 6. Hemodynamically and clinically stable according to the acute SCI condition atBaseline 7. For patients of childbearing potential, use of reliable means of contraception asdescribed below during the treatment phase and for at least 6 months after the last dose of IP: a. Men and women of childbearing potential, who are willing to use a highlyeffective method of contraception [either combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner or sexual abstinence)], or women not of childbearing potential, defined as women who have been surgically sterilized (total hysterectomy or bilateral oophorectomy, bilateral tubal ligation, staples, or another type of sterilization) or have been postmenopausal for at least 2 years. Individuals who are convincingly sexually abstinent are also eligible. b. Sexual inactivity by abstinence must be consistent with the preferred and usuallifestyle of the patient. Periodic abstinence (e.g., calendar ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. 8. Written informed consent by patient or witness (for patients who could consent onlyverbally), provided prior to participation in the trial 9. Cooperation and willingness to complete all aspects of the trial10. Ability of patient to understand character and individual consequences of the trialExclusion Criteria

[0176] A patient who meets any of the following exclusion criteria at Screeningand / or Baseline is excluded from participation in this trial:1. Trauma caused by ballistic or other injury that directly penetrates the spinal cordincluding gunshot and knife wounds 2. Multiple levels of clinically relevant spinal cord lesions (CAVE: patients with stablefractures e.g., on a thoracic level can be included)3. Major brachial or lumbar plexus damage / trauma4. Significant head trauma (e.g., cortical damage / lesion), or other injury that is, in theopinion of the investigator, sufficient to interfere with the assessment of the spinal cord function or may otherwise compromise the validity of the patient’s data 5. Other significant pre-existing or current severe systemic diseases such as lung, liver(exception: history of uncomplicated hepatitis A), gastrointestinal, cardiac, immunodeficiency (including anamnestic known HIV) or kidney disease; or active malignancy or any other condition as determined by history or laboratory investigation that could cause a neurological deficit including syphilis, myelopathy, clinically relevant polyneuropathy, etc. 6. History of or an acute episode of Multiple Sclerosis or Guillain-Barre syndrome7. History of recent meningitis or meningoencephalitis (within last 6 months beforeBaseline) 8. History of refractory epilepsy9. Patients with uncontrolled bleeding diathesis and / or who require concomitanttherapeutic anticoagulation (e.g., phenoprocoumon [Marcumar®],heparin / heparinoids and new oral anticoagulants at a higher dose than for the prophylaxis of venous thromboembolism) and not related to SCI 10. Presence of any unstable medical or psychiatric condition (defined by the Diagnosticand Statistical Manual of Mental Disorders, Edition 4 [DSM-IV]) that may expose the patient to an unwarranted risk from participation in the trial or result in a significant deterioration of the patient’s clinical course 11. Drug dependence (as defined by DSM-IV) any time within last 6 months beforeBaseline 12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of awoman after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin laboratory test (>5 mIU / mL) 13. History of a life-threatening allergic or immune-mediated reaction14. Patients with the presence of infection around the location where the spinal needleinsertions are planned for applying the intrathecal injections 15. Inability to communicate effectively with the neurological examiner such that thevalidity of the patient’s data may be compromised 16. Participation in any clinical investigation within 4 weeks prior to dosing or longer ifrequired by local regulations, and for any other limitation of participation based on local regulations 17. Patients who are unconscious, including those patients who are unconscious due tomedication causing marked sedation 18. Known hypersensitivity to any excipients of the IP or to any drug with similarchemical structure

[0177] Pharmacokinetics and anti-drug antibodies are assessed as following:Blood collections for the PK analysis of Ab1 CSF collections for the analysis of Ab1 concentrationBlood collections for the analysis of anti-drug antibodies (to be analyzed only if required for safety or PK considerations)

[0178] Pharmacodynamics is assessed as following:Motor and sensory function (ISNCSCI: AIS, UEMS, lower extremities motor score, total motor score, light touch, pin prick) Daily life functioning (SCIM-III)

[0179] Trial flow chart is provided in FIG. 3.6.1.4 Treatment Details

[0180] Specifics regarding products used in trial are provided in Table 5 below.Table 5. Product used in the trial

[0181] Ab1 DP concentrate for solution for injection (0.5 mL at a concentration of100 mg / mL) is provided in 2 mL glass vials. Preparation of the injection solution must becarried out using the dual control principle. On the day of IP injection, the required number ofvials with Ab1 DP concentrate must be thawed for injection preparation at room temperaturefor 30-40 minutes, and then mixed gently by swirling without rubber stopper contact norinverting the vials. If Ab1 diluent is required, it should be equilibrated at room temperaturefor 30-40 minutes before use. The prepared solution for injection must be used immediately, and not later than 4 hours after the preparation.

[0182] Detailed instructions for the preparation of IP solutions in the different doselevels and the IP administration itself are described in the corresponding IP manual. Each vial of IP and diluent buffer is for single use and must not be used to prepare a second reconstitution of injection solution.

[0183] A total of 4.5 mL of the IP solution in the respective dose (50 mg, 150 mg, or450 mg Ab1 / injection) is administered by the investigator or qualified site staff with experience in aseptic technique via slow bolus (over 100 seconds) i.t. injection at the lumbar level. Each patient receives 6 single-dose injections within 4 weeks (Day 1, Day 6 ±2, Day 11±2, Day 16 ±2, Day 21 ±2, and Day 26 ±2 days; an interval between injections of 3-7 days should be maintained). 6.1.5 Pharmacokinetic and Anti-drug Antibody Assessments

[0184] Blood and CSF samples for Ab1 concentration measurements, as well as bloodsamples for ADA analysis, are obtained at the visits.

[0185] Blood samples for PK assessments are taken:At Day 1 and Day 26 at: oPre dose: during the treatment day before IP injection (preferably togetherwith blood collection for safety laboratory)o Post dose: 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15minutes), 24 hours (±30 minutes), and 48 hours (±60 minutes) after IPinjection At Days 6, 11, 16 and 21 at pre dose At Days 31, 43, 57, 71, 85, 127 and 169 at any time

[0186] CSF samples for Ab1 concentration measurement are taken at pre-dose atDays 1, 6, 11, 16, 21 and 26.

[0187] Blood samples for ADA analysis are taken on Day 1 and Day 26 before IPinjection and at any time at Days 43, 85, 127 and 169.

[0188] The concentrations of Ab1 in serum and CSF are analyzed by validatedenzyme-linked immunosorbent assay methods. Samples for the analysis of anti-Ab1antibodies are screened using an immunoassay and possibly go through other characterizationassays. Ab1 concentrations in serum and CSF are determined. Blood samples for theanalyses of anti-Ab1 antibodies are collected for anti-drug antibody analysis.6.1.6 Pharmacodynamic assessments

[0189] The motor and sensory function are assessed according to the ISNCSCI.

[0190] The AIS is a standardized and routinely used classification for patients withSCI. in which the ASIA scores for motor and sensory function are used to determine the AIS grade (A, B, C, D). AIS grade A denotes no motor function beneath the level of injury (i.e., lowest spinal level with normal neurological function) and no sensory function at the lowestsacral level (i.e., on rectal examination), grade B denotes presence of rectal sensation but nomotor function below the level of injury, grade C denotes sensory function and some motor function below the level of injury, and grade D denotes sensory function and substantial motor function beneath the level of injury (American Spinal Injury Association 2002).

[0191] Perceptions of light touch (LT) and pin prick (PP) stimuli are scored as 0 forabsent, 1 for impaired and 2 for normal. Each sensory dermatome is tested for LT and PP, and a summary score that ranges from 0 to 112 is calculated by adding up the dermatome scores.

[0192] Motor function is scored on the Medical Research Council Scale of 0 for totalparalysis to 5 for normal strength. Ten muscles are tested bilaterally and individual muscle scores are added together, yielding a motor score that ranges from 0 to 100. If possible, the same examiner should complete the ASIA motor score.

[0193] The upper and lower limb motor scores are compiled separately as the UEMSand lower extremities motor score (LEMS) shown in Table 6. This enables a change in motor function to be more clearly tracked and recorded as specific to either the cervical or lumbar levels. Separation of the motor scores into UEMS and LEMS also reduces the influence that a large change in the functional strength in 1 or a few muscles might have on the interpretation of therapeutic benefit. Table 6. Key muscles used for ASIA motor score assessment, with muscle gradescategorizing functional assessment of each muscle’s contraction Left side Key muscles for ASIA motor score assessment and primary level of Right side (max. grade) spinal innervation (max. grade) 5Elbow flexors (biceps brachialis) – C5 55 Wrist extensors (extensor carpi radialis longus and brevis) – C6 55 Elbow extensor (triceps) – C7 55 Finger flexors (flexor digitorum profundus, middle finger) – C8 55 Finger abductors (abductor digiti minimi, little finger) – T1 525 Upper Extremity Motor Score (UEMS) 255 Hip flexors (iliopsoas) – L2 55 Knee extensors (quadriceps) – L3 55 Ankle dorsiflexors (tibialis anterior) – L4 55 Long toe extensors (extensor hallucis longus) – L5 55 Ankle plantar flexors (gastrocnemius, soleus) – S1 525 Lower Extremity Motor Score (LEMS) 25 50 Total ASIA motor score (=100 for both sides) 50 ASIA muscle grades: 0=total paralysis; 1=palpable or visible contraction; 2=active movement, gravity eliminated; 3=active movement, against gravity; 4=active movement, against some resistance; 5=active movement

[0194] Patient’s daily life functioning is assessed using the SCIM-III. The SCIM-IIIis a comprehensive functional outcome measure that sensitively and accurately assesses the ability to perform activities of daily living after SCI. The SCIM-III is a 100-point disabilityscale developed specifically for SCI with emphasis on 18 activities associated with:Self-care (feeding, bathing, dressing, grooming), maximum=20 points Respiration and sphincter management (ventilation, bladder, bowel, use of toilet), maximum=40 points (clinically weighted) Mobility (in bed, transfers, indoors and outdoors, wheelchair, walking), maximum=40 points 6.2 Example 2: A First-In-Human (FIH) Clinical Trial to Investigate the UmanMonoclonal Antibody Ab1, Administrated Intrathecally in Acute Spinal Cord Injury (SCI) Patients

[0195] An updated clinical trial is performed, with certain changes (e.g., dosinglevels) made from the study of Example 1, as detailed below.

[0196] The structure, properties, and sequences of Ab1, and the formulation beingused in the instant Example 2 are the same as those disclosed in Section 6.1.1 of Example 1.

[0197] Trial period and objectives and endpoints are the same as those disclosed in,Section 6.1.2 of Example 1.6.2.1 Methodology

[0198] Without being bound by any theory, Ab1 can stimulate the outgrowth andregeneration of nerve fibers in the injured spinal cord and in the brain by blocking the nerve fiber growth inhibitor Nogo-A to establish novel functional connections and higher levels of functional recovery following traumatic injury in acute SCI patients.

[0199] The instant clinical trial is a FIH, multicenter, open-label, sequential, multipleascending dose trial of Ab1 in patients with acute incomplete cervical SCI. The trial evaluatesthe safety, tolerability, and PK of Ab1, and determines the maximum tolerated dose (MTD) of Ab1.

[0200] Patients who remain eligible after the Screening visit undergo baselineassessments, receive 6 intrathecal (i.t.) injections of Ab1 (1 injection every 5 days) over aperiod of 4 weeks and are followed up for 20 weeks after the last Ab1 injection. Follow-upvisits are performed after treatment completion at Days 31 (±2), and 43, 57, 71, 85, 127, 169 (±7). Safety assessments (safety laboratory, physical and neurological examinations, vital signs, ECG evaluations) and clinical examinations (ISNCSCI assessment) are done at regularintervals during the treatment and follow-up phase. CSF samples for Ab1 concentrationmeasurement are taken prior to each i.t. bolus injection. Serum samples for the PK analyses are collected during the treatment and follow-up phase. Daily life functioning is assessed during the follow-up. A trial completion evaluation is performed at Day 169 (±7) including spinal magnetic resonance imaging (MRI) scan.

[0201] Patients are treated in 4 partially overlapping sequential cohorts. The planneddose levels for Cohorts 1 to 4 are 50 mg, 100 mg, 200 mg, and 400 mg Ab1 per injection.Each cohort comprises 1 sentinel patient and 2 additional patients. Sentinel patients aretreated first, receive at least 2 i.t. injections and complete a 24-hour safety surveillanceperiod, before subsequent patients of the same cohort can be dosed. Subsequent patients areonly treated if, as assessed by the investigator, physical and neurological examination and safety laboratory data (hematology, blood chemistry, coagulation, and urinalysis) aftersentinel patient’s second injection reveal no safety concerns. A minimum interval of 48hours must be maintained between the first Ab1 dose of the second and third patient of acohort.

[0202] Ab1 DP (drug product) concentrate for solution for injection (100 mg / mL): 0.5mL in a 2 mL glass vial. The Ab1 DP concentrate are reconstituted with an appropriatevolume of dilution buffer (4.0 mL phosphate buffer in a 10 mL glass vial) as required toprepare injection doses of 50 to 400 mg / injection.

[0203] 1 dose of 50, 100, 200, or 400 mg Ab1 is given as single slow bolus i.t.injection of 4.5 mL at the lumbar level at Days 1, 6, 11, 16, 21, and 26 (±2 days).

[0204] Approximately 12 patients are planned to be enrolled and treated, 3 patients ineach cohort. Additional patients may be enrolled and treated, if replacements are required orif the occurrence of clinically significant Ab1 related adverse events (Grade 3 according toNCI CTCAE Version 5.0) requires an increase in the number of patients in the cohort. If all Cohorts 1, 2 and 3 need to be extended to 6 patients, approximately 21 patients are enrolled and treated.

[0205] Adult male and female patients with acute incomplete cervical SCI arerecruited.

[0206] Inclusion criteria and exclusion criteria are the same as those disclosed inSection 6.1.3 of Example 1. Pharmacokinetics and anti-drug antibodies assessment andpharmacodynamics assessment are the same as those disclosed in Section 6.1.3, Section6.1.5, and Section 6.1.6 of Example 1. Trial flow chart is provided in FIG. 3.6.2.2 Treatment Details

[0207] Specifics regarding products used in trial are provided in Table 7 below.Table 7: Product Used in the Trial Intervention name Ab1Type DrugDose formulation Ab1 DP concentrate for solution for injection(100 mg / mL)Unit dose strength(s) 50 mg, 100 mg, 200 mg, or 400 mgThe formulation has to be reconstituted with an appropriate volume of dilution buffer as required to prepare injection doses of 50 to 400 mg / injection. Dosage level(s) 6 single-dose injections within 4 weeks at intervals of5 (±2) days Route of administration Intrathecal slow bolus injectionIP and AxMP IP Sourcing Provided centrally by the sponsor’s designeePackaging and labeling 0.5 mL of Ab1 DP concentrate (100 mg / mL) will beprovided in a 2 mL (2R) glass vial. 2 glass vials of theAb1 DP concentrate are packed in a kit container.4.0 mL of the diluent (phosphate buffer manufactured by the sponsor) will be provided in a 10 mL (10R) glass vial. 8 glass vials of the diluent are packed in a kit container. Each glass vial and kit will be labeled as required per country requirement. Packaging and labeling will be done by Almac Clinical Services Ltd.

[0208] Ab1 DP concentrate for solution for injection (0.5 mL at a concentration of100 mg / mL) will be provided in 2 mL glass vials. Preparation of the injection solution mustbe carried out using the dual control principle. On the day of IP injection, the requirednumber of vials with Ab1 DP concentrate must be thawed for injection preparation at roomtemperature for 30-40 minutes, and then mixed gently by swirling without rubber stoppercontact nor inverting the vials. If Ab1 diluent is required, it should be equilibrated at roomtemperature for 30-40 minutes before use. The prepared solution for injection must be usedimmediately, and not later than 4 hours after the preparation.

[0209] Detailed instructions for the preparation of IP solutions in the different doselevels and the IP administration itself are described in the corresponding IP manual. Each vialof IP and diluent buffer is for single use and must not be used to prepare a second reconstitution of injection solution.

[0210] A total of 4.5 mL of the IP solution in the respective dose (50 mg, 100 mg,200 mg, or 400 mg Ab1 / injection) will be administered by the investigator or qualified sitestaff with experience in aseptic technique via slow bolus (over 100 seconds) i.t. injection atthe lumbar level using a 22G atraumatic needle. Each patient will receive 6 single-doseinjections within 4 weeks (Day 1, Day 6 ±2, Day 11 ±2, Day 16 ±2, Day 21 ±2, and Day 26±2 days; an interval between injections of 3-7 days should be maintained).EQUIVALENTS

[0211] All patents and publications mentioned in this specification are incorporatedherein by reference in their entireties. From the foregoing description, it will be apparent that variations and modifications can be made to the invention described herein to adopt it to various uses and conditions. Such embodiments are also within the scope of the following claims. SEQUENCES SEQ IDDescription SequenceNO. 1Ab1 VH nucleotidegaggtgcagctggtggagtctgggggaggcgtggtccagcc sequence tgggaggtccctgagactctcctgtgcagcctctggattca ccttcaggagccatgctatgcactgggtccgccaggctcca ggcaaggggctggagtgggtggcagttacatcatatgatgg aaccaataaatactacgcagactccgtgaagggccgattca ccatctccaaagacaattccaagaacacgctgtatctgcaa atggacagcctcagagttgaggacacggctgtgtattactg tgcgagaggccgagcagtggctggtacgagggaagattatt ggggccagggaaccctggtcaccgtctcctcg 2Ab1 VH EVQLVESGGGVVQPGRSLRLSCAASGFTFRSHAMHWVRQAPGKGLEWVAVTSYDGTNKYYADSVKGRFTISKDNSKNTLYLQ MDSLRVEDTAVYYCARGRAVAGTREDYWGQGTLVTVSS 3Ab1 VH-CDR1 SHAMH4 Ab1 VH-CDR2 VTSYDGTNKYYADSVKG5 Ab1 VH-CDR3 GRAVAGTREDY6 Ab1 VL nucleotidegacatccagatgacccagtctccagactccctggctgtgtc sequence tctgggcgagagggccaccatcaactgcaagtccagccaga gtgttttattcagctccaacagtaagaactacttagcttgg taccagcagaaaccaggacagcctcctaaggtgctcattta ctgggcatctacccgggaatccggggtccctgaccgattca gtggcagcgggtctgggacagatttcactctcaccatcagc agcctgcaggctgaagatgtggcagtttattactgtcagcaSEQ IDDescription SequenceNO. atattatactactcgccctacgttcggcctagggaccaaag tggatatcaaa7 Ab1 VL amino acidDIQMTQSPDSLAVSLGERATINCKSSQSVLFSSNSKNYLAW sequence YQQKPGQPPKVLIYWASTRESGVPDRFSGSGSGTDFTLTIS SLQAEDVAVYYCQQYYTTRPTFGLGTKVDIK8 Ab1 VL-CDR1 KSSQSVLFSSNSKNYLA9 Ab1 VL-CDR2 WASTRES10 Ab1 VL-CDR3 QQYYTTRPT11 Ab2 VH nucleotidegaggtgcagctggtggagactgggggaggcttggtcccacc sequence gggggggtccctgagactctcctgtgcagcctctggattca ccttcaccaactattctatgcactgggtccgcctggctcca gggaagagactggaatatatttcagctattagtagtgatgg cggtgacccattttatgcaagctctgtgaagggcagagtcg ccatctccagagacaattccaagaagacgttgtatcttcaa atgggcagactgagacctgaggacacggctgtatattattg tgtgagtgatgcttttgatgtctggggccaggggacaatgg tcaccgtctcttcg12 Ab2 VH EVQLVETGGGLVPPGGSLRLSCAASGFTFTNYSMHWVRLAPGKRLEYISAISSDGGDPFYASSVKGRVAISRDNSKKTLYLQ MGRLRPEDTAVYYCVSDAFDVWGQGTMVTVSS13 Ab2 VH-CDR1 NYSMH14 Ab2 VH-CDR2 AISSDGGDPFYASSVKG15 Ab2 VH-CDR3 DAFDV16 Ab2 VL nucleotidegaaattgtgctgacccagtctccactctccctgtccgtcac sequence ccttggacagccggcctccatctcctgcaggtctagtcaaa gcctcctatacagtaatggcaacacctacttgaattggttt cagcagaggccaggccaatctccaaggcgcctactttatag ggtttctaaccgggactctggggtcccagacagattcagcg gcagtgggtcaggcactcatttcacactgaaaattagtagg gtggaggctgaggatgttggagtttattactgcatgcaagg tacacactggcctcgcacgttcggccaagggaccaaggtgg agatcaaa17 Ab2 VL EIVLTQSPLSLSVTLGQPASISCRSSQSLLYSNGNTYLNWFQQRPGQSPRRLLYRVSNRDSGVPDRFSGSGSGTHFTLKISR VEAEDVGVYYCMQGTHWPRTFGQGTKVEIK18 Ab2 VL-CDR1 RSSQSLLYSNGNTYLN19 Ab2 VL-CDR2 RVSNRDS20 Ab2 VL-CDR3 MQGTHWPRT21 Binding epitope ofINAALQE Ab122 Ab1 heavy chainMEFGLSWLFLVAILKGVQCEVQLVESGGGVVQPGRSLRLSC (signal peptide is AASGFTFRSHAMHWVRQAPGKGLEWVAVTSYDGTNKYYADS underlined) VKGRFTISKDNSKNTLYLQMDSLRVEDTAVYYCARGRAVAG TREDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGKSEQ IDDescription SequenceNO.23 Ab1 heavy chainEVQLVESGGGVVQPGRSLRLSCAASGFTFRSHAMHWVRQAP (without signal GKGLEWVAVTSYDGTNKYYADSVKGRFTISKDNSKNTLYLQ peptide) MDSLRVEDTAVYYCARGRAVAGTREDYWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNA KTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK24 Ab1 light chainMVLQTQVFISLLLWISGAYGDIQMTQSPDSLAVSLGERATI (signal peptide is NCKSSQSVLFSSNSKNYLAWYQQKPGQPPKVLIYWASTRES underlined) GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTRPT FGLGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC25 Ab1 light chainDIQMTQSPDSLAVSLGERATINCKSSQSVLFSSNSKNYLAW (without signal YQQKPGQPPKVLIYWASTRESGVPDRFSGSGSGTDFTLTIS peptide) SLQAEDVAVYYCQQYYTTRPTFGLGTKVDIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC26 Human IgG4 heavyASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW chain constant NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT region (CH1-hinge- CNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLF CH2-CH3) PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEV HNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK27 Human Nogo-A MEDLDQSPLVSSSDSPPRPQPAFKYQFVREPEDEEEEEEEEEEDEDEDLEELEVLERKPAAGLSAAPVPTAPAAGAPLMDFG NDFVPPAPRGPLPAAPPVAPERQPSWDPSPVSSTVPAPSPL SAAAVSPSKLPEDDEPPARPPPPPPASVSPQAEPVWTPPAP APAAPPSTPAAPKRRGSSGSVDETLFALPAASEPVIRSSAE NMDLKEQPGNTISAGQEDFPSVLLETAASLPSLSPLSAASF KEHEYLGNLSTVLPTEGTLQENVSEASKEVSEKAKTLLIDR DLTEFSELEYSEMGSSFSVSPKAESAVIVANPREEIIVKNK DEEEKLVSNNILHNQQELPTALTKLVKEDEVVSSEKAKDSF NEKRVAVEAPMREEYADFKPFERVWEVKDSKEDSDMLAAGG KIESNLESKVDKKCFADSLEQTNHEKDSESSNDDTSFPSTP EGIKDRSGAYITCAPFNPAATESIATNIFPLLGDPTSENKT DEKKIEEKKAQIVTEKNTSTKTSNPFLVAAQDSETDYVTTD NLTKVTEEVVANMPEGLTPDLVQEACESELNEVTGTKIAYE TKMDLVQTSEVMQESLYPAAQLCPSFEESEATPSPVLPDIV MEAPLNSAVPSAGASVIQPSSSPLEASSVNYESIKHEPENP PPYEEAMSVSLKKVSGIKEEIKEPENINAALQETEAPYISI ACDLIKETKLSAEPAPDFSDYSEMAKVEQPVPDHSELVEDS SPDSEPVDLFSDDSIPDVPQKQDETVMLVKESLTETSFESM IEYENKEKLSALPPEGGKPYLESFKLSLDNTKDTLLPDEVS TLSKKEKIPLQMEELSTAVYSNDDLFISKEAQIRETETFSD SSPIEIIDEFPTLISSKTDSFSKLAREYTDLEVSHKSEIANSEQ IDDescription SequenceNO. APDGAGSLPCTELPHDLSLKNIQPKVEEKISFSDDFSKNGS ATSKVLLLPPDVSALATQAEIESIVKPKVLVKEAEKKLPSD TEKEDRSPSAIFSAELSKTSVVDLLYWRDIKKTGVVFGASL FLLLSLTVFSIVSVTAYIALALLSVTISFRIYKGVIQAIQK SDEGHPFRAYLESEVAISEELVQKYSNSALGHVNCTIKELR RLFLVDDLVDSLKFAVLMWVFTYVGALFNGLTLLILALISL FSVPVIYERHQAQIDHYLGLANKNVKDAMAKIQAKIPGLKR KAE28 Binding epitope ofPDFSDY Ab2

Claims

WHAT IS CLAIMED IS:

1. A method for treating a neurological disease in a subject in need thereof, the methodcomprising sequentially administering to the subject at least two doses of an anti-Nogo-Aantibody or an antigen-binding fragment thereof, wherein each of the at least two doses isbetween about 50 mg and about 450 mg.

2. The method of claim 1, wherein the anti-Nogo-A antibody or antigen-bindingfragment thereof binds Nogo-A- .

3. The method of claim 1 or 2, wherein the anti-Nogo-A antibody or antigen-bindingfragment thereof recognizes an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355.

4. The method of any one of claims 1-3, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof does not compete with 11C7 and / or Ozanezumab for binding toNogo-A.

5. The method of any one of claims 1-4, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof binds a Nogo-A epitope comprising the amino acid sequence ofSEQ ID NO:21 or SEQ ID NO:28.

6. The method of any one of claims 1-5, wherein each dose is about 50 mg.

7. The method of any one of claims 1-5, wherein each dose is about 100 mg.

8. The method of any one of claims 1-5, wherein each dose is about 150 mg.

9. The method of any one of claims 1-5, wherein each dose is about 200 mg.

10. The method of any one of claims 1-5, wherein each dose is about 400 mg.

11. The method of any one of claims 1-5, wherein each dose is about 450 mg.

12. The method of any one of claims 1-11, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is administered at an interval of from 3 days to 7 days between twoconsecutively administered doses.

13. The method of any one of claims 1-12, wherein the first dose is administered on day1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28.

14. The method of any one of claims 1-13, wherein the method comprises sequentiallyadministering to the subject 6 doses of the anti-Nogo-A antibody or antigen-binding fragment thereof within 4 weeks.

15. The method of any one of claims 1-14, wherein each dose is administered as a single-dose injection.

16. The method of any one of claims 1-15, wherein each dose is administered via slowbolus, optionally wherein each dose is administered via slow bolus over about 100 seconds.

17. The method of any one of claims 1-16, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is administered via intrathecal injection.

18. The method of claim 17, wherein the intrathecal injection is administered at thelumbar level.

19. A method for treating a neurological disease in a subject in need thereof, the methodcomprising sequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof within 4 weeks, wherein each dose is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, or about 450 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection, optionally wherein the intrathecal injection is administered at the lumbar level.

20. The method of claim 19, wherein the anti-Nogo-A antibody or antigen-bindingfragment thereof binds Nogo-A- .

21. The method of claim 19 or 20, wherein the anti-Nogo-A antibody or antigen-bindingfragment thereof recognizes an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355.

22. The method of any one of claims 19-21, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof does not compete with 11C7 and / or Ozanezumab forbinding to Nogo-A.

23. The method of any one of claims 19-22, wherein the anti-Nogo-A antibody orantigen-binding fragment thereof binds a Nogo-A epitope comprising the amino acidsequence of SEQ ID NO:21 or SEQ ID NO:28.

24. The method of any one of claims 19-23, wherein each dose is about 50 mg.

25. The method of any one of claims 19-23, wherein each dose is about 100 mg.

26. The method of any one of claims 19-23, wherein each dose is about 150 mg.

27. The method of any one of claims 19-23, wherein each dose is about 200 mg.

28. The method of any one of claims 19-23, wherein each dose is about 400 mg.

29. The method of any one of claims 19-23, wherein each dose is about 450 mg.

30. The method of any one of claims 1-29, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is administered to the subject in a pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) the anti-Nogo-A antibody or antigen-binding fragment thereof, optionallywherein the anti-Nogo-A antibody or antigen-binding fragment thereof is at a concentration of between about 50 mg / ml and about 150 mg / ml;(ii) a buffer, optionally wherein the buffer is at a concentration of between about 1mM and about 50 mM;(iii) a carbohydrate, optionally wherein the carbohydrate is at a concentration ofbetween about 1.0% (w / v) and about 10% (w / v); (iv) a salt, optionally wherein the salt is at a concentration of between about 10mM and about 200 mM; and(v) a surfactant, optionally wherein the surfactant is at a concentration of betweenabout 0.002% (w / v) and about 0.05% (w / v); wherein the pharmaceutical composition has a pH of between about 5.0 and about 7.0.

31. The method of claim 30, wherein the pharmaceutical composition comprises:(i) the anti-Nogo-A antibody or antigen-binding fragment thereof at aconcentration of about 100 mg / ml; (ii) phosphate buffer at a concentration of about 5 mM;(iii) sucrose at a concentration of about 4.2% (w / v);(iv) sodium chloride at a concentration of about 50 mM; and(v) polysorbate 80 at a concentration of about 0.01% (w / v);wherein the pharmaceutical composition has a pH of about 5.8.

32. The method of any one of claims 1-31, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is a recombinant human antibody or an antigen-binding fragment thereof.

33. The method of any one of claims 1-32, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is capable of neutralizing the biological activity of Nogo-A.

34. The method of claim 33, wherein the anti-Nogo-A antibody or antigen-bindingfragment thereof is capable of neutralizing the biological activity of Nogo-A by inducing neurite outgrowth and / or angiogenesis in stroke penumbra.

35. The method of any one of claims 1-34, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a heavychain variable region complementarity determining region 1 (VH-CDR1), a heavy chain variable region complementarity determining region 2 (VH-CDR2), and a heavy chainvariable region complementarity determining region 3 (VH-CDR3) as set forth in a VHcomprising the amino acid sequence of SEQ ID NO:2; and a light chain variable region (VL) comprising a light chain variable region complementarity determining region 1 (VL-CDR1), a light chain variable region complementarity determining region 2 (VL-CDR2), and a lightchain variable region complementarity determining region 3 (VL-CDR3) as set forth in a VLcomprising the amino acid sequence of SEQ ID NO:7.

36. The method of claim 35, wherein the VH-CDR1 comprises the amino acid sequenceof SEQ ID NO:3, the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:4, the VH-CDR3 comprises the amino acid sequence of SEQ ID NO:5, the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:8, the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:9, and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO:10, and wherein the amino acid sequences of the VH-CDR1, VH-CDR2, VH-CDR3, VL- CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition.

37. The method of claim 35 or 36, wherein(i) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:2, or the VL comprises anamino acid sequence at least 80% or at least 90% identical to the amino acidsequence of SEQ ID NO:7; (ii) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:2, and the VL comprisesan amino acid sequence at least 80% or at least 90% identical to the aminoacid sequence of SEQ ID NO:7; or(iii) the VH comprises the amino acid sequence of SEQ ID NO:2 or the VLcomprises the amino acid sequence of SEQ ID NO:7.

38. The method of any one of claims 35-37, wherein the VH comprises the amino acidsequence of SEQ ID NO:2 and the VL comprises the amino acid sequence of SEQ ID NO:7.

39. The method of any one of claims 1-34, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:12; and a VLcomprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising theamino acid sequence of SEQ ID NO:17.

40. The method of claim 39, wherein the VH-CDR1 comprises the amino acid sequenceof SEQ ID NO:13, the VH-CDR2 comprises the amino acid sequence of SEQ ID NO:14, the VH-CDR3 comprises the amino acid sequence of SEQ ID NO:15, the VL-CDR1 comprises the amino acid sequence of SEQ ID NO:18, the VL-CDR2 comprises the amino acid sequence of SEQ ID NO:19, and the VL-CDR3 comprises the amino acid sequence of SEQID NO:20, wherein the amino acid sequences of the VH-CDR1, VH-CDR2, VH-CDR3, VL- CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition.

41. The method of claim 39 or 40, wherein(i) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, or the VL comprisesan amino acid sequence at least 80% or at least 90% identical to the aminoacid sequence of SEQ ID NO:17; (ii) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, and the VL comprisesan amino acid sequence at least 80% or at least 90% identical to the aminoacid sequence of SEQ ID NO:17; or(iii) the VH comprises the amino acid sequence of SEQ ID NO:12 or the VLcomprises the amino acid sequence of SEQ ID NO:17.

42. The method of any one of claims 39-41, wherein the VH comprises the amino acidsequence of SEQ ID NO:12 and the VL comprises the amino acid sequence of SEQ IDNO:17.

43. The method of any one of claims 1-42, wherein the anti-Nogo-A antibody comprises aheavy chain constant region, wherein the heavy chain constant region is of human IgG4 type.

44. The method of claim 43, wherein the heavy chain constant region comprises an aminoacid substitution S228P (numbering according to EU numbering) relative to the amino acid sequence of SEQ ID NO:26.

45. The method of any one of claims 1-44, wherein the anti-Nogo-A antibody comprises ahuman kappa light chain constant region.

46. The method of any one of claims 1-38 and 43-45, wherein the anti-Nogo-A antibodycomprises (i) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 or a light chain comprising an amino acid sequence at least 80% or at least 90% identical tothe amino acid sequence of SEQ ID NO:25;(ii) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 and a light chain comprising an amino acid sequence at least 80% or at least 90% identical tothe amino acid sequence of SEQ ID NO:25.; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:23 or alight chain comprising the amino acid sequence of SEQ ID NO:25.

47. The method of claim 46, wherein the heavy chain comprises the amino acid sequenceof SEQ ID NO:23 and the light chain comprises the amino acid sequence of SEQ ID NO:25.

48. The method of any one of claims 1-38 and 43-47, wherein the anti-Nogo-A antibodycomprises a first and a second heavy chain each comprising the amino acid sequence of SEQID NO:23 and a first and a second light chains each comprising the amino acid sequence ofSEQ ID NO:25.

49. The method of claim 48, wherein disulfide bridges are formed(i) between C134 of the first heavy chain and C220 of the first light chain,between C134 of the second heavy chain and C220 of the second light chain,between C226 of the first heavy chain and C226 of the second heavy chain,and between C229 of the first heavy chain and C229 of the second heavy chain; or (ii) between C134 of the first heavy chain and C220 of the first light chain,between C134 of the second heavy chain and C220 of the second light chain, between C226 of the first heavy chain and C229 of the second heavy chain, and between C229 of the first heavy chain and C226 of the second heavy chain, wherein the amino acid numberings are based on EU numbering.

50. The method of any one of claims 46-49, wherein the heavy chain comprises an N-linked glycan site at amino acid residue N297 (numbering according to EU numbering).

51. The method of any one of claims 1-50, wherein the neurological disorder is a traumaof peripheral nervous system (PNS) or central nervous system (CNS).

52. The method of claim 51, wherein the neurological disorder is a cranial trauma, acerebral trauma, a spinal trauma, a brain trauma, or a stroke.

53. The method of claim 52, wherein the neurological disorder is a spinal cord injury(SCI).

54. The method of claim 53, wherein the SCI is an acute SCI, a cervical SCI, an acutecervical SCI, an incomplete cervical SCI, or an acute incomplete cervical SCI.

55. The method of any one of claims 1-50, wherein the neurological disorder is aneurodegenerative disease, optionally wherein the neurodegenerative disease is selected from the group consisting of Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis(ALS), Lewy like pathologies, and dementia.

56. The method of any one of claims 1-50, wherein the neurological disorder is ademyelinating disease or an ophthalmologic disease, optionally wherein the ophthalmologic disease is selected from the group consisting of diabetic retinopathy, diabetic macular edema, and wet and dry age-related macular degeneration (AMD).

57. A method for treating a neurological disorder in a subject in need thereof, the methodcomprising sequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof within 4 weeks, wherein each dose is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, or about 450 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection, optionally wherein the intrathecal injection is administered at the lumbar level; wherein the anti-Nogo-A antibody or antigen-binding fragment thereof comprises aVH and a VL, wherein (a) the VH comprises a VH-CDR1 comprising the amino acidsequence of SEQ ID NO:3, a VH-CDR2 comprising the amino acid sequence of SEQ IDNO:4, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:5; and (b) the VLcomprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VL-CDR2comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising theamino acid sequence of SEQ ID NO:10, wherein the amino acid sequences of the VH-CDR1,VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition.

58. The method of claim 57, wherein the neurological disorder is a spinal cord injury(SCI).

59. The method of claim 58, wherein the SCI is an acute SCI, a cervical SCI, an acutecervical SCI, an incomplete cervical SCI, or an acute incomplete cervical SCI.

60. The method of any one of claims 57-59, wherein(i) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, or the VL comprises an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:17; (ii) the VH comprises an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:12, and the VL comprises an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:17; or (iii) the VH comprises the amino acid sequence of SEQ ID NO:12 or the VLcomprises the amino acid sequence of SEQ ID NO:17.

61. The method of any one of claims 57-60, wherein the VH comprises the amino acidsequence of SEQ ID NO:12 and the VL comprises the amino acid sequence of SEQ ID NO:17.

62. The method of any one of claims 57-61, wherein the anti-Nogo-A antibody comprises(i) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 or a light chain comprising an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:25;(ii) a heavy chain comprising an amino acid sequence at least 80% or at least 90%identical to the amino acid sequence of SEQ ID NO:23 and a light chain comprising an amino acid sequence at least 80% or at least 90% identical to the amino acid sequence of SEQ ID NO:25.; or(iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:23 or alight chain comprising the amino acid sequence of SEQ ID NO:25.

63. The method of claim 62, wherein the heavy chain comprises the amino acid sequenceof SEQ ID NO:23 and the light chain comprises the amino acid sequence of SEQ ID NO:25.

64. The method of any one of claims 57-63, wherein the anti-Nogo-A antibody comprisesa first and a second heavy chain each comprising the amino acid sequence of SEQ ID NO:23 and a first and a second light chains each comprising the amino acid sequence of SEQ ID NO:25.

65. The method of any one of claims 57-64, wherein each dose is about 50 mg.

66. The method of any one of claims 57-64, wherein each dose is about 100 mg.

67. The method of any one of claims 57-64, wherein each dose is about 150 mg.

68. The method of any one of claims 57-64, wherein each dose is about 200 mg.

69. The method of any one of claims 57-64, wherein each dose is about 400 mg.

70. The method of any one of claims 57-64, wherein each dose is about 450 mg.

71. The method of any one of claims 1-70, wherein the neurological disease is a SCI notat the lumbar level and the anti-Nogo-A antibody or antigen-binding fragment thereof isadministered to the subject via intrathecal injection at the lumbar level.

72. The method of any one of claims 1-71, wherein the SCI is an injury at C1-C8 leveland the anti-Nogo-A antibody or antigen-binding fragment thereof is administered to thesubject via intrathecal injection at L1-L5 level.

73. An anti-Nogo-A antibody or an antigen-binding fragment thereof for use in treating aneurological disorder in a subject in need thereof, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is to be administered to the subject in at least two doses sequentially, wherein each of the at least two doses is between about 50 mg and about 450 mg; optionally wherein the anti-Nogo-A antibody or antigen-binding fragment thereof: (i) binds Nogo-A-(ii) recognizes an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355; (iii) does not compete with 11C7 and / or Ozanezumab for binding to Nogo-A;and / or (iv) binds a Nogo-A epitope comprising the amino acid sequence of SEQ IDNO:21 or SEQ ID NO:28.

74. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toclaim 73, wherein administration is performed as defined in any one of claims 12-18.

75. An anti-Nogo-A antibody or an antigen-binding fragment thereof for use in a methodof treating a neurological disease in a subject in need thereof, wherein the method comprisessequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen-binding fragment thereof within 4 weeks, wherein each dose is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, or about 450 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection, optionally wherein the intrathecal injection is administered at the lumbar level; optionally wherein the anti-Nogo-A antibody or antigen-binding fragment thereof: (i) binds Nogo-A-(ii) recognizes an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355; (iii) does not compete with 11C7 and / or Ozanezumab for binding to Nogo-A; and / or (iv) binds a Nogo-A epitope comprising the amino acid sequence of SEQ ID NO:21 or SEQ ID NO:28.

76. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toany one of claims 73-75, wherein each dose is the dose as defined in any one of claims 6-11.

77. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toany one of claims 73-76, wherein the anti-Nogo-A antibody or antigen-binding fragmentthereof is administered to the subject in a pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) the anti-Nogo-A antibody or antigen-binding fragment thereof, optionally whereinthe anti-Nogo-A antibody or antigen-binding fragment thereof is at a concentration of between about 50 mg / ml and about 150 mg / ml; (ii) a buffer, optionally wherein the buffer is at a concentration of between about 1 mM and about 50 mM; (iii) a carbohydrate, optionally wherein the carbohydrate is at a concentration ofbetween about 1.0% (w / v) and about 10% (w / v); (iv) a salt, optionally wherein the salt is at a concentration of between about 10 mM and about 200 mM; and (v) a surfactant, optionally wherein the surfactant is at a concentration of between about 0.002% (w / v) and about 0.05% (w / v); wherein the pharmaceutical composition has a pH of between about 5.0 and about 7.0.

78. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toclaim 77, wherein the pharmaceutical composition comprises: (i) the anti-Nogo-A antibody or antigen-binding fragment thereof at a concentration ofabout 100 mg / ml; (ii) phosphate buffer at a concentration of about 5 mM; (iii) sucrose at a concentration of about 4.2% (w / v); (iv) sodium chloride at a concentration of about 50 mM; and (v) polysorbate 80 at a concentration of about 0.01% (w / v); wherein the pharmaceutical composition has a pH of about 5.8.

79. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toany one of claims 73-78, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is the antibody or antigen-binding fragment thereof as defined in any one of claims 32-50.

80. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toany one of claims 73-79, wherein the neurological disease or disorder is a disease or disorderas defined in any one of claims 51-56.

81. An anti-Nogo-A antibody or an antigen-binding fragment thereof for use in a methodof treating a neurological disorder in a subject in need thereof, the method comprising sequentially administering to the subject 6 doses of an anti-Nogo-A antibody or an antigen- binding fragment thereof within 4 weeks, wherein each dose is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 400 mg, or about 450 mg; wherein the first dose is administered on day 1, the second dose is administered between day 4 and day 8, the third dose is administered between day 9 and day 13, the fourth dose is administered between day 14 and day 18, the fifth dose is administered between day 19 and day 23, and the sixth dose is administered between day 24 and day 28, and each dose is administered as a single-dose injection via intrathecal injection, optionally wherein the intrathecal injection is administered at the lumbar level; wherein the anti-Nogo-A antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein (a) the VH comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:4, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:5; and (b) the VL comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:10, wherein the amino acid sequences of the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are determined by Kabat definition.

82. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toclaim 81, wherein the neurological disorder is a spinal cord injury (SCI), optionally whereinthe SCI is an acute SCI, an incomplete cervical SCI, or an acute incomplete cervical SCI.

83. The anti-Nogo-A antibody or antigen-binding fragment thereof for use according toclaim 81 or 82, wherein the antibody or antigen-binding fragment thereof is the antibody orantigen-binding fragment thereof as defined in any one of claims 60-64.

84. Use of an anti-Nogo-A antibody or an antigen-binding fragment thereof in themanufacture of a medicament for the treatment of a neurological disorder in a subject in need thereof, wherein the anti-Nogo-A antibody or antigen-binding fragment thereof is to be administered to the subject in at least two doses sequentially, wherein each of the at least twodoses is between about 50 mg and about 450 mg; optionally wherein the anti-Nogo-A antibody or antigen-binding fragment thereof: (i) binds Nogo-A-(ii) recognizes an epitope that is different from the binding epitope of anti-Nogo-A antibodies 11C7, Ozanezumab, and / or ATI355; (iii) does not compete with 11C7 and / or Ozanezumab for binding to Nogo-A;and / or (iv) binds a Nogo-A epitope comprising the amino acid sequence of SEQ IDNO:21 or SEQ ID NO:28.

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