WO2024041450A1 - Antibody for specifically recognizing nogo-a and use thereof - Google Patents

Antibody for specifically recognizing nogo-a and use thereof Download PDF

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WO2024041450A1
WO2024041450A1 PCT/CN2023/113657 CN2023113657W WO2024041450A1 WO 2024041450 A1 WO2024041450 A1 WO 2024041450A1 CN 2023113657 W CN2023113657 W CN 2023113657W WO 2024041450 A1 WO2024041450 A1 WO 2024041450A1
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amino acid
acid sequence
sequence seq
seq
nogo
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PCT/CN2023/113657
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French (fr)
Chinese (zh)
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张帅
刘洪洋
刘俊勇
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舒泰神（北京）生物制药股份有限公司
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Publication of WO2024041450A1 publication Critical patent/WO2024041450A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators

Definitions

  • the present invention relates to antibodies that specifically recognize NogoA, preparation methods and uses thereof, including methods of using them to treat diseases and/or conditions caused by disorders of the Nogo-A signaling pathway, such as central nervous system and/or peripheral nervous system diseases or trauma. .
  • central nervous system After central nervous system (CNS) injury in adults, nerve regeneration is limited due to the presence of an inhibitory myelin environment that coats axons and the formation of scar tissue. Studies have shown that factors that inhibit nerve growth largely affect the regeneration capacity of the adult central nervous system after injury. These factors play an important role in stabilizing the complex wiring of the central nervous system of adult higher vertebrates and establishing neuronal pathways in nervous system development (Akbik FV et al. Exp Neurol. 2012.; Schwab ME.te al. Nat Rev Neurosci .2010.), molecules including Nogo-A, myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein (OMGP) have been described as potent neurite inhibitory factors.
  • MAG myelin-associated glycoprotein
  • OMGP myelin oligodendrocyte glycoprotein
  • Nogo-A a member of the serosal protein family, which occurs in myelin and certain neurons and inhibits axon regeneration and plasticity after central nervous system injury (Filbin at al. Nat Rev Neurosci. 2003 ; Yiu G et al. Nat Rev Neurosci. 2006).
  • Nogo-A exerts its inhibitory activity through two different extracellular domains, Nogo-A- ⁇ 20 (mouse aa544-725) and Nogo-66 (mouse aa1026-1091) (Schwab ME et al., Nat Rev Neurosci). Anissa Kempf et al.
  • GPCR G protein-coupled receptor
  • S1PR2 sphingosine 1-phosphate receptor 2
  • Nogo-A binds to the receptor NgR1 through its inhibitory Nogo-66 domain and forms a complex with the transmembrane protein LINGO1, p75 or TROY, thereby inhibiting neurite growth.
  • This binding leads to an increase in intracellular Ca 2+ through an unknown intermediate and the activation of the Rho-related protein kinase (ROCK) signaling pathway (Nash M et al., Mol Neurobiol, 2009; Fournier AE et al., J. Neurosci. 2003).
  • RhoA signaling Through RhoA signaling, the actin cytoskeleton is destabilized, leading to growth cone collapse (Hsieh et al., J. Neurosci, 2006; Montani, L et al., J. Biol. Chem, 2009).
  • Nogo-66 also interacts with accessory proteins and paired immunoglobulin-like receptor B (PIRB) (Atwal JK et al., Science. 2008) to induce growth inhibition.
  • Nogo-A is mainly expressed in the nervous system and has three different expression windows during development (Huber et al., Trends Cell Biol, 2007; Wang, X et al., J. Neurosci. 2002.).
  • Nogo-A is predominantly expressed in oligodendrocytes.
  • Nogo-A a cell type in the peripheral nervous system (Schwann cells) does not express Nogo-A (Huber et al., J. Neurosci, 2002). Outside the central nervous system, Nogo-A is expressed in developing skin, skeletal muscle during differentiation, and heart. Heart tissue from adult rats, mice and humans, as well as certain immune cells in mice and humans, especially macrophages, express Nogo-A and components of the Nogo receptor complex such as NgR1.
  • Nogo-A-deficient mice the inhibitory effect of spinal cord extracts on neurite growth in the deficient mice was reduced.
  • CST corticospinal tract
  • This study shows that systemic deletion of the myelin-associated growth inhibitor Nogo-A can improve regeneration and plasticity responses after spinal cord injury (M Simonen et al., Neuron, 2003). Additionally, neutralizing Nogo-A has been shown to promote axonal growth and compensatory sprouting in the adult spinal cord and brain and improve functional recovery after central nervous system injury (Schwab ME et al.
  • Nogo-A signaling plays a new important role in inhibiting synaptic plasticity in mature neuronal networks, suggesting that the inhibitory potential of Nogo-A far exceeds its already studied limitation on axonal growth (Kempf A et al. PLoS Biol. 2014.; Delekate et al. Proc Natl Acad Sci. 2011.; Tews B et al. Proc Natl Acad Sci. 2013.).
  • Nogo-A regulates the migration of neural precursors in the mouse embryonic cortex.
  • Patent application WO2004052932A2 discloses a monoclonal antibody or fragment thereof that binds human Nogo-A polypeptide, and the use of these antibodies to treat diseases related to nerve repair.
  • WO2009056509A1 discloses a monoclonal antibody of human Nogo-A polypeptide or a fragment thereof, as well as the use of such binding molecules as drugs, especially in the treatment of peripheral and/or central nervous system diseases.
  • Nogo-A-mediated diseases or conditions such as central nervous system injury and/or repair, spinal cord injury, Alzheimer's disease Alzheimer's disease and other diseases.
  • an isolated anti-Nogo-A antibody comprising a heavy chain variable domain (V H ), the V H comprising: heavy chain complementarity determining region (HC-CDR) 1 comprising DYGMH (SEQ ID NO: 1); HC-CDR2 comprising SISHTGKTVFYGESVKG (SEQ ID NO: 3); and HC-CDR3 comprising TELGGDNWFDV (SEQ ID NO: 5); and light chain variable domain (V L ) , the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes TGSSSNIGGYDVY (SEQ ID NO: 7); LC-CDR2, which includes DNKRPS (SEQ ID NO: 9); and LC-CDR3, It contains AAWDDSLYGYI (SEQ ID NO: 11).
  • an isolated anti-Nogo-A antibody which includes VH , and the VH includes: HC-CDR1, which includes the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, wherein The variants comprise substitutions of up to about 3 amino acids; HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 3 or a variant thereof, the variants comprising substitutions of up to about 3 amino acids; and HC-CDR3 , which comprises the amino acid sequence shown in SEQ ID NO: 5 or a variant thereof, said variant comprising a substitution of up to about 3 amino acids; and V L , said V L comprising: LC-CDR1, which comprises SEQ ID NO : The amino acid sequence shown in SEQ ID NO: 9 or a variant thereof, the variant comprising a substitution of at most about 3 amino acids; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 9 or a variant thereof, the variant Comprised of substitutions of up to about 3 amino acids
  • an isolated anti-Nogo-A antibody comprising: VH , the VH comprising a VH comprising HC- as shown in any of the amino acid sequences of SEQ ID NOs: 13-16 CDR1, HC- CDR2 and HC-CDR3, and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in any one of the amino acid sequences of SEQ ID NOs: 18-19 .
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 13 and HC-CDR3; and V L comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by V L as shown in the amino acid sequence SEQ ID NO: 18; (ii) V H comprising the amino acid sequence SEQ V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in ID NO :14; and V L comprising LC-CDR1, LC- CDR2 and LC-CDR3; (iii) VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence SEQ ID NO: 15; and VL comprising the amino acid sequence as shown LC-CDR1, LC-CDR2 and LC-C
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2, It contains the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which contains the amino acid sequence SEQ ID NO: 5, or a variant of the V H containing up to about 5 amino acids in its HC-CDRs.
  • the VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence SEQ ID NO:9, and LC-CDR3, which includes The amino acid sequence SEQ ID NO: 11, or a variant of said V L , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • any of the isolated anti-Nogo-A antibodies as described above which includes: VH , which includes the amino acid sequence shown in any one of SEQ ID NOs: 13-16 or a variant thereof, said A variant having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 13-16; and a VL comprising an amino acid sequence set forth in any one of SEQ ID NOs: 18-19 or a V L thereof Variants having at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 18-19.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO: 13 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 18 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 18; (ii ) V H comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 14; and V L comprising the amino acid sequence SEQ ID NO : 19 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 19; (iii) V H comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof, the A variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 15; and a V L comprising the amino acid sequence SEQ ID NO
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 17 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO:20.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 2, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 6, or a variant of said V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 8, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 10, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 12 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • any of the isolated anti-Nogo-A antibodies as described above includes: VH , which includes the amino acid sequence shown in SEQ ID NO: 17 or a variant thereof, which variant is identical to SEQ ID NO.
  • the amino acid sequence shown in NO:17 has at least about 80% sequence identity; and
  • VL which includes the amino acid sequence shown in SEQ ID NO:20 or a variant thereof, which is identical to the amino acid sequence shown in SEQ ID NO:20
  • the amino acid sequences have at least about 80% sequence identity.
  • an isolated anti-Nogo-A antibody comprising a heavy chain variable domain ( VH ), the VH comprising: heavy chain complementarity determining region (HC-CDR) 1 comprising SYGMH (SEQ ID NO:28); HC-CDR2, which contains VIWYHGSKKYYADSVKD (SEQ ID NO:48); and HC-CDR3, which contains SIAETTDYGLDS (SEQ ID NO: 65); and a light chain variable domain (V L ), the V L comprising: light chain complementarity determining region (LC-CDR) 1, which includes RSSQSLLYRGGKTFLY (SEQ ID NO: 85); LC-CDR2, It contains ELSNRAS (SEQ ID NO:100); and LC-CDR3, which contains MQGIQLPWT (SEQ ID NO:111).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • HC-CDR2 heavy chain complementarity determining region comprising SYGMH (SEQ ID
  • an isolated anti-Nogo-A antibody comprising a V H comprising: HC- CDR1 comprising the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof, wherein The variants comprise substitutions of up to about 3 amino acids; HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 48 or a variant thereof, the variants comprising substitutions of up to about 3 amino acids; and HC-CDR3 , which comprises the amino acid sequence set forth in SEQ ID NO: 65 or a variant thereof, said variant comprising a substitution of up to about 3 amino acids; and V L , said V L comprising: LC-CDR1, which comprises SEQ ID NO : The amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, the variant comprising a substitution of at most about 3 amino acids; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, the variant Comprising a substitution of up to about 3 amino acids;
  • an isolated anti-Nogo-A antibody comprising: VH , the VH comprising a VH comprising HC- as shown in any one of the amino acid sequences of SEQ ID NOs: 127-128 CDR1, HC-CDR2 and HC-CDR3, and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in any one of the amino acid sequences of SEQ ID NOs : 150-151 .
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 127 and HC-CDR3; and V L comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by V L as set forth in the amino acid sequence SEQ ID NO: 150; (ii) V H comprising the amino acid sequence SEQ V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in ID NO : 128; and V L comprising LC-CDR1, LC- as shown in amino acid sequence SEQ ID NO: 151.
  • VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence SEQ ID NO: 128 of VH ; and VL comprising the amino acid sequence VL shown in SEQ ID NO:150 contains LC-CDR1, LC-CDR2 and LC-CDR3.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 28, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 48, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 65, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 85, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 100, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 111 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • any of the isolated anti-Nogo-A antibodies as described above which includes: VH , which includes the amino acid sequence shown in any one of SEQ ID NOs: 127-128 or a variant thereof, said A variant having at least about 80% sequence identity with the amino acid sequence set forth in any of SEQ ID NOs: 127-128; and a VL comprising the amino acid sequence set forth in any of SEQ ID NOs: 150-151 or its Variants having at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 150-151.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 127 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO: 127 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 150 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 150; (ii ) V H comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 128; and V L comprising the amino acid sequence SEQ ID NO :151 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:151; (iii) V H comprising the amino acid sequence SEQ ID NO:128 or a variant thereof, the A variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 128; and a V L comprising the amino acid sequence SEQ ID NO
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 129 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 152.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 29, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 49, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 66, or a variant of the V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 86, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 101, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 112 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • any of the isolated anti-Nogo-A antibodies as described above includes: VH , which includes the amino acid sequence shown in SEQ ID NO: 129 or a variant thereof, which variant is identical to SEQ ID NO.
  • the amino acid sequence shown in NO:129 has at least about 80% sequence identity; and
  • VL which includes the amino acid sequence shown in SEQ ID NO:152 or a variant thereof, which is identical to the amino acid sequence shown in SEQ ID NO:152
  • the amino acid sequences have at least about 80% sequence identity.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 130 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 153.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 30, HC-CDR2, It includes the amino acid sequence SEQ ID NO: 50, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 67, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 87, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 102, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 113 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :130 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 153 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 153.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 131 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 154.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 68, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :131 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:154 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:154.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 132 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 155.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 32, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 69, or a variant of the V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :132 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:155 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:155.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 133 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 156.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 33, HC-CDR2, It contains the amino acid sequence SEQ ID NO: 52, and HC-CDR3, which contains the amino acid sequence SEQ ID NO: 70, or a variant of the V H containing up to about 5 in its HC-CDRs substitutions of amino acids; and V L comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 89, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 104, and LC-CDR3 comprising The amino acid sequence SEQ ID NO: 115, or a variant of the V L containing up to about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :133 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:156 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:156.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 134 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 157.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 34, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 71, or a variant of the V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :134 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:157 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:157.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 135. and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 158.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 35, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 54, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 72, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 90, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 105, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 116 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :135 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:158 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:158.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 136 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 159.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 36, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 55, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 73, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 91, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 117 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :136 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 137 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 159.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 37, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 56, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 74, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 91, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 117 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :137 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 138 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 160.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 57, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 75, or a variant of the V H comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 92, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 107, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 118, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :138 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:160 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:160.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 139 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 161.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 38, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 58, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 76, or a variant of said V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 93, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 108, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 119 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :139 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:161 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:161.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 140 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 162.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 39, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 77, or a variant of said V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 120 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :140 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:162 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:162.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 141 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 163.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 40, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 59, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 78, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 94, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 121 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 141 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :141 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:163 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:163.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 142 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 164.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 41, HC-CDR2, It includes the amino acid sequence SEQ ID NO: 60, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 79, or a variant of the V H , including up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :142 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:164 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:164.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 143 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 165.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 42, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 120, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :143 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:165 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:165.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 144 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 166.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2, It includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81, or a variant of the V H , including up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 95, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 122 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :144 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:166 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:166.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 145 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 167.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 44, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 62, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 82, or a variant of the V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 96, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 110, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 123 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :145 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:167 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:167.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 146 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 168.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 45, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 63, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 83, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 97, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 124 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :146 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:168 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:168.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 147 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 169.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 46, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 98, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :147 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:169 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:169.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 148 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 170.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 47, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 64, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 84, or a variant of said V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 99, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 125, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :148 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:170 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:170.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 149 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 171.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2, It includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81, or a variant of the V H , including up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 95, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 126 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • an isolated anti-Nogo-A antibody comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :149 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:171 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:171.
  • the isolated anti-Nogo-A antibody binds to human Nogo-A with a Kd value of 0.1 pM to about 10 nM.
  • an isolated anti-Nogo-A antibody is provided that competes with any of the above-described isolated anti-Nogo-A antibodies for specific binding to Nogo-A. In some embodiments, an isolated anti-Nogo-A antibody is provided that specifically binds to the same epitope as any of the isolated anti-Nogo-A antibodies described above.
  • any of the isolated anti-Nogo-A antibodies described above, the isolated anti-Nogo-A antibody comprises an Fc fragment.
  • the isolated anti-Nogo-A antibody is a full-length IgG antibody.
  • the isolated anti-Nogo-A antibody is a full-length IgGl, IgG2, IgG3 or IgG4 antibody.
  • the isolated anti-Nogo-A antibody is a chimeric, fully human, or humanized antibody.
  • the isolated anti-Nogo-A antibody is an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab)' 2 , Fab'-SH, single chain Fv (scFv) , Fv fragments, dAb, Fd, nanobodies, diabodies and linear antibodies.
  • an isolated nucleic acid molecule encoding any of the anti-Nogo-A antibodies described above is provided.
  • a vector is provided comprising any of the nucleic acid molecules described above.
  • a host cell is provided, the host cell comprising any one of the anti-Nogo-A antibodies described above, any one of the nucleic acid molecules described above, or any one of the vectors described above.
  • a method of preparing an anti-Nogo-A antibody comprising: a) Cultivate any of the above host cells under conditions that can effectively express anti-Nogo-A antibodies; and b) obtain expressed anti-Nogo-A antibodies from the host cells.
  • a method of treating a disease or condition in a desired individual comprising administering to the individual an effective amount of any of the anti-Nogo-A antibodies described above.
  • provided is the use of any of the anti-Nogo-A antibodies described above in the preparation of a pharmaceutical composition for treating a disease or condition in a desired individual.
  • the use of any of the anti-Nogo-A antibodies described above or a pharmaceutical composition comprising an anti-Nogo-A antibody in the preparation of a medicament for treating a disease or condition is provided.
  • the disease or disorder is associated with the Nogo-A signaling pathway, including central nervous system and/or peripheral nervous system disease or trauma or disorder.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), ischemic
  • compositions, kits and manufactured products containing any of the anti-Nogo-A antibodies mentioned above are also provided.
  • Figure 1 shows the binding affinity of anti-Nogo-A antibody to hNiG analyzed by ELISA.
  • Figure 1A shows the binding affinity of exemplary antibody mkNG-22 to hNiG analyzed by ELISA.
  • Figure 1B shows the binding affinity of exemplary antibodies L82, H-L82-1, H-L82-2, and H-L82-3 to hNiG analyzed by ELISA.
  • Figure 2 shows the inhibitory activity of anti-Nogo-A antibodies on the binding of hNiG to Nogo-A receptors on the cell membrane surface analyzed by ELISA.
  • Figure 2A shows the inhibitory activity of exemplary antibodies L82, H-L82-1, H-L82-2 and H-L82-3 on the binding of hNiG and Nogo-A receptors on PC12 cell membranes analyzed by ELISA.
  • Figure 2B shows the inhibitory activity of exemplary antibodies L82, H-L82-1, H-L82-2 and H-L82-3 on the binding of hNiG and Nogo-A receptors on 3T3 cell membranes analyzed by ELISA.
  • Figure 3 shows the cross-binding activity of anti-Nogo-A antibodies analyzed by FACS with Nogo-A of different species including humans, rhesus monkeys, rats and mice.
  • Figure 3A shows the binding activity of anti-Nogo-A antibodies mkNG-22, L82, H-L82-1, H-L82-2 and H-L82-3 to human Nogo-A analyzed by FACS.
  • Figure 3B shows the cross-binding activity of anti-Nogo-A antibodies mkNG-22, L82, H-L82-1, H-L82-2 and H-L82-3 with rhesus monkey Nogo-A analyzed by FACS.
  • Figure 3C shows the cross-binding activity of anti-Nogo-A antibodies mkNG-22, L82, H-L82-1, H-L82-2 and H-L82-3 with rat Nogo-A analyzed by FACS.
  • Figure 3D shows the cross-binding activity of anti-Nogo-A antibodies mkNG-22, L82, H-L82-1, H-L82-2 and H-L82-3 with mouse Nogo-A analyzed by FACS.
  • Figure 4 shows the relative fluorescence quantitative PCR analysis of the effects of anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 on Nogo-A's inhibition of GAP-43 transcription levels. Blocking activity.
  • Figure 5 shows the recovery effect of anti-Nogo-A antibody on hNiG-inhibited neurite growth of N1E-115 cells.
  • Figure 5A shows the restoration effect of anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 on hNiG-inhibited N1E-115 cell neurite growth morphology observed under a microscope.
  • Figure 5B shows the quantitative analysis of the restoration effect of anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 on the proportion of hNiG-inhibited neurite growth of N1E-115 cells.
  • Figure 5C shows the quantitative analysis of the restoration effect of anti-Nogo-A antibody mkNG-362 on the proportion of hNiG inhibiting neurite growth of N1E-115 cells.
  • Figure 6 shows the recovery effect of anti-Nogo-A antibody on the inhibition of neurite growth of N1E-115 cells by monkey spinal cord extract.
  • Figure 6A shows the inhibition of N1E-115 cell neurite growth morphology by anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 on monkey spinal cord extracts observed under a microscope. restorative effect.
  • Figure 6B shows the quantitative analysis of anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 inhibiting the neurite growth morphology of N1E-115 cells in monkey spinal cord extracts. The restorative effect of proportion.
  • Figure 6C shows the quantitative analysis of the restoration effect of exemplary anti-Nogo-A antibodies mkNG-360 and mkNG-362 on the proportion of hNiG inhibiting neurite growth of PC12 cells.
  • Figure 7 shows that exemplary anti-Nogo-A antibody H-L82-3 has the effect of treating spinal cord injury in a mouse model of spinal cord injury.
  • the present application provides anti-Nogo-A antibody molecules.
  • scFv antibody yeast library screening scFv phage library screening
  • CHO-IgG antibody display library screening humanization, affinity maturation, and appropriately designed biochemical and biological experiments.
  • individuals capable of binding to and inhibiting human Nogo-A have been identified
  • a highly effective antibody molecule that interacts with human Nogo-A and its receptor The results presented here demonstrate that the antibody in this application binds Nogo-A compared to the known anti-Nogo-A antibodies ATI-355, or 11C7 (Novartis), and surprisingly, in various biological experiments The antibody in this application was demonstrated to be even more effective than ATI-355.
  • Anti-Nogo-A antibodies provided by the application include, for example, full-length anti-Nogo-A antibodies, anti-Nogo-A single chain antibodies (scFvs), anti-Nogo-A Fc fusion proteins, multispecific (such as bispecific) Anti-Nogo-A antibodies, anti-Nogo-A immunoconjugates, and the like.
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYGMH (SEQ ID NO: 1); HC-CDR2, which includes SISHTGKTVFYGESVKG (SEQ ID NO: 3); and HC-CDR3, which includes TELGGDNWFDV (SEQ ID NO: 5); and the light chain variable domain and _ LC-CDR3 containing AAWDDSLYGYI (SEQ ID NO: 11).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • HC-CDR2 which includes DYGMH (SEQ ID NO: 1)
  • HC-CDR2 which includes SISHTGKTVFYGESVKG
  • HC-CDR3 which includes TELGGDNWFDV (SEQ ID NO: 5)
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SHGMN (SEQ ID NO:2); HC-CDR2, which includes YISNGGDSTYYADSVKG (SEQ ID NO:4); and HC-CDR3, which includes TFSH (SEQ ID NO:6); and the light chain variable domain (V L ), the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes RSSQSLLHSNGNTYLH (SEQ ID NO:8); LC-CDR2, which contains GGSNRAS (SEQ ID NO:10); and LC-CDR3, which contains VQAIAFPYS (SEQ ID NO:12).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SYGMH (SEQ ID NO:28); HC-CDR2, which includes VIWYHGSKKYYADSVKD (SEQ ID NO:48); and HC-CDR3, which includes SIAETTDYGLDS (SEQ ID NO:65); and light chain variable domains and _ LC-CDR3 comprising MQGIQLPWT (SEQ ID NO: 111).
  • VH heavy chain variable domain
  • HC-CDR2 which includes VIWYHGSKKYYADSVKD
  • HC-CDR3 which includes SIAETTDYGLDS (SEQ ID NO:65)
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DHYMD (SEQ ID NO:29); HC-CDR2, which includes FIRNKAKGGTTEYAASVKG (SEQ ID NO:49); and HC-CDR3, which includes LYGAYY (SEQ ID NO:66); and the light chain variable domain and _ LC-CDR3 comprising QQYNSAPPT (SEQ ID NO: 112).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • HC-CDR2 which includes FIRNKAKGGTTEYAASVKG
  • HC-CDR3 which includes LYGAYY (SEQ ID NO:66)
  • the light chain variable domain and _ LC-CDR3 comprising QQYNSAPPT (SEQ ID NO: 112).
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYAMS (SEQ ID NO:30); HC-CDR2, which includes YIRTKSHNSAAEYAASVKG (SEQ ID NO:50); and HC-CDR3, which includes VGGY (SEQ ID NO:67); and the light chain variable domain and _ LC-CDR3 comprising GQGAHFPFT (SEQ ID NO: 113).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • HC-CDR2 which includes DYAMS (SEQ ID NO:30)
  • HC-CDR2 which includes YIRTKSHNSAAEYAASVKG
  • HC-CDR3 which includes VGGY (SEQ ID NO:67)
  • the light chain variable domain and _ LC-CDR3
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYMQ (SEQ ID NO:31); HC-CDR2, which includes RINPKTGGTNYAQKFQG (SEQ ID NO:51); and HC-CDR3, which includes GSAAVRD (SEQ ID NO:68); and light chain variable domain and _ LC-CDR3 containing QQYYSTPLT (SEQ ID NO: 114).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • HC-CDR2 which includes DYYMQ
  • HC-CDR2 which includes RINPKTGGTNYAQKFQG
  • HC-CDR3 which includes GSAAVRD (SEQ ID NO:68)
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes NYYIQ (SEQ ID NO:32); HC-CDR2, which includes RINPKTGGTNYAQKFQG (SEQ ID NO:51); and HC-CDR3, which includes GAAAAY (SEQ ID NO:69); and the light chain variable domain and _ LC-CDR3 containing QQYYSTPLT (SEQ ID NO: 114).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • HC-CDR2 which includes NYYIQ
  • HC-CDR2 which includes RINPKTGGTNYAQKFQG
  • HC-CDR3 which includes GAAAAY (SEQ ID NO:69)
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which contains NYDIH (SEQ ID NO:33); HC-CDR2, It includes LVRNKANTYTTEYAAAVKG (SEQ ID NO:52); and HC-CDR3, which includes PGTYSGSLDV (SEQ ID NO:70); and a light chain variable domain ( VL ), which VL includes: a light chain complementarity determining region (LC-CDR)1, which contains RASQGIINYLA (SEQ ID NO:89); LC-CDR2, which contains KASTLQS (SEQ ID NO:104); and LC-CDR3, which contains QQHNSYPLT (SEQ ID NO:115).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • HC-CDR2 contains NYDI
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYIQ (SEQ ID NO:34); HC-CDR2, which includes RINPRTGGTNYAQKFQG (SEQ ID NO:53); and HC-CDR3, which includes GAAAVSY (SEQ ID NO:71); and the light chain variable domain and _ LC-CDR3 containing QQYYSTPLT (SEQ ID NO: 114).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • HC-CDR2 which includes DYYIQ (SEQ ID NO:34)
  • HC-CDR2 which includes RINPRTGGTNYAQKFQG
  • HC-CDR3 which includes GAAAVSY (SEQ ID NO:71)
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes GSAMH (SEQ ID NO:35); HC-CDR2, which includes RIRSKSNNYATEYAASVKG (SEQ ID NO:54); and HC-CDR3, which includes GKIGTTPKFGSY (SEQ ID NO:72); and the light chain variable domain and _ LC-CDR3 comprising LQSKNSPLT (SEQ ID NO: 116).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • GSAMH SEQ ID NO:35
  • HC-CDR2 which includes RIRSKSNNYATEYAASVKG
  • HC-CDR3 which includes GKIGTTPKFGSY (SEQ ID NO:72)
  • the light chain variable domain and _ LC-CDR3 comprising
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SHGMN (SEQ ID NO:36); HC-CDR2, which includes YISNGGDSTYYADSVKG (SEQ ID NO:55); and HC-CDR3, which includes TFSH (SEQ ID NO:73); and the light chain variable domain and _ LC-CDR3 containing VQAIAFPRT (SEQ ID NO: 117).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • SHGMN SEQ ID NO:36
  • HC-CDR2 which includes YISNGGDSTYYADSVKG
  • HC-CDR3 which includes TFSH (SEQ ID NO:73)
  • the light chain variable domain and _ LC-CDR3 containing VQAIAFPRT SEQ ID NO
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SYTMH (SEQ ID NO:37); HC-CDR2, which includes TIHSGGDTTYYTDSVKG (SEQ ID NO:56); and HC-CDR3, which includes SDV (SEQ ID NO:74); and the light chain variable domain and _ LC-CDR3 containing VQAIAFPRT (SEQ ID NO: 117).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • SYTMH SEQ ID NO:37
  • HC-CDR2 which includes TIHSGGDTTYYTDSVKG
  • HC-CDR3 which includes SDV (SEQ ID NO:74)
  • the light chain variable domain and _ LC-CDR3 containing VQAIAFPRT SEQ ID NO:
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYMQ (SEQ ID NO:31); HC-CDR2, which includes FIRNKPNGGTAEYAASVKG (SEQ ID NO:57); and HC-CDR3, which includes ADYYGSGLLFNY (SEQ ID NO:75); and the light chain variable domain and _ LC-CDR3 containing LQSLEYPFT (SEQ ID NO: 118).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1 , which includes DYYMQ (SEQ ID NO:31); HC-CDR2, which includes FIRNKPNGGTAEYAASVKG (SEQ ID NO:57); and HC-CDR3, which includes ADYYGSGLLFNY (SEQ ID NO:75); and the light chain
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYAMT (SEQ ID NO:38); HC-CDR2, which includes YIRSKSNNYATVYAASVKG (SEQ ID NO:58); and HC-CDR3, which includes GLTATN (SEQ ID NO:76); and the light chain variable domain and _ LC-CDR3 containing QQYYGPPLT (SEQ ID NO: 119).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1 , which includes DYAMT (SEQ ID NO:38)
  • HC-CDR3 which includes GLTATN (SEQ ID NO:76)
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes HYYIQ (SEQ ID NO:39); HC-CDR2, which includes RINPKTGGTNYAQKFQG (SEQ ID NO:51); and HC-CDR3, which includes GPAAISD (SEQ ID NO:77); and light chain variable domain and _ LC-CDR3 containing HQYYSTPLT (SEQ ID NO: 120).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • HC-CDR2 which includes RINPKTGGTNYAQKFQG
  • HC-CDR3 which includes GPAAISD (SEQ ID NO:77)
  • light chain variable domain and _ LC-CDR3 containing HQYYSTPLT SEQ ID NO: 120.
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYVQ (SEQ ID NO:40); HC-CDR2, which includes RINPRTGGTNYAQKFRG (SEQ ID NO:59); and HC-CDR3, which includes GPAAVAY (SEQ ID NO:78); and the light chain variable domain and _ LC-CDR3 containing QQFYSTPLT (SEQ ID NO: 121).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • HC-CDR2 which includes DYYVQ
  • HC-CDR2 which includes RINPRTGGTNYAQKFRG
  • HC-CDR3 which includes GPAAVAY (SEQ ID NO:78)
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising a heavy chain complementarity determining region (HC-CDR) 1: , which includes SYYIQ (SEQ ID NO:41); HC-CDR2, which includes RINPKTGGTNFAQKFQG (SEQ ID NO:60); and HC-CDR3, which includes GVAAASY (SEQ ID NO:79); and the light chain variable domain ( V L ), said V L comprising light chain complementarity determining region (LC-CDR) 1:, comprising KSSQSLLYSSNNKNYLA (SEQ ID NO:88); LC-CDR2, comprising WASTRES (SEQ ID NO:103); and LC - CDR3 comprising QQYYSTPLT (SEQ ID NO: 114).
  • VH heavy chain variable domain
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes AYYIQ (SEQ ID NO:42); HC-CDR2, which includes RINPKTGGTNYAQKFQG (SEQ ID NO:51); and HC-CDR3, which includes GAAAVNY (SEQ ID NO:80); and the light chain variable domain and _ LC-CDR3 containing HQYYSTPLT (SEQ ID NO: 120).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • HC-CDR2 which includes RINPKTGGTNYAQKFQG
  • HC-CDR3 which includes GAAAVNY (SEQ ID NO:80)
  • the light chain variable domain and _ LC-CDR3 containing HQYYSTPLT SEQ ID NO: 120.
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYLQ (SEQ ID NO:43); HC-CDR2, which includes RINPKTGATNYTQKFQG (SEQ ID NO:61); and HC-CDR3, which includes VVY (SEQ ID NO:81); and the light chain variable domain (V L ), the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes RASQGITNDLL (SEQ ID NO:95); LC-CDR2, which contains EASSLQG (SEQ ID NO:109); and LC-CDR3, which contains QQYKGAPYS (SEQ ID NO:122).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • HC-CDR2 heavy chain complementarity determining region
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes TYWWG (SEQ ID NO:44); HC-CDR2, which includes EINTNSGSTSYNPSLKS (SEQ ID NO:62); and HC-CDR3, which includes AAAYYYALDS (SEQ ID NO:82); and light chain variable domains (V L ), said V L comprising: light chain complementarity determining region (LC-CDR) 1, comprising RASQNVSSWLA (SEQ ID NO: 96); LC-CDR2, comprising KTSSLRS (SEQ ID NO: 110); and LC-CDR3 comprising QQYNCAPLT (SEQ ID NO: 123).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • HC-CDR2 which includes TYWWG (S
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DSYMH (SEQ ID NO:45); HC-CDR2, which includes LVRNKDKSYTTEYAAAVKG (SEQ ID NO:63); and HC-CDR3, which includes FNH (SEQ ID NO:83); and the light chain variable domain and _ LC-CDR3 comprising QQYKSAPYN (SEQ ID NO: 124).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • HC-CDR2 which includes DSYMH (SEQ ID NO:45)
  • HC-CDR2 which includes LVRNKDKSYTTEYAAAVKG
  • HC-CDR3 which includes FNH (SEQ ID NO:83)
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes NFYIQ (SEQ ID NO:46); HC-CDR2, which includes RINPRTGGTNYAQKFQG (SEQ ID NO:53); and HC-CDR3, which includes GAAAVNY (SEQ ID NO:80); and the light chain variable domain and _ LC-CDR3 containing QQYYSTPLT (SEQ ID NO: 114).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1 , which includes NFYIQ (SEQ ID NO:46); HC-CDR2, which includes RINPRTGGTNYAQKFQG (SEQ ID NO:53); and HC-CDR3, which includes GAAAVNY (SEQ ID NO:80); and the light chain variable domain and _ LC-
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SYSMQ (SEQ ID NO:47); HC-CDR2, which includes AINSGGGTTYYADSVKG (SEQ ID NO:64); and HC-CDR3, which includes GGGNHDAIDF (SEQ ID NO:84); and the light chain variable domain and _ LC-CDR3 comprising QHYYSIPWT (SEQ ID NO: 125).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region 1
  • HC-CDR2 which includes AINSGGGTTYYADSVKG
  • HC-CDR3 which includes GGGNHDAIDF (SEQ ID NO:84)
  • the light chain variable domain and _ LC-CDR3 comprising QHYYSIPWT (SEQ ID NO: 125
  • the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYLQ (SEQ ID NO:43); HC-CDR2, which includes RINPKTGATNYTQKFQG (SEQ ID NO:61); and HC-CDR3, which includes VVY (SEQ ID NO:81); and the light chain variable domain (V L ), said V L comprising: light chain complementarity determining region (LC-CDR) 1, comprising RASQGITNDLL (SEQ ID NO: 95); LC-CDR2, comprising EASSLQG (SEQ ID NO: 109); and LC-CDR3 containing QHYYTTPFT (SEQ ID NO: 126).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • HC-CDR2 which includes DYYL
  • nucleic acids encoding anti-Nogo-A antibodies are also provided.
  • compositions containing anti-Nogo-A antibodies are also provided.
  • treatment is a method of obtaining beneficial or desired results, including clinical results.
  • said beneficial or desired clinical results Including but not limited to one or more of the following: alleviating one or more symptoms caused by the disease, reducing the severity of the disease, stabilizing the disease (e.g., preventing or delaying the progression of the disease), preventing or delaying the spread of the disease (e.g., metastasis) , prevent or delay disease recurrence, delay or slow disease progression, improve disease status, alleviate disease (partial or complete), reduce the dose of one or more other drugs required to treat the disease, delay disease progression, improve or improve quality of life , increased body weight, and/or prolonged survival.
  • treatment includes reduction of the pathological consequences of the disease (e.g., for nerve damage, inhibition of neurite growth). The methods of the present application contemplate any of these treatments or Many aspects.
  • antibody includes full-length antibodies and antigen-binding fragments thereof.
  • Full-length antibodies include two heavy chains and two light chains.
  • the variable regions of the light and heavy chains are responsible for antigen binding.
  • the variable regions in the two chains usually include three hypervariable loops, called complementarity determining regions (CDRs) (light chain (LC) CDRs include LC-CDR1, LC-CDR2 and LC-CDR3, heavy chain (HC) )CDRs include HC-CDR1, HC-CDR2 and HC-CDR3).
  • CDRs complementarity determining regions
  • the CDR boundaries of the antibodies or antigen-binding fragments disclosed herein may be defined or identified by the Kabat, Chothia or Al-Lazikani conventions (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991).
  • the three CDR regions of the heavy or light chain are inserted between flanking segments called framework regions (FRs), which are more conserved than the CDR regions and form a scaffold supporting the hypervariable loops.
  • FRs flanking segments
  • the constant regions of the heavy and light chains are not involved in antigen binding but exhibit a variety of effector functions.
  • Antibodies are classified based on the amino acid sequence of their heavy chain constant region.
  • the five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by heavy chains of the alpha, delta, epsilon, gamma, and mu types, respectively.
  • major antibody classes are divided into subclasses, such as IgG1 ( ⁇ 1 heavy chain), IgG2 ( ⁇ 2 heavy chain), IgG3 ( ⁇ 3 heavy chain), IgG4 ( ⁇ 4 heavy chain), IgA1 ( ⁇ 1 heavy chain), or IgA2 ( ⁇ 2 heavy chain).
  • antigen-binding fragment includes antibody fragments, e.g., diabodies, Fab, Fab', F(ab') 2 , Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv) 2.
  • Bispecific dsFv (dsFv-dsFv'), disulfide bond-stabilized diabody (ds diabody), single-chain Fv (scFv), scFv dimer (bivalent diabody), Multispecific antibodies consisting of antibody fragments containing one or more CDRs, single domain antibodies, nanobodies, domain antibodies, bivalent domain antibodies, or any other antibody fragment capable of binding to an antigen but not containing a complete antibody structure .
  • the antigen-binding fragment is capable of binding to the same antigen as the parent antibody or parent antibody fragment (eg, parent scFv).
  • Antigen-binding fragments also include fusion proteins containing the above-described antibody fragments.
  • the antigen-binding fragment may include one or more CDRs from a specific human antibody grafted to framework regions from one or more different human antibodies.
  • epitope refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they may bind to the same epitope on the antigen.
  • a first antibody inhibits binding of a second antibody to a Nogo-A target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99%), the first antibody "competes" with the second antibody for binding to the Nogo-A target, and vice versa.
  • PCT publication WO 03/48731 describes a cross-competition based high-throughput antibody "epitope classification" approach.
  • the terms “specifically bind,” “specifically recognize,” or “specific for” refer to a measurable and reproducible interaction, e.g., binding of an antibody to a target can The presence of the target in a heterogeneous population of molecules, including biomolecules, is determined.
  • the ability of an antibody to specifically recognize a target means that the antibody binds to the target with higher affinity, avidity, easier and/or longer duration than to other targets.
  • an antibody that specifically recognizes an antigen reacts with one or more epitopes of the antigen with a binding affinity that is at least 10 times greater than its binding affinity to other targets.
  • an "isolated" anti-Nogo-A antibody is an anti-Nogo-A antibody that (1) is not associated with naturally occurring proteins, (2) does not contain other proteins from the same source, (3 ) is expressed by cells of different species, or (4) does not exist in nature.
  • isolated nucleic acid refers to nucleic acids of genomic, cDNA or synthetic origin, or combinations thereof. Depending on its source, the “isolated nucleic acid” refers to (1) not related to all or part of the polynucleotides in the "isolated nucleic acid” found in nature, (2) may not be related to polynucleotides that are not associated with it in the natural state. The nucleotides are operably linked, or (3) do not occur in nature as part of a longer sequence.
  • CDR or "complementarity determining region” means the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides.
  • CDR or "complementarity determining region” means the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides.
  • Kabat et al. J. Biol. Chem. 252:6609-6616 (1977); Kabat et al., U.S. Dept. of Health and Human Services, "Sequences of proteins of immunological interest” (1991); Chothia et al. al., J. Mol. Biol. 196: 901-917 (1987); Al-Lazikani B. et al., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J.
  • chimeric antibody means that a portion of the heavy chain and/or light chain is identical or homologous to the corresponding sequence in an antibody from a specific species or belonging to a specific antibody class or subclass, and this chain(s) Antibodies whose remainder are identical to or homologous to corresponding sequences in antibodies from another genus or belonging to other antibody classes or subclasses, as well as fragments of such antibodies, as long as they have the biological activity in this application ( See U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
  • Fv is the smallest antibody fragment that contains complete antigen recognition and binding sites. This fragment is a dimer formed by a heavy chain variable domain and a light chain variable domain tightly non-covalently linked. The folding of these two domains results in 6 hypervariable loops (3 loops each in the light chain and heavy chain), which provide the antibody with the amino acid residues for binding to the antigen and confer a binding relationship between the antibody and the antigen. Binding specificity. However, even a single variable domain (or half of an Fv fragment, which contains only the 3 CDRs specific for the antigen) has the ability to recognize and bind the antigen, albeit with lower affinity than the complete binding site.
  • the scFv polypeptide further includes a linker polypeptide between the VH and VL domains that allows the scFv to form an ideal structure for antigen binding.
  • diabody is a small antibody fragment prepared by using a short linker (for example, 5 to 10 residues) between the V H and V L domains to construct an scFv fragment (see the previous paragraph). This allows the variable domains to pair inter-chain rather than intra-chain, resulting in a bivalent fragment, that is, a fragment with two antigen-binding sites.
  • Bispecific diabodies are heterodimers of two "cross-over" scFv fragments, in which the VH and VL domains of the two antibodies are located on different polypeptide chains.
  • Diabodies are fully described in EP 404,097; WO 93/11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).
  • Humanized forms of non-human (eg, rodent) antibodies are chimeric antibodies, which include minimal sequence from the non-human antibody.
  • humanized antibodies are human immunoglobulins (recipient antibodies) in which the hypervariable region (HVR) residues of the receptor antibody are modified from a non-human species such as mouse, rat, rabbit or Replacement of hypervariable region residues that are non-human mammalian and possess the desired antibody specificity, affinity and performance (donor antibody).
  • HVR hypervariable region residues of the receptor antibody
  • donor antibody residues in the human immunoglobulin framework region are replaced with corresponding non-human residues.
  • humanized antibodies may include residues that are not present in either the recipient antibody or the donor antibody. These modifications can further improve antibody performance.
  • a humanized antibody will contain substantially all, at least one, and usually two variable domains in which all or substantially all of the hypervariable loops correspond to hypervariable loops of a non-human immunoglobulin, and all or Essentially all framework regions are human immunoglobulin sequences.
  • the human antibody optionally also includes an immunoglobulin constant region At least a portion of (Fc), usually the constant region of a human immunoglobulin.
  • Fc immunoglobulin constant region At least a portion of (Fc), usually the constant region of a human immunoglobulin.
  • Percent amino acid sequence identity or “homology” of the polypeptide and antibody sequences identified herein is defined as follows: Sequence comparisons are made where conservative substitutions are considered part of the sequence identity, and the candidate sequence is compared with the candidate sequence to be Compares the percentage of identical amino acid residues in a polypeptide sequence. Percent amino acid sequence identity can be determined by a variety of alignment methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to maximize alignment over the full length of the sequences being compared.
  • Fc receptor or "FcR” is used to describe a receptor that binds to the Fc region of an antibody.
  • the FcR described herein is an FcR that binds an IgG antibody, a gamma receptor, including receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and agonist variants of these receptors. Change splicing form.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (“activating receptor”) and Fc ⁇ RIIB (“inhibitory receptor”), which have similar amino acid sequences and differ mainly in the cytoplasmic domain.
  • the cytoplasmic domain of activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine activation motif (ITAM).
  • the cytoplasmic domain of the inhibitory receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) (see M.in Annu. Rev. Immunol. 15:203-234 (1997)).
  • ITAM immunoreceptor tyrosine activation motif
  • ITIM immunoreceptor tyrosine inhibitory motif
  • FcR in this application covers other types of FcRs, including FcRs identified in the future.
  • FcR also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgGs to the neonate (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994) )).
  • FcRn refers to the neonatal Fc receptor (FcRn).
  • FcRn is structurally similar to the major histocompatibility complex (MHC) and consists of an ⁇ chain non-covalently bound to ⁇ 2 microglobulin.
  • MHC major histocompatibility complex
  • FcRn plays an important role in the passive transport of immunoglobulin IgGs from mother to newborn and in regulating serum IgG levels.
  • FcRn serves as a rescue receptor that binds and transports endocytosed IgG in an intact form within and between cells and protects them from default degradation pathways.
  • the "CH1 domain" of the human IgG heavy chain constant region generally extends from amino acid 118 to amino acid 215 (EU numbering system).
  • the "hinge region” is generally defined as extending from position Glu 216 to position Pro 230 of human IgG1 (Burton, Molec. Immunol. 22:161-206 (1985)). By placing the first and last cysteine residues that form the inter-heavy chain disulfide bond after the same position as IgG1, the hinge regions of other IgG isotypes can be aligned with the IgG1 sequence.
  • the "CH2 domain" of the human IgG Fc region usually extends from amino acid 231 to amino acid 340.
  • the unique feature of the CH2 domain is that it does not pair closely with another region, but instead has two N-terminal linked branched sugar chains inserted between the two CH2 domains of the intact natural IgG molecule. It is speculated that sugars may serve as a surrogate for domain-to-domain pairing, helping to keep the CH2 domain stable.
  • the "CH3" domain includes the region extending from the C-terminal residues within the Fc region to the CH2 domain (from amino acid 341 to the C-terminus of the antibody sequence, usually amino acid residue 446 or 447 of IgG).
  • a “functional Fc fragment” has the "effector function” possessed by a native Fc region sequence.
  • exemplary “effector functions” include Clq binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors ( Such as B cell receptor; BCR), etc.
  • effector functions typically require the binding of an Fc region to a binding domain (eg, an antibody variable region) and can be assessed using a variety of experimental methods well known in the art.
  • Antibodies with IgG Fc variants that have "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and/or ADCC activity compared to the parent polypeptide or a polypeptide comprising a native Fc sequence.
  • An Fc variant that exhibits "enhanced binding" to an FcR has a higher binding affinity (e.g., a lower apparent Kd or IC50 value) to at least one FcR compared to the parent polypeptide or a polypeptide comprising a native IgG Fc sequence. ).
  • the binding capacity is enhanced 3-fold, such as 5, 10, 25, 50, 60, 100, 150, 200, even up to 500-fold or a 25% to 1000% increase in binding capacity compared to the parent polypeptide.
  • An Fc variant exhibits "reduced binding" to an FcR, having a lower affinity (eg, a higher apparent Kd or IC50 value) for at least one FcR compared to the parent polypeptide. Its binding capacity is reduced by 40% or more compared to the parent polypeptide.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • cytotoxic cells e.g., natural killer cells (NK), neutrophils
  • FcRs Fc receptors
  • Antibodies “arm” cytotoxic cells and are required for this killing.
  • NK cells only express Fc ⁇ RIII
  • monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • FcR FcR on hematopoietic cells
  • Table 3 The expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991).
  • an in vitro ADCC assay can be performed, as described in U.S. Patent No. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK).
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • the ADCC activity of the target molecule can also be assessed in vivo, for example in an animal model as disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).
  • the amount of the antibody polypeptide is substantially the same as that of the wild-type IgG Fc polypeptide (or parent polypeptide) during the experiment, it can more effectively mediate ADCC both in vitro and in vivo.
  • Such variants are generally identified using any in vitro ADCC assay known in the art, such as assays or methods for identifying ADCC activity, such as in animal models and the like. In some embodiments, such variants mediate ADCC 5- to 100-fold, for example, 25- to 50-fold more efficiently than wild-type Fc (or the parent polypeptide).
  • “Complement-dependent cytotoxicity” or “CDC” refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (subclasses with appropriate structures) that bind cognate antigens.
  • C1q the first component of the complement system
  • CDC experiments can be performed as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). Polypeptide variants with altered Fc region amino acid sequences and increased or decreased Clq binding capacity are described in US Patent No. 6,194,551 Bl and WO99/51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al. J. Immunol. 164:4178-4184 (2000).
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerates of each other and encode the same amino acid sequence. Nucleotide sequences encoding proteins or RNA may also include introns, for example, nucleotide sequences encoding proteins may include introns in some forms.
  • operably linked refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence, thereby allowing expression of the latter.
  • a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence.
  • a promoter is operably linked to a coding sequence if it affects the transcription or expression of the coding sequence.
  • operably linked DNA sequences are contiguous and, if necessary, two protein-coding regions can be joined in the same reading frame.
  • “Homology” refers to sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position of two compared sequences contains the same base or amino acid monomer subunit, for example, the same position of two DNA molecules both contains adenine, then the two DNA molecules are homologous at that position.
  • the percent homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the total number of positions multiplied by 100. For example, if 6 out of 10 positions in two sequences match or are homologous, the two sequences are 60% homologous. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. Generally speaking, when comparing two sequences, the comparison is performed with the purpose of obtaining maximum homology.
  • an “effective amount” of an anti-Nogo-A antibody or composition disclosed herein is an amount sufficient to achieve a specified purpose.
  • An “effective amount” can be determined empirically and by methods known to be relevant to the stated purpose.
  • a therapeutically effective amount refers to an amount of an anti-Nogo-A antibody or composition thereof disclosed herein that is effective in treating a disease or condition in an individual.
  • a therapeutically effective amount of an anti-Nogo-A antibody or composition thereof is one capable of promoting (i.e., restoring to a certain extent) the sprouting and regeneration of the injured corticospinal tract (CST); promoting (i.e., restoring to a certain extent) To restore (to a certain extent) the growth of growth cones; to promote (i.e. to restore to a certain extent) the regeneration of damaged neurites; to reduce (i.e.
  • a therapeutically effective amount refers to an amount capable of prolonging the survival of a patient. In some embodiments, a therapeutically effective amount refers to an amount capable of improving progression-free survival of a patient.
  • pharmaceutically acceptable refers to a material that has no biological activity or other undesirable properties, e.g., the material can be incorporated into a pharmaceutical composition administered to a patient, and Does not cause significant adverse biological reactions or interact in a deleterious manner with any other components contained in the composition.
  • Pharmaceutically acceptable carriers or excipients preferably meet required standards for toxicological or manufacturing testing and/or are included in the Inactive Ingredient Guidelines prepared by the U.S. Food and Drug Administration.
  • Embodiments of the application described herein should be understood to include embodiments “consisting of” and/or “consisting essentially of.”
  • references herein to "about” a value or parameter include (and describe) variations on the value or parameter itself. For example, descriptions referring to “about X” include descriptions of "X”.
  • reference to "not" a value or parameter generally means and describes “other than” a value or parameter.
  • the method cannot be used to treat type X cancer, meaning the method is typically used to treat other types of cancer besides type X cancer.
  • the application provides anti-human and/or rhesus Nogo-A antibodies that specifically bind Nogo-A.
  • anti-Nogo-A antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy chain and/or light chain CDRs as described herein.
  • the application provides isolated antibodies that bind Nogo-A.
  • Contemplated anti-Nogo-A antibodies include, for example, full-length anti-Nogo-A antibodies (e.g., full-length IgG1 or IgG4), anti-Nogo-A single chain antibodies, anti-Nogo-A Fc fusion proteins, multispecific (e.g., bispecific properties) anti-Nogo-A antibodies, anti-Nogo-A immunoconjugates, and the like.
  • the anti-Nogo-A antibody is a full-length antibody (eg, full-length IgG1 or IgG4) or an antigen-binding fragment thereof that specifically binds Nogo-A.
  • the anti-Nogo-A antibody is Fab, Fab', F(ab)' 2 , Fab'-SH, single chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, bis Chain antibody (diabody) or linear antibody.
  • an antibody that specifically binds Nogo-A means that the affinity of the antibody for binding to Nogo-A is at least 10 times greater than the binding affinity for the non-target (including, for example, 10, 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 times).
  • non-target refers to an antigen that is not Nogo-A.
  • Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence-activated cell sorting (FACS) analysis or radioimmunoprecipitation analysis (RIA).
  • the Kd value can be determined by methods known in the art, such as surface plasmon resonance (SPR) technology or biolayer interference (BLI) technology.
  • non-human anti-Nogo-A antibodies comprising human sequences are discussed broadly herein (eg, human heavy and light chain variable domains comprising human CDR sequences), non-human anti-Nogo-A antibodies are also contemplated.
  • non-human anti-Nogo-A antibodies include human CDR sequences and non-human framework region sequences of the anti-Nogo-A antibodies described herein.
  • non-human framework region sequences include any for Sequences for heavy and/or light chain variable domains are generated using one or more human CDR sequences as described herein, including, for example, mammals, such as mouse, rat, rabbit, porcine, bovine (e.g., bovine , bulls, buffalo), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., small apes, macaques), etc.
  • non-human anti-Nogo-A antibodies include anti-Nogo-A antibodies generated by grafting one or more human CDR sequences described herein into non-human framework regions (e.g., murine or chicken framework sequences). -A antibody.
  • the NiG amino acid sequence encoded by exon 3 of an exemplary human Nogo-A includes or consists of the amino acid sequence shown in SEQ ID NO: 25.
  • An exemplary rhesus NiG amino acid sequence contains SEQ ID NO: 26 The amino acid sequence shown may consist of the amino acid sequence shown in SEQ ID NO: 26.
  • An exemplary rat NiG amino acid sequence includes or consists of the amino acid sequence set forth in SEQ ID NO: 27.
  • the anti-Nogo-A antibodies described herein specifically recognize an epitope in human Nogo-A. In some embodiments, the anti-Nogo-A antibodies cross-react with Nogo-A from species other than human. In some embodiments, the anti-Nogo-A antibody is fully specific for human Nogo-A and does not cross-react with other non-human species.
  • the anti-Nogo-A antibody cross-reacts with at least one allelic variant of Nogo-A protein (or fragment thereof).
  • the allelic variant has up to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) compared to the naturally occurring Nogo-A protein (or fragment thereof). , 10, 15, 20, 25 or 30) amino acid substitutions (eg, conservative substitutions).
  • the anti-Nogo-A antibody does not cross-react with any allelic variant of the Nogo-A protein (or fragment thereof).
  • the anti-Nogo-A antibody cross-reacts with at least one interspecies variant of Nogo-A protein.
  • the Nogo-A protein (or fragment thereof) is human Nogo-A
  • the interspecies variant of the Nogo-A protein (or fragment thereof) is a variant in cynomolgus monkey.
  • the anti-Nogo-A antibody does not cross-react with any interspecies variant of Nogo-A protein.
  • the anti-Nogo-A antibody comprises an antibody heavy chain constant region and an antibody light chain constant region.
  • the anti-Nogo-A antibody comprises an IgG1 heavy chain constant region.
  • the anti-Nogo-A antibody comprises an IgG2 type heavy chain constant region.
  • the anti-Nogo-A antibody comprises an IgG3 type heavy chain constant region.
  • the anti-Nogo-A antibody comprises an IgG4 type heavy chain constant region.
  • the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 22.
  • the anti-Nogo-A antibody comprises a kappa light chain constant region.
  • the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 23.
  • the anti-Nogo-A antibody comprises a lambda light chain constant region.
  • the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 24.
  • the anti-Nogo-A antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
  • the anti-Nogo-A antibody includes a heavy chain variable domain ( VH ), and the VH includes: heavy chain complementarity determining region (HC-CDR) 1, which includes DYGMH (SEQ ID NO: 1); HC-CDR2 comprising SISHTGKTVFYGESVKG (SEQ ID NO: 3); and HC-CDR3 comprising TELGGDNWFDV (SEQ ID NO: 5); and light chain variable domain (V L ), VL contains: light chain complementarity determining region (LC-CDR) 1, which contains TGSSSNIGGYDVY (SEQ ID NO:7); LC-CDR2, which contains DNKRPS (SEQ ID NO:9); and LC-CDR3, which contains AAWDDSLYGYI (SEQ ID NO:11).
  • HC-CDR heavy chain complementarity determining region
  • LC-CDR2 contains SISHTGKTVFYGESVKG
  • HC-CDR3 comprising TELGGDNWFDV
  • V L light chain variable domain
  • the anti-Nogo-A antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 3 or a variant thereof, said variant comprising up to about 3 (for example (e.g., 1, 2, or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2, or 3 ) amino acid substitutions.
  • HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids
  • HC-CDR2 which comprises the amino acid sequence shown in SEQ ID NO: 3 or a variant thereof, said variant
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, HC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 3, HC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 5.
  • the anti-Nogo-A antibody comprises VL , and the VL comprises: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 7 or a variant thereof, the variant comprising up to Substitution of about 3 (for example, 1, 2 or 3) amino acids; LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 9 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 11 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids replacement.
  • LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 7 or a variant thereof, the variant comprising up to Substitution of about 3 (for example, 1, 2 or 3) amino acids
  • LC-CDR2 which comprises the amino acid sequence shown in SEQ ID NO: 9 or a variant thereof, said variant comprising up to about 3 (for
  • the anti-Nogo-A antibody comprises a V L comprising: LC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 7, LC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 9, LC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 11.
  • the anti-Nogo-A antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 3 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 5 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids and VL , the VL comprising: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:7 or a variant thereof, the variant comprising up to about 3 (e.g.
  • LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 9 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acid substitutions
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, HC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 3, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:5; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence shown in SEQ ID NO:7 Sequences, LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO:9, and LC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:11.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3 , HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 5, or a variant of the V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , the V L comprises: LC- CDR1, which comprises the amino acid sequence SEQ ID NO: 7, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 9, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 11, or a variant of said V L , which LC-CDRs contain substitutions of up to about 5 amino acids.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:5; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:7, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:9, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:11.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2 and a VH as set forth in any of the amino acid sequences of SEQ ID NOs: 13-16.
  • the anti-Nogo-A antibody comprises a V H comprising HC- CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 13; and V L , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 18.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 14; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 19.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 15; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 19.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 16; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 19.
  • the anti-Nogo-A antibody comprises: VH , the VH comprises the amino acid sequence shown in any one of SEQ ID NOs: 13-16 or a variant thereof, the variant is identical to SEQ ID NOs: 13-16.
  • the amino acid sequence shown in any one of NOs: 13-16 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity;
  • V L the V L includes the amino acid sequence shown in any one of SEQ ID NOs: 18-19 or a variant thereof, and the variant has at least the same amino acid sequence as the amino acid sequence shown in any one of SEQ ID NOs: 18-19 About 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity.
  • the anti-Nogo-A antibody comprises a V H comprising the amino acid sequence set forth in any one of SEQ ID NOs: 13-16, and a V L comprising SEQ ID NOs : The amino acid sequence shown in any one of 18-19.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 13 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 18 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 18 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:13, and a VL comprising the amino acid sequence SEQ ID NO:18.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 14 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 19 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 19 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:14, and a VL comprising the amino acid sequence SEQ ID NO:19.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 15 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 19 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 19 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:15, and a VL comprising the amino acid sequence SEQ ID NO:19.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 16 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 19 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 19 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:16, and a VL comprising the amino acid sequence SEQ ID NO:19.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4 , HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 6, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC- CDR1, which comprises the amino acid sequence SEQ ID NO: 8, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 10, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 12, or a variant of said V L , which LC-CDRs contain substitutions of up to about 5 amino acids.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 6; and VL , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 8, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 10, and LC-CDR3, which contains the amino acid sequence SEQ ID NO: 12.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 17; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO:20.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 17 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence SEQ ID NO:20 Identity.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:17, and a VL comprising the amino acid sequence SEQ ID NO:20.
  • the anti-Nogo-A antibody comprises a heavy chain variable domain (V H ), and the V H comprises: heavy chain complementarity determining region (HC-CDR) 1, which comprises SYGMH (SEQ ID NO:28); HC-CDR2 comprising VIWYHGSKKYYADSVKD (SEQ ID NO:48); and HC-CDR3 comprising SIAETTDYGLDS (SEQ ID NO:65); and light chain variable domain (V L ), VL contains: light chain complementarity determining region (LC-CDR) 1, which contains RSSQSLLYRGGKTFLY (SEQ ID NO:85); LC-CDR2, which contains ELSNRAS (SEQ ID NO:100); and LC-CDR3, which contains MQGIQLPWT (SEQ ID NO:111).
  • HC-CDR heavy chain complementarity determining region
  • LC-CDR light chain complementarity determining region
  • LC-CDR2 contains RSSQSLLYRGGKTFLY
  • the anti-Nogo-A antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 65 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids replacement.
  • HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids
  • HC-CDR2 which comprises the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof, said variant comprising up to about 3 (for
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, HC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 48, HC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 65.
  • the anti-Nogo-A antibody comprises VL , the VL comprises: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:85 or a variant thereof, the variant comprising up to Substitution of about 3 (for example, 1, 2 or 3) amino acids; LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 111 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids replacement.
  • LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:85 or a variant thereof, the variant comprising up to Substitution of about 3 (for example, 1, 2 or 3) amino acids
  • LC-CDR2 which comprises the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, said variant comprising up to about 3 (for
  • the anti-Nogo-A antibody comprises a VL comprising: LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:85, LC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 100, LC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 111.
  • the anti-Nogo-A antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 65 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids and VL , the VL comprising: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:85 or a variant thereof, the variant comprising up to about 3 (e.g.
  • LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, HC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 48, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:65; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence shown in SEQ ID NO:85 Sequences, LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO: 100, and LC-CDR3, which includes the amino acid sequence shown in SEQ ID NO: 111.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 28, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 48 , HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 65, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC- CDR1, which comprises the amino acid sequence SEQ ID NO: 85, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 100, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 111, or a variant of said V L , which LC-CDRs contain substitutions of up to about 5 amino acids.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 28, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 48 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:65; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:85, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 100, and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 111.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2 and a VH as set forth in any one of the amino acid sequences of SEQ ID NOs: 127-128. HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in any one of the amino acid sequences of SEQ ID NOs: 150-151.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 127; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 150.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 128; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 151.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 128; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 150.
  • the anti-Nogo-A antibody comprises: VH , the VH comprises the amino acid sequence shown in any one of SEQ ID NOs: 127-128 or a variant thereof, the variant is identical to SEQ ID NOs: 127-128 or a variant thereof.
  • the amino acid sequence shown in any one of NOs: 127-128 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and V L , the V L includes the amino acid sequence shown in any one of SEQ ID NOs: 150-151 or a variant thereof, and the variant has at least the same amino acid sequence as the amino acid sequence shown in any one of SEQ ID NOs: 150-151.
  • the anti-Nogo-A antibody comprises VH
  • the VH comprises The amino acid sequence shown in any one of SEQ ID NOs: 127-128, and V L comprising the amino acid sequence shown in any one of SEQ ID NOs: 150-151.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 127 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 127 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 150 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 150 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:127, and a VL comprising the amino acid sequence SEQ ID NO:150.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 128 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 151 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 151 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:128, and a VL comprising the amino acid sequence SEQ ID NO:151.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 128 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 150 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 150 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:128, and a VL comprising the amino acid sequence SEQ ID NO:150.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 29, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 49 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 66, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:86, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:101, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:112, or a variant of said VL , whose LC-CDRs contain up to about 5 amino acid substitutions
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 29, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 49 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 66; and VL , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 86, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:101, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:112.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised of VH as set forth in the amino acid sequence SEQ ID NO: 129; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 152.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 129 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 152 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 152 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:129, and a VL comprising the amino acid sequence SEQ ID NO:152.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 30, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 50 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 67, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 87, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 102, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 113, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 30, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 50 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:67; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:87, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 102, and LC-CDR3, which contains the amino acid sequence SEQ ID NO: 113.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 130; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 153.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 130 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 153 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 153 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:130, and a VL comprising the amino acid sequence SEQ ID NO:153.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 68, or a variant of said V H , whose HC-CDRs comprise substitutions of up to about 5 amino acids; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114, or a variant of the V L containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:68; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:114.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 131; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 154.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 154 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 154 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:131, and a VL comprising the amino acid sequence SEQ ID NO:154.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 32, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 69, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:114, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 32, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:69; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:114.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 132; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 155.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 132 80% (e.g. at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 155 or a variant thereof that is identical to the amino acid sequence SEQ ID NO. :155 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:132, and a VL comprising the amino acid sequence SEQ ID NO:155.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 33, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 52 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 70, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:89, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:104, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:115, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 33, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 52 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:70; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:89, LC-CDR2, which includes the amino acid sequence SEQ ID NO:104, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:115.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 133; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 156.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 156 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 156 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:133, and a VL comprising the amino acid sequence SEQ ID NO:156.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 34, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 71, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:114, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 34, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53 , and HC-CDR3, which contains the amino acid Sequence SEQ ID NO:71; and VL comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:88, LC-CDR2 comprising the amino acid sequence SEQ ID NO:103, and LC-CDR3, It contains the amino acid sequence SEQ ID NO:114.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 134; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 157.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 157 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 157 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:134, and a VL comprising the amino acid sequence SEQ ID NO:157.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 35, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 72, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 90, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 105, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 116, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 35, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:72; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:90, LC-CDR2, which includes the amino acid sequence SEQ ID NO:105, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:116.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 135; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 158.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 135 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 158 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 158 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:135, and a VL comprising the amino acid sequence SEQ ID NO:158.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 36, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 55 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 73, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 91, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 117, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 36, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 55 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:73; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:91, LC-CDR2, which includes the amino acid sequence SEQ ID NO:106, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:117.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 136; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 159.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 159 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 159 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:136, and a VL comprising the amino acid sequence SEQ ID NO:159.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 37, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 56 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 74, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 91, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 117, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 37, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 56 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:74; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:91, LC-CDR2, which includes the amino acid sequence SEQ ID NO:106, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:117.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 137; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 159.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 159 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 159 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:137, and a VL comprising the amino acid sequence SEQ ID NO:159.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 57 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 75, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 92, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 107, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 118, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 57 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:75; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:92, LC-CDR2, which includes the amino acid sequence SEQ ID NO:107, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:118.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 138; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 160.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 160 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 160 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:138, and a VL comprising the amino acid sequence SEQ ID NO:160.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 38, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 58 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 76, or a variant of the V H whose HC-CDRs comprise substitutions of up to about 5 amino acids; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 93, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 108, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 119, or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 38, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 58 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:76; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:93, LC-CDR2, which includes the amino acid sequence SEQ ID NO:108, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:119.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 139; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 161.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 139 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 161 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 161 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:139, and a VL comprising the amino acid sequence SEQ ID NO:161.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 39, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 77, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:120, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 39, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:77; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:120.
  • the anti-Nogo-A antibody comprises a V H comprising HC- CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 140; and V L , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 162.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 140 80% (e.g. at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 162 or a variant thereof that is identical to the amino acid sequence SEQ ID NO. :162 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:140, and a VL comprising the amino acid sequence SEQ ID NO:162.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 40, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 59 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 78, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 94, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 121, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 40, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 59 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:78; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:94, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:121.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 141; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 163.
  • the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO:141 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO:141 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 163 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 163 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:141, and a VL comprising the amino acid sequence SEQ ID NO:163.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 41, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 60 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 79, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:114, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 41, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 60 , and HC-CDR3, which contains the amino acid Sequence SEQ ID NO:79; and VL comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:88, LC-CDR2 comprising the amino acid sequence SEQ ID NO:103, and LC-CDR3, It contains the amino acid sequence SEQ ID NO:114.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 142; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 164.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 164 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 164 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:142, and a VL comprising the amino acid sequence SEQ ID NO:164.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 42, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:120, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 42, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:80; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:120.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 143; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 165.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 165 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 165 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:143, and a VL comprising the amino acid sequence SEQ ID NO:165.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 61 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 81, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 122, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 61 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:81; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:109, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:122.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 144; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 166.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 166 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 166 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:144, and a VL comprising the amino acid sequence SEQ ID NO:166.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 44, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 62 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 82, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 96, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 110, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 123, or a variant of said V L , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 44, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 62 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:82; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:96, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 110, and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 123.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 145; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 167.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 167 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 167 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:145, and a VL comprising the amino acid sequence SEQ ID NO:167.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 45, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 63 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 83, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 97, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 124, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 45, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 63 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:83; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:97, LC-CDR2, which includes the amino acid sequence SEQ ID NO:104, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:124.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 146; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 168.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 168 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 168 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:146, and a VL comprising the amino acid sequence SEQ ID NO:168.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 46, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V H , whose HC-CDRs comprise substitutions of up to about 5 amino acids; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 98, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114, or a variant of the V L containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 46, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:80; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:98, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:114.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 147; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 169.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 169 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 169 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:147, and a VL comprising the amino acid sequence SEQ ID NO:169.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 47, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 64 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 84, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 99, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 125, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 47, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 64 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:84; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:99, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:125.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 148; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 170.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof that is at least about 80% (e.g. at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 170 or a variant thereof that is identical to the amino acid sequence SEQ ID NO. :170 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:148, and a VL comprising the amino acid sequence SEQ ID NO:170.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 61 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 81, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 126, or a variant of said V L , containing up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 61 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:81; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:109, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:126.
  • the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 149; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 171.
  • the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 171 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 171 sex.
  • the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:149, and a VL comprising the amino acid sequence SEQ ID NO:171.
  • amino acid substitutions are limited to the "exemplary substitutions” set forth in Table 4 herein. In some embodiments, amino acid substitutions are limited to the "preferred substitutions” set forth in Table 4 herein.
  • functional epitopes can be resolved by combined alanine scanning methods.
  • combinatorial alanine scanning technology can be used to identify amino acids in the Nogo-A protein that are necessary for interaction with anti-Nogo-A antibodies.
  • the epitope is conformational and the crystal structure of an anti-Nogo-A antibody bound to Nogo-A protein can be used to identify the epitope.
  • the application provides antibodies that compete for binding to Nogo-A with any of the anti-Nogo-A antibodies described herein.
  • antibodies are provided that are capable of binding to an epitope on Nogo-A competitively with any of the anti-Nogo-A antibodies described herein.
  • anti-Nogo-A antibodies are provided that bind to anti-Nogo-A antibody molecules comprising VH and VL The same epitope, wherein the V H includes the amino acid sequence shown in any one of SEQ ID NOs: 13-17 and 127-149, and the V L includes any of SEQ ID NOs: 18-20 and 150-171. The amino acid sequence shown in 1.
  • anti-Nogo-A antibodies are provided that compete for binding to Nogo-A with anti-Nogo-A antibodies comprising V H and V L , wherein the V H comprises SEQ ID NOs: 13-17, 127 The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171, and the V L includes the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171.
  • competition experiments can be used to identify monoclonal antibodies that compete with the anti-Nogo-A antibodies described herein for binding to Nogo-A. Competition experiments can determine whether two antibodies bind the same epitope by identifying the same or spatially overlapping epitope or by one antibody competitively inhibiting the binding of another antibody to the antigen. In certain embodiments, such competing antibodies bind the same epitope as the antibodies described herein.
  • Some exemplary competition experiments include, but are not limited to, conventional experiments as mentioned in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).
  • each antibody is said to bind the same epitope if it blocks 50% or more of the binding of the other antibody.
  • the antibody that competes with an anti-Nogo-A antibody described herein is a chimeric antibody, a humanized antibody, or a fully human antibody.
  • Exemplary anti-Nogo-A antibody sequences are shown in Table 2 and Table 3, where CDR numbering is performed according to Kabat definition. Those skilled in the art will recognize that there are a variety of known algorithms for predicting the location of CDRs and defining antibody light and heavy chain variable regions. Antibodies containing the CDRs, VH and/or VL sequences of antibodies as described herein, but based on prediction algorithms other than those exemplified in the table below are also within the scope of the present application.
  • Nogo-A protein is a member of the plasma membrane protein family.
  • Nogo-A, Nogo-B and Nogo-C are three protein products encoded by the plasma membrane protein 4 (RTN4, also known as NOGO) gene. These three isoforms share the same carboxy-terminal reticular homology domain (RTN).
  • RTN4 plasma membrane protein 4
  • This RTN domain is highly similar to the proteins encoded by the other three reticular structure genes RTN1, RTN2 and RTN3 (GrandPre et al., Nature, 2000; Oertle et al., Trends Cell Biol. 2003), which are involved in the nervous system and other organs. The functions in are mostly unknown.
  • the RTN domain of Nogo protein contains two long hydrophobic segments, each of which is long enough to span the cell membrane twice.
  • Nogo-66 66-amino acid segment
  • Nogo-66 66-amino acid segment
  • the N-terminal structures of Nogo-A, Nogo-B and Nogo-C are quite different, among which only Nogo-A has been shown to exert a strong inhibitory effect in the central nervous system (GrandPre et al., Nature, 2000; Huber et al., J Neurosci, 2002), suggesting that there is an important functional domain located in a specific portion of the amino terminus of Nogo-A.
  • Nogo-A- ⁇ 20 a region with neurite growth and fibroblast spreading inhibitory activity was discovered, which was named Nogo-A- ⁇ 20 (Oertle et al., J Neurosci, 2003; Kempf A et al., PLoS Biol. 2014.).
  • the carboxy-terminal Nogo-66 domain of Nogo-A is also considered to have strong neurite growth inhibitory activity (Fournier et al., Nature, 2001).
  • Nogo-A- ⁇ 20 and Nogo-66 were shown to be more active when part of a larger Nogo-A-derived fragment, such as Nogo-A-ext (also known as NiR-G, mouse aa 1-979) or Nogo-22 (mouse aa 966-1163) (Huebner et al., J Biol Chem, 2011; Oertle et al., J Neurosci, 2003).
  • Nogo-A exerts its inhibitory activity through two different extracellular domains, Nogo-A- ⁇ 20 (mouse aa544-725) and Nogo-66 (mouse aa1026-1091) (Schwab ME et al., Nat Rev Neurosci. 2010; Oertle T et al., J Neurosci. 2003).
  • the first Nogo receptor to be identified was the glycosylphosphatidylinositol (GPI)-linked leucine-rich repeat (LRR) protein Nogo receptor 1 (NgR1, also known as the Nogo-66 receptor and plasma membrane protein 4 receptor) (Fournier AE et al., Nature, 2001).
  • GPI glycosylphosphatidylinositol
  • LRR leucine-rich repeat
  • NgR1 consists of 473 amino acids, including an N-terminal signal sequence, eight leucine-rich repeats (LRR) LRR1-LRR8, and a leucine-rich repeat C-terminal domain (LRRCT) (these three regions Together they form the extracellular domain) and the GPI anchoring domain.
  • LRR leucine-rich repeats
  • LRR1-LRR8 leucine-rich repeat C-terminal domain
  • LRR leucine-rich repeat C-terminal domain
  • Nogo-A binds to NgR1 through its inhibitory Nogo-66 domain to initiate intracellular signaling cascades. Because NgR does not contain a transmembrane domain, signal transduction requires transducing the NgR/ligand interaction signal to the co-receptor p75 or TROY and LINGO1 to form a functional ternary complex, thereby inhibiting neurite growth. This binding leads to an increase in intracellular Ca 2+ and activation of the Rho-Rho-related Frizzled-containing kinase (ROCK) pathway through unknown intermediates.
  • ROCK Rho-Rho-related Frizzled-containing kinase
  • NgR1 Nogo-66 also induces growth inhibition through interaction with accessory proteins and paired immunoglobulin-like receptor B (PIRB) (Atwal JK et al., Science. 2008). NgR1 also binds to the growth-inhibitory myelin-associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (OMGP) (Domeniconi, M et al., Neuron, 2002; Wang, KC et al., Nature, 2002).
  • MAG growth-inhibitory myelin-associated glycoprotein
  • OMGP myelin oligodendrocyte glycoprotein
  • GPCR G protein-coupled receptor
  • S1PR2 G protein-coupled receptor sphingosine 1-phosphate receptor 2
  • Nogo-A sphingosine 1-phosphate receptor 2
  • Nogo-A- ⁇ 20 binds S1PR2 via extracellular receptor loops 2 and 3, which is distinct from the previously described S1P binding site (Hanson MA et al., Scince. 2012.).
  • the anti-Nogo-A antibody is a full-length anti-Nogo-A antibody.
  • the full-length anti-Nogo-A antibody is IgA, IgD, IgE, IgG, or IgM.
  • the full-length anti-Nogo-A antibody comprises an IgG constant region, such as that of IgG1, IgG2, IgG3, IgG4, or a variant thereof.
  • the full-length anti- The Nogo-A antibody contains the lambda light chain constant region.
  • the full-length anti-Nogo-A antibody comprises a kappa light chain constant region.
  • the full-length anti-Nogo-A antibody is a full-length human anti-Nogo-A antibody. In some embodiments, the full-length anti-Nogo-A antibody comprises mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-Nogo-A antibody comprises an Fc sequence that has been altered or otherwise altered such that it has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent Cytotoxicity (CDC) effector function.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent Cytotoxicity
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region, the anti-Nogo-A antibody specifically binding to Nogo-A.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG2 constant region
  • the anti-Nogo-A antibody specifically binding to Nogo-A.
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a full-length anti-Nogo-A antibody comprising an IgG3 constant region is provided, the anti-Nogo-A antibody specifically binding to Nogo-A.
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, the anti-Nogo-A antibody specifically binding to Nogo-A.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3) amino acids Substitution; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3 ) amino acid substitution; and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG2 constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3) amino acids Substitution; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3 ) amino acid substitution; and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) substitution of amino acids; and b) light chain variable domain, said light chain variable domain comprising: LC-CDR1,
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a full-length anti-Nogo-A antibody comprising an IgG3 constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3) amino acids Substitution, HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3 ) amino acid substitution; and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) substitution of amino acids; and b) light chain variable domain, said light chain variable domain comprising: LC-CDR1,
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3) amino acids Substitution; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3 ) amino acid substitution; and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) substitution of amino acids; and b) light chain variable domain, said light chain variable domain comprising: LC-CDR1,
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 Amino acid sequence, and HC-CDR3, which includes the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84, or a variant of the heavy chain variable domain, whose HC-CDR sequence includes Substitutions of up to about 5 (eg, 1, 2, 3, 4, or 5) amino acids; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ ID NOs : The amino acid sequence shown in any one of 7-8 and 85-99, LC-CDR2, which includes the amino acid sequence shown
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 sequence, and HC-CDR3, which contains the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84, or a variant of the heavy chain variable domain, whose HC-CDR sequence contains up to A substitution of about 5 (e.g., 1, 2, 3, 4, or 5) amino acids; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ ID NOs: The amino acid sequence shown in any one of 7-8 and 85-99, LC-CDR2, including the amino acid sequence shown in any one of SEQ ID NOs:
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 Amino acid sequence, and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84; and b) light chain variable domain, the light chain variable domain comprising: LC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 7-8, 85-99, LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 9-10, 100-110 sequence, and LC-CDR3, which includes the amino acid sequence shown in any one of SEQ ID
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 Amino acid sequence, and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84; and b) light chain variable domain, said light chain variable domain comprising: LC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 7-8, 85-99, LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 9-10, 100-110 sequence, and LC- CDR3, which includes the amino acid sequence shown in any one of SEQ ID
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 5; and b) the light chain may Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence SEQ ID NO:9, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:11.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 2, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 6; and b) the light chain may Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 8, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 10, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:12.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 28, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 48, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 65; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 85, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 100, and LC-CDR3, which comprises the amino acid sequence sequenceSEQ ID NO:111.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 29, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 49, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 66; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:86, LC-CDR2, which includes the amino acid sequence SEQ ID NO:101, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:112.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 30, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 50, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 67; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:87, LC-CDR2, which includes the amino acid sequence SEQ ID NO:102, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:113.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 31, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 68; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of an amino group The acid sequence consists of SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 32, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 69; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 33, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 52, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 70; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:89, LC-CDR2, which includes the amino acid sequence SEQ ID NO:104, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:115.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 34, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 71; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23 become.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 35, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 54, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 72; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 90, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 105, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:116.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 36, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 55, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 73; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 91, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:117.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 37, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 56, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 74; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 91, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:117.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • heavy The chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 31, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 57, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 75; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 92, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 107, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:118.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 38, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 58, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 76; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 93, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 108, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:119.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 39, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 77; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:120.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 40, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 59, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 78; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 94, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:121.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 41, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 60, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 79; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 42, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:120.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 42, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:120.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 95, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:122.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 44, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 62, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 82; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 96, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 110, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:123.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 45, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 63, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 83; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 97, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:124.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 46, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 98, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 47, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 64, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 84; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 99, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:125.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:126.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 5; and b) the light chain may Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence SEQ ID NO:9, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:11.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 2, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 6; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 8, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 10, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:12.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 28, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 48, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 65; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:85, LC-CDR2, which includes the amino acid sequence SEQ ID NO:100, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:111.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 29, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 49, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 66; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:86, LC-CDR2, which includes the amino acid sequence SEQ ID NO:101, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:112.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 30, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 50, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 67; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 87, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 102, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:113.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 31, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 68; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 32, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 69; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 33, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 52, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 70; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 89, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:115.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 34, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 71; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 35, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 54, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 72; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 90, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 105, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:116.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 36, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 55, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 73; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 91, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:117.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 37, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 56, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 74; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 91, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:117.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 31, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 57, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 75; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 92, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 107, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:118.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 38, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 58, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 76; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 93, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 108, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:119.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 39, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 77; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:120.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 40, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 59, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 78; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 94, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:121.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 41, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 60, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 79; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 42, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:120.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 42, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:120.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 43, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 81; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:122.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 44, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 62, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 82; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 96, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 110, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:123.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 45, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 63, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 83; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 97, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:124.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 46, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 98, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:114.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 47, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 64, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 84; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 99, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:125.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 95, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:126.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 or a variant thereof, which has at least about 80% ( For example, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising SEQ ID NOs : The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21 The component and the light chain constant region comprise or consist of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG2 constant region wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 or a variant thereof, which has at least about 80% ( For example, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising SEQ ID NOs : The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG3 constant region wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 or a variant thereof, which has at least about 80% ( For example, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising SEQ ID NOs : The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 or a variant thereof, which has at least about 80% ( For example, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising SEQ ID NOs : The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgGl constant region wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 column, and a light chain variable domain ( VL ), the VL comprising the amino acid sequence shown in any one of SEQ ID NOs: 18-20, 150-171.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149, and the light chain variable domain ( VL ), the VL comprising the amino acid sequence shown in any one of SEQ ID NOs: 18-20, 150-171 Amino acid sequence.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:13; and VL comprising the amino acid sequence SEQ ID NO:18 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:18 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14; and VL , which comprises the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:15; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof, the variant V L has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 17; and VL comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 20 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 127 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 127; and V L comprising the amino acid sequence set forth in SEQ ID NO: 150 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 150 has at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of amino acids The sequence SEQ ID NO:21 consists of and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 128; and V L comprising the amino acid sequence set forth in SEQ ID NO: 151 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 151 has at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 128; and V L comprising the amino acid sequence set forth in SEQ ID NO: 150 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 150 has at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 129 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 129; and V L comprising the amino acid sequence set forth in SEQ ID NO: 152 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 152 has at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:130; and VL comprising the amino acid sequence SEQ ID NO:153 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:153. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:131; and VL comprising the amino acid sequence SEQ ID NO:154 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:154. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:132; and VL comprising the amino acid sequence SEQ ID NO:155 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:155. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:133; and VL comprising the amino acid sequence SEQ ID NO:156 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:156. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21 and The light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:134; and VL comprising the amino acid sequence SEQ ID NO:157 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:157. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:135; and VL comprising the amino acid sequence SEQ ID NO:158 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:158. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:136; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:137; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant The defined region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:138; and VL comprising the amino acid sequence SEQ ID NO:160 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:160. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:139; and VL comprising the amino acid sequence SEQ ID NO:161 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:161 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:140; and VL comprising the amino acid sequence SEQ ID NO:162 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:162 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 141 or a variant thereof, the variant V L has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 141; and VL comprising the amino acid sequence SEQ ID NO: 163 or a variant thereof, which variant is identical to the amino acid sequence SEQ ID NO: 141.
  • the amino acid sequence SEQ ID NO: 163 has at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:142; and VL comprising the amino acid sequence SEQ ID NO:164 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:164. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:143; and VL comprising the amino acid sequence SEQ ID NO:165 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:165. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:144; and VL comprising the amino acid sequence SEQ ID NO:166 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:166 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:145; and VL comprising the amino acid sequence SEQ ID NO:167 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:167. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:146; and VL comprising the amino acid sequence SEQ ID NO:168 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:168 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:147; and VL comprising the amino acid sequence SEQ ID NO:169 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:169 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:148; and VL comprising the amino acid sequence SEQ ID NO:170 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:170. Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21 and The light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG1 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:149; and VL comprising the amino acid sequence SEQ ID NO:171 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:171 Approximately 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:13; and VL comprising the amino acid sequence SEQ ID NO:18 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:18 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:15; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region Comprising or consisting of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof, the variant V L has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 17; and VL comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 20 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 127 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 127; and V L comprising the amino acid sequence set forth in SEQ ID NO: 150 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 150 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, Said variant is identical to that shown in SEQ ID NO:128 The amino acid sequence has at least about 80% sequence identity; and V L includes the amino acid sequence set forth in SEQ ID NO: 151 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 151 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 128; and V L comprising the amino acid sequence set forth in SEQ ID NO: 150 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 150 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 129 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 129; and V L comprising the amino acid sequence set forth in SEQ ID NO: 152 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 152 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:130; and VL comprising the amino acid sequence SEQ ID NO:153 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:153. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence Composed of SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:131; and VL comprising the amino acid sequence SEQ ID NO:154 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:154. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:132; and VL comprising the amino acid sequence SEQ ID NO:155 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:155. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:133; and VL comprising the amino acid sequence SEQ ID NO:156 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:156. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:134; and VL comprising the amino acid sequence SEQ ID NO:157 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:157. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:135; and VL comprising the amino acid sequence SEQ ID NO:158 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:158. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:136; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:137; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region comprising an IgG4 constant region, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof, the variant Body and amino acid sequence SEQ ID NO: 138 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 160 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 160.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:139; and VL comprising the amino acid sequence SEQ ID NO:161 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:161 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:140; and VL comprising the amino acid sequence SEQ ID NO:162 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:162 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 141 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:141; and VL comprising the amino acid sequence SEQ ID NO:163 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:163. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:142; and VL comprising the amino acid sequence SEQ ID NO:164 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:164. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:143; and VL comprising the amino acid sequence SEQ ID NO:165 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:165. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:144; and VL comprising the amino acid sequence SEQ ID NO:166 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:166 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:145; and VL comprising the amino acid sequence SEQ ID NO:167 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:167. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22 and The light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:146; and VL comprising the amino acid sequence SEQ ID NO:168 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:168. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:147; and VL comprising the amino acid sequence SEQ ID NO:169 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:169 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:148; and VL comprising the amino acid sequence SEQ ID NO:170 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:170. Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a full-length anti-Nogo-A antibody comprising an IgG4 constant region wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:149; and VL comprising the amino acid sequence SEQ ID NO:171 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:171 Approximately 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant The defined region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • Binding affinity is expressed as Kd, Koff, Kon or Ka.
  • Koff refers to the rate constant for the dissociation of an antibody from an antigen/antibody complex, as measured by a kinetic selection device.
  • Kon refers to the binding rate constant at which an antibody binds to an antigen to form an antigen/antibody complex.
  • the equilibrium dissociation constant Kd used in this article refers to the dissociation constant when a specific antibody-antigen interacts. It refers to the antigen concentration required when the antigen occupies half of all antibody binding sites in the antibody molecule solution and reaches equilibrium, which is equal to Koff /Kon. The determination of Kd assumes that all bound molecules are in solution.
  • the corresponding equilibrium dissociation rate constant is expressed as EC 50 , which is a good approximation of Kd.
  • the affinity binding constant Ka is the reciprocal of the dissociation constant Kd.
  • the dissociation constant (Kd) can be used as an indicator of the affinity of the reactive antibody moiety to the antigen.
  • Kd dissociation constant
  • a simple analysis can be performed by the Scatchard method using antibodies labeled with various markers and a Biacore instrument (manufactured by Amersham Biosciences) to analyze interactions between biomolecules by surface plasmon resonance according to the user manual or the included kit. .
  • the Kd value obtained using these methods is expressed in the unit M.
  • Antibodies that specifically bind a target may have, for example, ⁇ 10 -7 M, ⁇ 10 -8 M, ⁇ 10 -9 M, ⁇ 10 -10 M, ⁇ 10 -11 M , ⁇ 10 -12 M, or ⁇ 10 - Kd value of 13 M.
  • the binding specificity of an antibody can be determined experimentally by methods known in the art. These methods include, but are not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore testing, and peptide scanning.
  • the anti-Nogo-A antibody specifically binds to the Nogo-A target with a Kd value of 10 -7 M to 10 -13 M (e.g., 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M).
  • the Kd value of the binding between the anti-Nogo-A antibody and Nogo-A is 10 -7 M to 10 -13 M, 1 ⁇ 10 -7 M to 5 ⁇ 10 - 13 M, 10 - 7 M to 10 -12 M, 10 -7 M to 10 -11 M, 10 -7 M to 10 -10 M, 10 -7 M to 10 -9 M, 10 -8 M to 10 - 13 M, 1 ⁇ 10 -8 M to 5 ⁇ 10 -13 M, 10 -8 M to 10 -12 M, 10 -8 M to 10 -11 M, 10 -8 M to 10 -10 M, 10 -8 M to 10 -9 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -13 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -12 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -11 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 - 10 M, 10 -9 M to 10 -13 M, 10 -9 M to 10 -12 M, 10 -9 M to 10 -12 M, 10 -9 M to 10 -12 M, 10 -9 M
  • the Kd value for binding between the anti-Nogo-A antibody and the non-target is higher than the Kd value for the anti-Nogo-A antibody and the target, and in some embodiments cited herein, the Kd value for the anti-Nogo-A antibody binding to the target (e.g., Nogo-A) has a higher binding affinity than the anti-Nogo-A antibody to the non-target.
  • non-target refers to an antigen other than Nogo-A.
  • the Kd value of the anti-Nogo-A antibody (for Nogo-A) binding to the non-Nogo-A target is at least 10 times different, such as 10-100 times, 100-1000 times, 10 3 -10 4 times, 10 4 -10 5 times, 10 5 -10 6 times, 10 6 -10 7 times, 10 7 -10 8 times, 10 8 -10 9 times, 10 9 -10 10 times, 10 10 -10 11 times, 10 11 -10 12 times.
  • the anti-Nogo-A antibody binds to a non-target with a Kd value of 10 -1 M to 10 -6 M (e.g., 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).
  • the non-target refers to an antigen other than Nogo-A.
  • the Kd value for binding between the anti-Nogo-A antibody and the non-Nogo-A target is 10 -1 M to 10 -6 M , 1 ⁇ 10 -1 M to 5 ⁇ 10 -6 M, 10 -1 M to 10 -5 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -5 M, 10 -1 M to 10 -4 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -4 M, 10 - 1 M to 10 -3 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -3 M, 10 -1 M to 10 -2 M, 10 -2 M to 10 -6 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -6 M, 10 -2 M to 10 -5 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -5 M, 10 -2 M to 10 -4 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -4 M, 10 -2 M to 10 -3 M, 10 -3 M to 10 -6 M, 1 ⁇ 10 -3 M to 5 ⁇ 10 -6 M, 10 -3 M to 10 -5
  • an anti-Nogo-A antibody binds to a Nogo-A target when it is referred to that an anti-Nogo-A antibody specifically recognizes a Nogo-A target with high binding affinity and binds to a non-target with low binding affinity.
  • the Kd value is 10 -7 M to 10 -13 M (such as 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M, 10 -10 M to 10 -12 M), and the Kd value for binding to non-target is 10 -1 M to 10 -6 M (for example, 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).
  • the binding affinity of the anti-Nogo-A antibody is compared to the binding affinity of a control anti-Nogo-A antibody (e.g., ATI-355). Compare.
  • the Kd value for the binding between the control anti-Nogo-A antibody and Nogo-A can be at least 2 times the Kd value for the binding between the anti-Nogo-A antibody and Nogo-A described herein, for example 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 10-100 times, 100-1000 times, 10 3 -10 4 times.
  • nucleic acid molecules encoding anti-Nogo-A antibodies are also considered.
  • a nucleic acid (or set of) nucleic acids encoding a full-length anti-Nogo-A antibody is provided, including any of the full-length anti-Nogo-A antibodies described herein.
  • the nucleic acid (or set of nucleic acids) of the anti-Nogo-A antibody described herein may also include a nucleic acid sequence encoding a polypeptide tag (eg, protein purification tag, His tag, HA tag).
  • isolated host cells comprising an anti-Nogo-A antibody, an isolated nucleic acid encoding an anti-Nogo-A antibody polypeptide component, or a vector comprising a nucleic acid encoding an anti-Nogo-A antibody polypeptide component described herein.
  • variants include nucleotide sequences that hybridize under at least moderately stringent hybridization conditions to a nucleic acid sequence encoding an anti-Nogo-A antibody of the present application.
  • the present application also provides a vector into which the nucleic acid sequence of the present application can be inserted.
  • the natural or synthetic nucleic acid encoding the anti-Nogo-A antibody is inserted into a suitable expression vector such that the nucleic acid is operably linked to the 5' and 3' end regulatory elements, such as a promoter (e.g., lymphocyte Specific promoter) and 3' untranslated region (UTR), can express anti-Nogo-A antibodies (such as full-length anti-Nogo-A antibodies).
  • a promoter e.g., lymphocyte Specific promoter
  • UTR 3' untranslated region
  • the vector is suitable for use in eukaryotic hosts Replication and integration in cells.
  • Typical cloning and expression vectors contain transcriptional and translational terminators, initiation sequences, and promoters that regulate expression of the nucleic acid sequence of interest.
  • nucleic acids described herein can also be used for nucleic acid immunization and gene therapy using standard gene delivery protocols.
  • Nucleic acid delivery methods are known in the art. See, for example, U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, the entire contents of which are incorporated herein by reference.
  • the application also provides gene therapy vectors.
  • Nucleic acids can be cloned into many types of vectors.
  • nucleic acids can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids.
  • Vectors of particular interest include expression vectors, replication vectors, probe generation vectors and sequencing vectors.
  • expression vectors can be provided to cells in the form of viral vectors.
  • Viral vector technology is well known in the art and is described, for example, in Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and other virology or molecular biology manuals.
  • Viruses that can be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses.
  • suitable vectors include an origin of replication functional in at least one organism, promoter sequences, convenient restriction enzyme sites, and one or more selectable markers (see, e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193).
  • retroviruses provide a convenient platform for gene delivery systems.
  • the selected genes can be inserted into vectors and packaged in retroviral particles using techniques known in the art.
  • the recombinant virus is then isolated and delivered to the subject's cells in vivo or in vitro.
  • Many retroviral systems are known in the art.
  • adenoviral vectors are used.
  • Many adenoviral vectors are known in the art.
  • lentiviral vectors are used.
  • Vectors derived from retroviruses, such as lentiviruses are suitable tools for long-term gene transfer because they enable long-term stable integration of the transgene and propagation in progeny cells.
  • Lentiviral vectors have an additional advantage over tumor-derived retroviruses such as murine leukemia virus in that they can transduce non-dividing cells such as hepatocytes. At the same time, it has the additional advantage of low immunogenicity.
  • promoter elements such as enhancers, regulate the frequency of transcription initiation. Typically they are located 30-110 bp upstream of the start site, although recently many promoters have been found to also contain functional elements downstream of the start site.
  • the spacing between promoter elements is usually flexible, so that promoter function is maintained when elements are interchanged or moved with each other. In the thymidine kinase (tk) promoter, activity does not begin to decrease until the spacing between promoter elements increases to 50 bp.
  • tk thymidine kinase
  • a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence that can drive high-level expression of any polynucleotide sequence operably linked to it.
  • CMV immediate early cytomegalovirus
  • EF-1 ⁇ elongation factor 1 ⁇
  • constitutive promoters may also be used, including, but not limited to, simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter , MoMuLV promoter, avian leukemia virus promoter, Epstein-Barr virus immediate early promoter, Rous sarcoma virus promoter and human gene promoters, such as but not limited to actin promoter, myosin promoter, Hemoglobin promoter and creatine kinase promoter.
  • SV40 simian virus 40
  • MMTV mouse mammary tumor virus
  • HV-LTR human immunodeficiency virus long terminal repeat
  • MoMuLV promoter avian leukemia virus promoter
  • Epstein-Barr virus immediate early promoter Epstein-Barr virus immediate early promoter
  • Rous sarcoma virus promoter Rous sarcoma virus promoter
  • human gene promoters such as but not
  • inducible promoters provides a molecular switch when needed This expression enables the expression of the polynucleotide sequence to which it is operably linked, and turns off the expression when it is not needed.
  • inducible promoters include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.
  • expression of anti-Nogo-A antibodies is inducible.
  • a nucleic acid sequence encoding an anti-Nogo-A antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.
  • an inducible promoter provides a molecular switch that turns on the expression of a polynucleotide sequence operably linked to it when expression is desired, and turns off expression when expression is not needed.
  • exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone regulatory elements (see, e.g., Mader, S. and White, J.H. (1993) Proc. Natl. Acad. Sci. USA 90:5603-5607 ), synthetic ligand regulatory elements (see Spencer, D.M. et al (1993) Science 262:1019-1024) and ionizing radiation regulatory elements (see Manome, Y. et al.
  • inducible promoter system used to express anti-Nogo-A antibodies is the Tet system.
  • inducible promoter system used to express anti-Nogo-A antibodies is an E. coli lac repressor system.
  • Tet system An exemplary inducible promoter system used in this application is the Tet system. This system is based on the Tet system described by Gossen et al. (1993).
  • the target polynucleotide is controlled by a promoter containing one or more Tet operator (TetO) sites.
  • TetO Tet operator
  • TetR Tet repressor
  • the activated state for example, in the presence of inducers such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox) or their active analogs, the inducer causes TetR to be released from TetO, resulting in transcription. .
  • Doxycycline is a member of the tetracycline antibiotic family, its chemical name is 1-dimethylamino-2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxy-1,4a ,11,11a,12,12a-hexahydrotetraene-3-carboxamide.
  • TetR is codon-optimized for expression in mammalian cells, such as mouse or human cells. Due to the degeneracy of the genetic code, most amino acids are encoded by more than one codon, resulting in a large number of variants in the sequence of a given nucleic acid without any change in the sequence of its encoded amino acid. However, many organisms have differences in codon usage, also known as "codon preference" (i.e., the preference for a given amino acid to use a specific codon). Codon preference is often associated with the presence of dominant tRNA species for specific codons, which in turn increases the efficiency of mRNA translation. Coding sequences derived from a specific species (e.g., prokaryotes) can thus be tailored through codon optimization to enhance their expression in different species (e.g., eukaryotes).
  • a specific species e.g., prokaryotes
  • Tet-Off transcription is inactive in the presence of Tc or Dox.
  • tTA tetracycline-regulated transcriptional activator
  • TRE tetracycline-responsive promoter element
  • the TRE element consists of a TetO sequence in tandem with a promoter (usually a minimal promoter derived from the human cytomegalovirus immediate early promoter). promoter sequence) fusion composition.
  • a promoter usually a minimal promoter derived from the human cytomegalovirus immediate early promoter. promoter sequence
  • rtTA is a fusion protein composed of the TetR repressor and the VP16 transcriptional activation domain.
  • a 4-amino acid change in the DNA-binding region of TetR changes the binding properties of rtTA, causing it to only recognize the tetO sequence on the target transgene TRE in the presence of Dox. Therefore, in the Tet-On system, rtTA can activate the transcription of TRE-regulated target genes only in the presence of Dox.
  • lac repressor system of E. coli (see Brown et al., Cell 49:603-612 (1987)).
  • the Lac repressor system functions by regulating the transcription of a target polynucleotide operably linked to a promoter containing the lac operator (lacO).
  • lacO lac operator
  • LacR Lac repressor
  • lacR binds to LacO, thereby preventing the transcription of the target polynucleotide.
  • Expression of the polynucleotide of interest is induced by a suitable inducer, for example, isopropyl- ⁇ -D thiogalactopyranoside (IPTG).
  • IPTG isopropyl- ⁇ -D thiogalactopyranoside
  • the expression vector to be introduced into the cell may also contain a selectable marker gene or a reporter gene or both to facilitate the identification and selection of expressing cells from a population of cells transfected or infected with the viral vector.
  • the selectable marker can be carried on separate DNA fragments and used in co-transfection experiments.
  • Either the selectable marker gene or the reporter gene can be flanked by appropriate regulatory sequences to enable expression in the host cell.
  • Useful selectable markers include, for example, antibiotic resistance genes such as neo and similar genes.
  • Reporter genes can be used to identify potentially transfected cells and evaluate the function of regulatory sequences.
  • a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and encodes a polypeptide whose expression is manifested by some readily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cells, the expression of the reporter gene is detected at the appropriate time.
  • Suitable reporter genes may include genes encoding luciferase, ⁇ -galactosidase, chloramphenicol acetyltransferase, secreted alkaline phosphatase, or green fluorescent protein (see, Ui-Tel et al., 2000 FEBS Letters 479 :79-82).
  • Suitable expression systems are well known and can be prepared by known techniques or commercially available.
  • the construct with the smallest 5' flanking region that shows the highest expression level of the reporter gene is considered the promoter.
  • Such promoter regions can be linked to reporter genes and used to assess the ability of certain substances to regulate promoter-driven transcription.
  • nucleic acids encoding any of the full-length anti-Nogo-A antibodies described herein are provided.
  • the nucleic acid includes one or more nucleic acid sequences encoding full-length anti-Nogo-A antibody heavy and light chains.
  • each of the one or more nucleic acid sequences is contained in a separate vector.
  • at least some of the nucleic acid sequences are included in the same vector.
  • all nucleic acid sequences are contained in the same vector.
  • Vectors may be selected, for example, from mammalian expression vectors and viral vectors (eg, vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses).
  • mammalian expression vectors and viral vectors eg, vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses.
  • the vector can be readily introduced into host cells, such as mammalian cells, bacteria, yeast or insect cells, by any method in the art.
  • expression vectors can be introduced into host cells by physical, chemical or biological methods.
  • polynucleotides are introduced into the host cell by calcium phosphate transfection.
  • Biological methods for introducing polynucleotides of interest into host cells include the use of DNA and RNA vectors.
  • Viral vectors especially retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells.
  • Other viral vectors can be derived from lentivirus, poxvirus, herpes simplex virus type 1, adenovirus, adeno-associated virus, etc. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362.
  • colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems including oil-in-water emulsions, micelles, and mixed gels pellets and liposomes.
  • colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems including oil-in-water emulsions, micelles, and mixed gels pellets and liposomes.
  • liposomes eg, artificial membrane vesicles.
  • an exemplary delivery vehicle is liposomes.
  • lipid formulations to introduce nucleic acids into host cells (in vitro, ex vivo, or in vivo).
  • the nucleic acid can be associated with lipids.
  • the nucleic acid bound to the lipid can be packaged into the aqueous interior of the liposome, spread within the lipid bilayer of the liposome, and connected to the liposome through a linker molecule that binds to the liposome and the oligonucleotide.
  • Lipid, lipid/DNA or lipid/expression vector related compositions are not limited to any particular structure in solution. For example, they may exist in bilayer structures, in micelles or in "collapsed" structures. They can also simply disperse in solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances that can be naturally occurring or synthetic lipids.
  • lipids include lipid droplets that occur naturally in the cytoplasm, as well as a class of compounds containing long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, aminoalcohols, and aldehydes.
  • experiments can be performed in order to confirm that the recombinant DNA sequence is present in the host cell.
  • Such experiments include, for example, "molecular biology” experiments well known to those skilled in the art. For example, Southern and Northern blotting, RT-PCR and PCR; "biochemical” experiments, such as detecting the presence or absence of a specific polypeptide, such as by immunological methods (ELISAs and Western blots) or by experiments described in this article All fall within the scope of this application.
  • the anti-Nogo-A antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-Nogo-A antibody comprises VH and VL from a monoclonal antibody, or a variant thereof. In some embodiments, the anti-Nogo-A antibody further includes CH1 and CL regions from a monoclonal antibody, or variants thereof.
  • Monoclonal antibodies can be prepared using, for example, methods known in the art, including hybridoma cell methods, phage display methods, or using recombinant DNA methods. Additionally, exemplary phage display methods are described herein and in the Examples below.
  • an immune agent is usually used to immunize hamsters, mice or other suitable host animals to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the immune agent.
  • lymphocytes can be immunized in vitro.
  • Immunizers can be included A polypeptide or fusion protein including the target protein.
  • PBLs peripheral blood lymphocytes
  • spleen cells or lymph node cells are used. Lymphocytes are fused to immortalized cell lines using an appropriate fusion agent, such as polyethylene glycol, to form hybridoma cells.
  • Immortal cell lines are typically transformed mammalian cells, particularly myeloma cells of rodent, bovine, and human origin. Typically, rat or mouse myeloma cell lines are used.
  • Hybridoma cells can be cultured in a suitable medium, which preferably contains one or more substances that inhibit the growth or survival of unfused immortal cells. For example, if the parent cells lack the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), hybridoma cell culture medium typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), which can Prevents the growth of HGPRT-deficient cells.
  • HGPRT hypoxanthine-guanine phosphoribosyltransferase
  • the immortalized cell lines fuse efficiently, ensure high-level and stable expression of the antibody by the selected antibody-producing cells, and are sensitive to certain media, such as HAT media.
  • the immortal cell line is a mouse myeloma cell line, available from, for example, the Salk Cell Collection in San Diego, California, and the American Type Culture Collection in Manassas, Virginia. Also described are human myeloma and mouse-human hybrid myeloma cell lines for the preparation of human monoclonal antibodies.
  • the culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide.
  • the binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by immunoprecipitation or in vitro binding experiments, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art.
  • the binding affinity of a monoclonal antibody can be determined by Scatchard analysis as described, for example, in Munson and Pollard, Anal. Biochem., 107:220 (1980).
  • hybridoma cells After the desired hybridoma cells are identified, the clones of interest can be subcloned by limiting dilution and cultured by standard methods. Suitable media for this purpose include, for example, modified Eagle's medium (DMEM) and RPMI-1640 medium. Alternatively, hybridoma cells can be grown in mammals in the form of ascites fluid.
  • DMEM modified Eagle's medium
  • RPMI-1640 medium RPMI-1640
  • Monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascitic fluid by conventional immunoglobulin purification methods, such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity Chromatography.
  • immunoglobulin purification methods such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity Chromatography.
  • the anti-Nogo-A antibody comprises sequences selected from clones of an antibody library (eg, a phage library displaying scFv or Fab fragments).
  • the clones can be identified by screening a combinatorial library of antibody fragments with the desired activity.
  • various methods are known in the art for generating phage display libraries and screening these libraries for antibodies with desired binding properties. These methods are reviewed, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and in, for example, McCafferty et al.
  • phage display methods all components of the V H and V L genes are cloned separately through polymerase chain reaction (PCR), randomly recombined in a phage library, and then screened for phages that can bind the antigen, such as Winter et al. ., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments as scFv fragments or as Fab fragments. Immunogenically derived library phages provide high-affinity antibodies against immunogens without the need to construct hybridoma cells.
  • PCR polymerase chain reaction
  • natural libraries can be cloned to provide a single source of antibodies against multiple non-self and self-antigens without the need for any immunization, as in Griffiths et al., EMBO J, 12:725-734 (1993 ) as stated in.
  • natural libraries can also be prepared by cloning non-rearranged V-gene fragments from stem cells and using PCR primers containing random sequences to encode the CDR3 hypervariable region and completing the rearrangement in vitro, such as Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992).
  • Patent publications describing human antibody phage libraries include, for example, US Pat. No. 5,750,373 and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/029 2936 and 2009/0002360.
  • the anti-Nogo-A antibody is prepared by phage display screening the anti-Nogo-A antibody part in the library that can specifically bind to the target Nogo-A.
  • the library may be a human scFv phage display library with at least 1 ⁇ 10 9 (e.g., at least 1 ⁇ 10 9 , 2.5 ⁇ 10 9 , 5 ⁇ 10 9 , 7.5 ⁇ 10 9 , 1 ⁇ 10 10 , 2.5 ⁇ 10 10 , 5 ⁇ 10 10 , 7.5 ⁇ 10 10 or 1 ⁇ 10 11 ) diversity of unique human antibody fragments.
  • the library is a human natural library, constructed from DNA extracted from PMBCs and spleens of healthy subjects, containing all human heavy and light chain subfamilies.
  • the library is a human natural library constructed from DNA extracted from PMBCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases.
  • the library is a semi-synthetic human library in which the heavy chain CDR3s are completely random and all amino acids (except cysteine) are present with equal probability at any given position. (See, eg, Hoet, RM et al., Nat. Biotechnol. 23(3):344-348, 2005).
  • the heavy chain CDR3 length of the semi-synthetic human library ranges from 5 to 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23 or 24) between amino acids.
  • the library is a fully synthetic phage display library.
  • the library is a non-human phage display library.
  • Phage clones with high affinity to target Nogo-A can be screened by iterative binding of phage to target Nogo-A bound to a solid support (e.g. beads for solution panning or cells for cell panned mammalian cells), followed by removal of unbound phage and elution of specifically bound phage. Subsequently, bound phage clones are eluted and used to infect suitable host cells, such as E. coli XL1-Blue, for expression and purification.
  • Phage clones that specifically bind Nogo-A can be enriched by multiple rounds of panning (eg, 2, 3, 4, 5, 6, or more rounds), such as solution panning, cell panning, or a combination of both. Specific binding of the enriched phage clones to the target Nogo-A can be detected by any method known in the art, including, for example, ELISA and FACS.
  • Another way to screen antibody libraries is to display proteins on the surface of yeast cells.
  • Wittrup et al. (US Patents 6,699,658 and 6,696,251) developed a method for displaying libraries in yeast cells.
  • one component includes the yeast lectin protein (Aga1), which is anchored to the yeast cell wall, and the other component includes the second subunit of the lectin protein Aga2, which can pass through disulfide bonds. Binds to the Aga1 protein and is displayed on the surface of yeast cells. Staining by integrating the Aga1 gene into yeast to express Aga1 protein in vivo.
  • a single-chain variable fragment (scFv) library is fused to the Aga2 gene in a yeast display plasmid and, after transformation, remains in the yeast due to the presence of an additional nutritional marker. Both Aga1 and Aga2 proteins are expressed under the control of galactose-inducible promoters.
  • the human antibody V gene library (V H and V K fragments) was obtained by PCR using a set of degenerate primers (Sblattero, D. and Bradbury, A. Immunotechnology 3, 271-278 1998).
  • PCR templates were derived from commercially available RNA or cDNA, including PBMC, spleen, lymph nodes, bone marrow, and tonsils.
  • Independent V H and V K PCR libraries were combined and assembled into scFv formats by overlap extension PCR (Sheets, MD et al, Proc. Natl. Acad. Sci. USA 95, 6157–6162 1998).
  • yeast scFv display library To construct a yeast scFv display library, the resulting scFv PCR product was cloned into a yeast display plasmid in yeast by homologous recombination. (Chao, G, et al, Nat Protoc. 2006; 1(2):755-68. Miller KD, et al. Current Protocols in Cytometry 4.7.1-4.7.30, 2008).
  • Anti-Nogo-A antibodies can be screened using a mammalian cell display system, in which the antibody moiety is displayed on the cell surface and antibodies specifically targeting Nogo-A are isolated by antigen-directed screening methods (as in U.S. patent No. 7,732,195B2 described).
  • a Chinese hamster ovary (CHO) cell library displaying a large number of human IgG antibody genes can be created and used to discover clones expressing high-affinity antibody genes.
  • An alternative display system has been developed that allows the same protein to be simultaneously displayed and secreted on the cell surface through alternative splicing, in which the phenotype of the displayed protein remains correlated with the genotype, allowing for simultaneous biophysical and cell function-based analyses. Characterize the secreted soluble antibodies.
  • This method overcomes many of the limitations of previous mammalian cell displays and enables direct screening and maturation of antibodies in the form of full-length, glycosylated IgGs (Peter M. Bowers, et al, Methods 2014, 65: 44-56) .
  • Transient expression systems are suitable for a single round of antigen selection prior to antibody gene recovery and are therefore most useful for selecting antibodies from smaller libraries.
  • Stable exosome vectors offer an attractive option. Exosome vectors can be efficiently transfected and stably maintained at low copy numbers, allowing for multiple rounds of panning and elucidation of more complex antibody libraries.
  • the IgG library was constructed based on the ligation of germline sequence V gene fragments isolated from a pool of human donors and rearranged (D)J regions. RNA collected from 2000 human blood samples was reverse transcribed into cDNA, VH and VK fragments were amplified using VH and VK specific primers, and purified by gel extraction. The VH and VK fragments were subcloned into display vectors containing IgG1 or K constant regions respectively, and then electroporated or transduced 293T into cells to prepare IgG libraries.
  • V H and V K are ligated to generate scFv, which is then subcloned into a display vector and electroporated or transduced into 293T cells.
  • IgG libraries are constructed based on germline sequence V gene fragments and rearranged (D)J regions isolated from a group of donors, which can be mice, rats, rabbits or monkeys.
  • Monoclonal antibodies can also be prepared by recombinant DNA methods, such as those described in US Patent No. 4,816,567.
  • DNA encoding the monoclonal antibodies described herein can be readily isolated and sequenced by conventional methods (eg, by oligonucleotide probes that specifically bind to genes encoding the light and heavy chains of murine antibodies).
  • Hybridoma cells as described above or Nogo-A specific phage clones of the present application can be used as a source of such DNA.
  • the DNA can be placed into an expression vector, which can then be transfected into host cells, such as simian COS cells, Chinese hamster ovary cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain the expression in the recombinant host.
  • host cells such as simian COS cells, Chinese hamster ovary cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain the expression in the recombinant host.
  • Monoclonal antibodies synthesized in cells may also be modified, for example, by replacing human heavy and light chain constant regions with coding sequences and/or by replacing homologous non-human sequences with framework regions (US Patent No.
  • non-immunoglobulin polypeptide linked by a covalent bond to the coding sequence for an immunoglobulin.
  • This non-immunoglobulin polypeptide can replace the constant region of the antibody in this application, or can replace an antigen-binding site in the variable domain of the antibody in this application, forming a chimeric bivalent antibody.
  • the antibody may be a monovalent antibody.
  • Methods of preparing monovalent antibodies are known in the art. For example, one involves a recombinant expression method involving an immunoglobulin light chain and a modified heavy chain.
  • the heavy chain is usually truncated at any position in the Fc region to prevent the heavy chains from cross-linking with each other.
  • the relevant cysteine residues are substituted with other amino acid residues or deleted to prevent cross-linking.
  • In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, can be accomplished using any method known in the art.
  • Antibody variable domains with the desired binding specificity can be fused to immunoglobulin constant regions. Fusions to the immunoglobulin heavy chain constant region, including at least part of the hinge, CH2 and CH3 regions, are preferred. In some embodiments, the first heavy chain constant region (CH1), which contains the necessary sites for light chain binding, is present in at least one fusion. DNA encoding the immunoglobulin heavy chain fusion, and if desired, DNA encoding the immunoglobulin light chain, is inserted into a separate expression vector and co-transfected into a suitable host organism.
  • the anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) can be a fully human antibody or a humanized antibody.
  • Humanized forms of non-human (e.g., mouse) antibody portions are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., Fv, Fab, Fab', F(ab') 2 , scFv, or other fragments of antibodies Antigen binder sequences), which generally include minimal sequences derived from non-human immunoglobulins.
  • Humanized antibodies include human immunoglobulins, immunoglobulin chains or fragments thereof (recipient antibodies) in which the residues of the acceptor CDRs are replaced by non-human (donor antibody) CDRs with the desired specificity, affinity and properties. Residue substitutions, such as mouse, rat or rabbit CDRs. In some embodiments, human immunoglobulin Fv framework residues are replaced with corresponding non-human residues. Humanized antibodies may also contain amino acid residues that neither belong to the recipient antibody nor are in the introduced CDR or framework sequence.
  • a humanized antibody contains at least one, and usually two variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are common to human immunoglobulins. sequence.
  • humanized antibodies typically contain one or more amino acid residues introduced from a non-human source. Those non-human amino acid residues are often referred to as "implanted” residues, usually from the "imported” variable domain. According to some embodiments, humanization can be performed essentially as described by Winter and colleagues (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 ( 1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by replacing the corresponding sequences of human antibodies with rodent CDRs or CDR sequences. Thus, this "humanized” antibody portion (U.S. Patent No.
  • a humanized antibody portion is a typical human antibody portion in which some CDR residues and possibly some framework region residues are replaced by residues from similar positions in rodent antibodies.
  • Fully human antibodies are an alternative to humanization. For example, it is now possible to generate transgenic animals (eg, mice) that are capable of producing a complete library of fully human antibodies upon immunization without producing endogenous immunoglobulins. For example, it has been reported that homozygous deletion of the antibody heavy chain junction region (JH) gene in chimeric and germline mutant mice completely inhibits endogenous antibody production.
  • JH antibody heavy chain junction region
  • Fully human antibodies can also be produced by activating B cells in vitro (see U.S. Patents 5,567,610 and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227: 381 (1991); Marks et al., J. Mol. Biol., 222: 581 (1991).
  • the technology of Cole et al. and Boerner et al. It can also be used to prepare fully human monoclonal antibodies. See Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991).
  • the amino acid sequences of anti-Nogo-A antibody variants are also contemplated.
  • the amino acid sequences of antibody variants can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the antibody amino acid sequence.
  • the final construct can be accomplished by any combination of deletions, insertions, and substitutions of amino acid residues to give it the desired characteristics. For example, antigen binding.
  • anti-Nogo-A antibody variants with one or more amino acid substitutions are provided.
  • Target sites for substitution mutations include hypervariable regions (HVRs) and framework regions (FRs).
  • Amino acid substitutions can be introduced into the antibody of interest and the product screened for the desired activity, for example, improved biological activity, maintained/improved antigen binding capacity, reduced immunogenicity, or improved ADCC or CDC.
  • Amino acids are divided into different categories based on the nature of their side chains:
  • Acidic amino acids aspartic acid Asp, glutamic acid Glu;
  • Aromatic amino acids tryptophan Trp, tyrosine Tyr, phenylalanine Phe.
  • Substitutions of non-conservative amino acids involve substitution of one category for another category.
  • An exemplary substitution variant is an affinity matured antibody, which can be conveniently produced using, for example, phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, variant antibody moieties are displayed on phage, and organisms screened for specific biological activity (e.g., based on hNiG-induced neurite growth inhibition in a restorative activity assay or binding affinity) chemical activity). Alterations (eg, substitutions) can be made in the HVRs region to obtain improved biological activity based on hNiG-induced neurite growth inhibition restoration assays or binding affinity.
  • Alterations can occur in "hot spots" of HVR, i.e., codon-encoded residues that are highly mutated during somatic cell maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or detect the binding affinity of the resulting variants VH and VL at specific decisive residues (SDRs).
  • SDRs decisive residues
  • variable genes selected for affinity maturation are introduced into the variable genes selected for affinity maturation by any of a variety of methods, such as error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis. .
  • Secondary libraries are then created. The library is screened to identify antibody variants with the desired affinity.
  • Another way to introduce diversity includes the HVR-mediated manner, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically recognized, for example, using alanine scanning mutagenesis or modeling. Usually the CDR-H3 and CDR-L3 regions are particularly focused targets.
  • substitutions, insertions, or deletions may occur within one or more HVRs, so long as such changes do not substantially reduce the ability of the antibody to bind the antigen.
  • conservative changes eg, conservative substitutions provided herein
  • HVRs that do not substantially reduce binding affinity. These changes may occur outside the HVR "hot zone" or SDRs area.
  • each HVR is either unchanged or contains no more than 1, 2, or 3 amino acid substitutions.
  • a useful method for identifying amino acid residues or regions of an antibody that can be targeted mutated is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085 .
  • target residues e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamic acid
  • neutral or negatively charged amino acids e.g., , alanine or glutamic acid
  • Further substitutions can be introduced at amino acid positions to demonstrate functional sensitivity of the position to the initial substitution.
  • the contact sites between the antibody and the antigen are identified through the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues can be targeted or eliminated as substitution candidates. Screen variants to determine if they have the desired properties.
  • Insertions of amino acid sequences including fusions at the amino and/or carboxyl terminus, ranging in length from 1 residue to polypeptides containing 100 or more residues, and including insertion of 1 or more amino acid residues within the sequence base.
  • terminal insertions include antibodies with a methionyl residue at the N-terminus.
  • Other insertional variants of antibody molecules include fusion of an enzyme (eg, ADEPT) or peptides that increase the serum half-life of the antibody to the N- or C-terminus of the antibody molecule.
  • one or more amino acid modifications are introduced into the Fc region of an antibody described herein (eg, a full-length anti-Nogo-A antibody or an anti-Nogo-A antibody fusion protein), thereby generating Fc region variants.
  • Fc region variants have enhanced ADCC potency, typically associated with binding to Fc receptors (FcRs).
  • Fc region variants have reduced ADCC efficacy.
  • changes or mutations in the Fc sequence affecting its potency For example, WO 00/42072 and Shields et al. J Biol. Chem. 9(2):6591-6604 (2001) describe enhanced binding to FcRs or Attenuated antibody variants. The contents of these publications are incorporated herein by reference.
  • ADCC Antibody-dependent cell-mediated cytotoxicity
  • NK cells activated by antibodies.
  • NK cells express the Fc receptor CD16. This receptor recognizes and binds to the Fc portion of the antibody molecule bound to the surface of the target cell.
  • the most common Fc receptors on the surface of NK cells are CD16 or Fc ⁇ RIII.
  • Binding of Fc receptors to the Fc region of antibodies results in activation of NK cells, release of cell lytic granules, and subsequent target cell apoptosis.
  • the killing effect of ADCC on tumor cells can be measured through specific experiments of NK-92 cells transfected with high-affinity FcR. The results were compared with wild-type NK-92, which does not express FcR.
  • the application also provides anti-Nogo-A antibody variants (e.g., full-length anti-Nogo-A antibody variants) that comprise an Fc region having some, but not all, of the effector functions such that they have extended in vivo half-life, however specific effector functions (such as CDC or ADCC) are non-essential or deleterious, making this anti-Nogo-A antibody an ideal candidate for this application.
  • Reduction/elimination of CDC and/or ADCC activity is confirmed by performing cytotoxicity assays in vitro and/or in vivo. For example, via Fc (FcR) binding assay to confirm that the antibody lacks Fc ⁇ R binding ability (and therefore may lack ADCC activity) but still retains FcRn binding ability.
  • NK cells only express Fc ⁇ RIII, while monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • the expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet Annu. Rev. Immunol. 9:457-492 (1991).
  • Non-limiting examples of in vitro assessment of ADCC activity of target molecules are described in US Pat. No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986 ) and Hellstrom, I et al., Proc. Nat'l Acad. Sci.
  • Nonradioactive detection methods can be used (see, e.g., ACTI TM Flow Cytometry Nonradioactive Cytotoxicity Assay (Cell Technology, Inc. Mountain View, Calif.) and CYTOTOX 96 TM Nonradioactive Cell Toxicity assays (Promega, Madison, Wis.). Effector cells used in these assays include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK).
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • the ADCC activity of the target molecule is performed in vivo Detection, for example, in animal models, as described in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998).
  • a C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q , thereby lacking CDC activity. See, for example, C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402.
  • a CDC assay can be performed (see, for example, Gazzano-Santoro et al., J. Immunol.
  • Antibodies with reduced effector function include substitution of one or more residues at residues 238, 265, 269, 270, 297, 327, and 329 of the Fc region (U.S. Pat. No. 6,737,056). These Fc variants include Fc variants with substitutions of two or more residues at positions 265, 269, 270, 297 and 327, including the Fc variant known as "DANA" which has substitutions at residues 265 and 297. The base is substituted with alanine (U.S. Pat. No. 7,332,581).
  • an anti-Nogo-A antibody (eg, a full-length anti-Nogo-A antibody) variant is provided that includes an Fc region variant with one or more amino acid substitutions capable of enhancing ADCC effects.
  • the Fc region variant contains one or more amino substitutions capable of enhancing the ADCC effect at positions 298, 333 and/or 334 (EU residue numbering) of the Fc region.
  • the anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) variant includes amino acid substitutions at positions S298A, E333A, and K334A in the Fc region.
  • changes in the Fc region result in changes (i.e., enhancement or attenuation) of Clq binding and/or complement-dependent cytotoxicity (CDC), see U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. al., J. Immunol. 164:4178-4184 (2000).
  • changes in the Fc region result in changes (i.e., enhancement or attenuation) of Clq binding and/or complement-dependent cytotoxicity (CDC), see U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. al., J. Immunol. 164:4178-4184 (2000).
  • an anti-Nogo-A antibody e.g., a full-length anti-Nogo-A antibody
  • an Fc region variant with one or more amino acid substitutions capable of extending half-life or enhancing association with the Fc Receptor (FcRn) binding is provided that includes an Fc region variant with one or more amino acid substitutions capable of extending half-life or enhancing association with the Fc Receptor (FcRn) binding.
  • FcRn Fc Receptor
  • Fc variants contain 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or One or more substitutions in residue 434, such as substitution of residue 434 in the Fc region (US Pat. No. 7,371,826).
  • anti-Nogo-A antibodies eg, full-length anti-Nogo-A antibodies
  • Fc variants described herein or combinations thereof.
  • anti-Nogo-A antibodies provided herein are altered to increase or decrease the extent of glycosylation of the anti-NGF antibody. Adding or deleting glycosylation sites on the anti-Nogo-A antibody can be easily accomplished by changing the amino acid sequence of the anti-NGF antibody or its polypeptide portion to add or remove one or more glycosylation sites.
  • the anti-Nogo-A antibody contains an Fc region that can change the sugar attached to it.
  • Natural antibodies produced by mammalian cells typically contain branched biantennary oligosaccharides that are often linked to the Fc region CH2 domain Asn297 via an N-link, see e.g. Wright et al., TIBTECH 15:26-32 (1997) .
  • the oligosaccharides can include a variety of sugars, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as trehalose linked to GlcNAc in the "stem" portion of the biantennary oligosaccharide structure.
  • the anti-Nogo-A antibodies of the present application can be subjected to oligosaccharide modifications, thereby producing anti-Nogo-A antibody variants with certain improved properties.
  • N-glycans linked to the CH2 domain of the Fc region are heterogeneous.
  • Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al., J. Biochem. 2006, 140:777-83.
  • a small proportion of naturally occurring afucosylated IgGs can be detected in human serum.
  • N-glycosylation of the Fc region is important for its binding to Fc ⁇ R; afucosylated N-glycan enhances the binding ability of Fc to Fc ⁇ RIIIa.
  • the enhanced binding ability to FcRIIIa results in enhanced ADCC effect, which is advantageous in certain antibody therapeutic applications that require cytotoxicity.
  • enhanced effector function may be detrimental when Fc-mediated cytotoxicity is not required.
  • the Fc fragment or CH2 domain is non-glycosylated.
  • glycosylation is prevented by mutating the N-glycosylation site in the CH2 domain.
  • anti-Nogo-A antibody e.g., full-length anti-Nogo-A antibody
  • variants comprise an Fc region, wherein the carbohydrate structure linked to the Fc region has reduced fucose or lacks fucose.
  • Sugar which may enhance ADCC function.
  • anti-Nogo-A antibodies that have reduced fucose relative to the same anti-Nogo-A antibody produced by wild-type CHO cells. That is, they are characterized by having smaller amounts of fucose than antibodies produced by native CHO cells (e.g., CHO cells that produce the native glycosylated form, CHO cells that contain the native FUT8 gene).
  • the N-linked glycan of the anti-Nogo-A antibody has less than 50%, 40%, 30%, 20%, 10%, or 5% fucose.
  • the fucose content of the anti-Nogo-A antibody may be 1%-80%, 1%-65%, 5%-65%, or 20%-40%.
  • the N-linked glycans of the anti-Nogo-A antibody do not contain fucose, i.e., wherein the anti-Nogo-A antibody contains no fucose at all, Either without fucose or defucosylated.
  • the fucose content is calculated by calculating the average fucose content within the sugar chain attached to Asn297 relative to the total of all sugar structures attached to Asn297 (such as complex, hybrid or mannose structures) measured by MALDI-TOF mass spectrometry. quantity, as described in WO 2008/077546.
  • Asn297 refers to the asparagine residue located at position 297 of the Fc region (EU Fc region residue numbering system). However, due to minor sequence changes in the antibody, Asn297 can also be located ⁇ 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. These fucosylation variants may have enhanced ADCC function. See, for example, US Patent Publication Nos.
  • Cell lines capable of producing afucosylated antibodies include Lec13 CHO cells lacking protein fucosylation function (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003 /0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially Example 11), and gene knockout cell lines, such as ⁇ -1,6-fucosyltransferase gene, FUT8 Gene knockout CHO cells (see Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003/085107).
  • Anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) variants further provide bisecting oligosaccharides, eg, wherein the biantennary oligosaccharide linked to the Fc region of the anti-Nogo-A antibody is bisected by GlcNAc.
  • Such anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) variants may have reduced fucosylation and/or enhanced ADCC function. Examples of such antibody variants are in WO 2003/011878 (Jean-Mairet et al.); U.S. Pat. No.
  • anti-Nogo-A antibody eg, full-length anti-Nogo-A antibody
  • anti-Nogo-A antibody variants having at least one galactose residue in the oligosaccharide linked to the Fc region.
  • anti-Nogo-A antibody variants may have enhanced CDC function.
  • Such variants are described, for example, in WO1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
  • the anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) variant comprises an Fc region capable of binding FcyRIII.
  • the anti-Nogo-A antibody (e.g., full-length anti-Nogo-A antibody) variant comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells), or is identical to a human wild-type
  • the Fc region of IgG1 has enhanced ADCC activity in the presence of human effector cells compared to other identical anti-Nogo-A antibodies (eg, full-length anti-Nogo-A antibodies).
  • cysteine-engineered anti-Nogo-A antibody e.g., a full-length anti-Nogo-A antibody
  • the substituted residue occurs in the anti- Accessible sites for Nogo-A antibodies.
  • reactive thiol groups are located in accessible sites of the anti-Nogo-A antibody and can be used to couple the anti-Nogo-A antibody to other moieties, such as drug moieties or linkers.
  • Cysteine-engineered anti-Nogo-A antibodies eg, full-length anti-Nogo-A antibodies
  • anti-Nogo-A antibodies eg, full-length anti-Nogo-A antibodies
  • anti-Nogo-A antibodies can be further modified to include other non-protein moieties known in the art and readily available.
  • Suitable moieties for derivatizing anti-Nogo-A antibodies include, but are not limited to, water-soluble polymers.
  • Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymer, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1 , 3-dioxopentane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer), dextran or poly(n- vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymer, propylene oxide/ethylene oxide copolymer, polyoxyethylated polyols (such as glycerol), polyvinyl alcohol, and mixtures thereof.
  • PEG polyethylene glycol
  • ethylene glycol/propylene glycol copolymer carboxymethylcellulose
  • dextran polyvinyl alcohol
  • polyvinylpyrrolidone poly-1 , 3-diox
  • Polyethylene glycol propionaldehyde offers advantages in manufacturing due to its stability in water.
  • the polymers can be of any molecular weight and can be branched or unbranched.
  • the number of polymers attached to the anti-Nogo-A antibody can vary, and if more than one polymer is attached, they can be the same or different molecules.
  • the amount and/or type of polymer used for derivatization can be determined based on considerations including, but not limited to, the need to improve the properties or functionality of the anti-Nogo-A antibody, whether the anti-Nogo-A antibody derivative is used Treatment for specific conditions, etc.
  • compositions comprising any anti-Nogo-A antibody (eg, a full-length anti-Nogo-A antibody), a nucleic acid encoding the antibody, a vector comprising a nucleic acid encoding an antibody, or a host cell comprising a nucleic acid or vector described herein (For example, pharmaceutical compositions, also referred to herein as formulations).
  • a pharmaceutical composition comprising any of the anti-Nogo-A antibodies described herein and a pharmaceutically acceptable carrier.
  • a suitable antibody can be obtained by mixing an anti-Nogo-A antibody of the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980))
  • Anti-Nogo-A antibody preparations are prepared in the form of lyophilized preparations or liquid preparations.
  • Acceptable carriers, excipients or stabilizers are non-toxic to the recipient at the doses and concentrations used and include buffers such as phosphates, citric acid and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g.
  • Octadecyldimethylbenzyl ammonium chloride hexamethylammonium chloride; benzalkonium chloride; benzethonium chloride; phenol; butanol or benzyl alcohol; alkyl parabens, such as p-hydroxybenzoate Methyl formate or propyl parahydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than 10 residues) peptides; proteins, e.g.
  • hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes such as zinc-protein complex); and/or non-ionic surfactants such as TWEEN TM , PLURONICS TM or polyethylene glycol (PEG); exemplary formulations are as described in WO98/56418, expressly incorporated herein by reference.
  • Lyophilized formulations suitable for subcutaneous administration are available in Described in WO97/04801. Such lyophilized formulations can be reconstituted with appropriate diluents into high protein concentration formulations, and the reconstituted formulations can be administered subcutaneously to the individuals to be treated herein. Cationic liposomes or liposomes can be used to deliver the anti-Nogo-A antibodies of the present application to cells.
  • the formulations described herein may also contain one or more other active substances necessary for the treatment of a specific disorder, preferably with complementary and mutually exclusive activities. adverse reaction substances.
  • anti-Nogo-A antibodies it may be necessary to further include corticosteroids, neurotrophic factors such as NGF, BDNF, or other drugs for neurodegenerative diseases such as Exelon TM , Levodopa, etc.
  • corticosteroids neurotrophic factors
  • neurotrophic factors such as NGF, BDNF
  • drugs for neurodegenerative diseases such as Exelon TM , Levodopa, etc.
  • Effective amounts of other substances will depend on the amount of anti-Nogo-A antibody in the formulation, the type of disease or condition or treatment, and other factors as discussed above.
  • These drugs are typically used at the same dosages and routes of administration as described herein, or at 1% to 99% of currently used doses.
  • the anti-Nogo-A antibody (e.g., full-length anti-Nogo-A antibody) can also be embedded in microcapsules prepared, for example, by coacervation techniques and interfacial polymerization, such as in colloidal drug delivery systems (e.g., liposomes, Hydroxymethylcellulose or gelatin-microcapsules and poly(methyl methacrylate) microcapsules in albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Sustained release formulations can be prepared.
  • colloidal drug delivery systems e.g., liposomes, Hydroxymethylcellulose or gelatin-microcapsules and poly(methyl methacrylate) microcapsules in albumin microspheres, microemulsions, nanoparticles and nanocapsules
  • Sustained release formulations can be prepared.
  • Sustained release formulations of anti-Nogo-A antibodies can be prepared.
  • suitable examples of sustained release formulations include solid hydrophobic polymeric semipermeable matrices containing the antibodies (or fragments thereof) in the form of shaped articles, for example, films or microcapsules.
  • sustained-release matrices include polyester, hydrogel (eg, poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid (U.S. Pat. No.
  • L-glutamine Acid and L-glutamic acid ethyl ester copolymer non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer such as LUPRON DEPOTTM (a biodegradable product composed of lactic acid-glycolic acid copolymer and leuprolide acetate) injection microspheres) and poly-D(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic-glycolic acid can release molecules over 100 days, certain hydrogels can release proteins in much shorter time periods.
  • encapsulated antibodies When encapsulated antibodies stay in the body for a long time, they will denature or aggregate due to exposure to a humid environment at 37°C, which may lead to loss of biological activity or changes in immunogenicity.
  • Reasonable strategies can be designed to stabilize anti-Nogo-A antibodies based on the corresponding mechanisms. For example, if the aggregation mechanism is found to be through thiodisulfide exchange to form intermolecular S-S bonds, this can be achieved by modifying sulfhydryl residues, lyophilizing in acidic solutions, controlling water content, using appropriate additives, and developing specific polymers. matrix composition to achieve stabilization.
  • the anti-Nogo-A antibody (e.g., full-length anti-Nogo-A antibody) is formulated in a solution containing citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 80) or any combination of the above buffers.
  • Preparations for in vivo administration must be sterile. This can be easily achieved, for example, by applying sterile filtration membrane filtration.
  • Anti-Nogo-A antibodies e.g., full-length anti-Nogo-A antibodies
  • compositions described herein can be administered to individuals (e.g., mammals, such as humans) to treat disorders resulting from dysregulation of the Nogo-A signaling pathway.
  • Neurodegenerative diseases and/or conditions e.g., central nervous system and/or peripheral nervous system disease or trauma
  • neurodegenerative diseases such as Alzheimer's disease Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, other common dementias, post-traumatic disorders of the head, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, Monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease, pontine myelmolysis, adrenoleukodystrophy, Pelizois-Metzbach disease, spongiform disease Encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabb's disease, degenerative visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration , diabetic
  • the present application provides a method of treating individuals suffering from diseases and/or conditions caused by dysregulation of the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system diseases or trauma), Comprised of administering to an individual an effective amount of a composition (e.g., a pharmaceutical composition) comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), such as any of the anti-Nogo-A antibodies described herein ( For example, a full-length anti-Nogo-A antibody), in some embodiments, the individual is a human.
  • a composition e.g., a pharmaceutical composition
  • an anti-Nogo-A antibody e.g., a full-length anti-Nogo-A antibody
  • the individual is a human.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The individual is administered an effective amount of a pharmaceutical composition comprising a Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody) that specifically binds to an epitope on human Nogo-A, wherein the epitope comprises an amino acid of human Nogo-A Residues.
  • a pharmaceutical composition comprising a Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody) that specifically binds to an epitope on human Nogo-A, wherein the epitope comprises an amino acid of human Nogo-A Residues.
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), ischemic
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), a heavy chain variable domain ( VH ) comprising: a heavy chain complementarity determining region ( HC-CDR)1, which contains DYGMH (SEQ ID NO:1); HC-CDR2, which contains SISHTGKTVFYGESVKG (SEQ ID NO:3); and HC-CDR3, which contains TELGGDNWFDV (SEQ ID NO:5); and light Chain variable domain (V L ), the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes TGSSSNIGGYDVY (SEQ ID NO: 7); LC-CDR2, which includes DNKRPS (SEQ ID NO:
  • the anti-Nogo-A antibody is fully long antibodies. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody includes VH , and the VH includes: HC-CDR1, which includes the amino acid sequence shown in SEQ ID NO: 1, HC-CDR2, which includes The amino acid sequence shown in SEQ ID NO:3, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:5, or a variant of the V H whose HC-CDRs include up to about 5 amino acids.
  • the VL includes: LC-CDR1, which includes the amino acid sequence shown in SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO:9, and LC-CDR3 , which includes the amino acid sequence shown in SEQ ID NO: 11, or a variant of said V L , which contains at most about 5 amino acid substitutions in its LC-CDRs.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence shown in any one of SEQ ID NOs: 13-16 or a variant thereof, the variant A body having at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 13-16; and a V L comprising an amino acid sequence shown in any one of SEQ ID NOs: 18-19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 18-19.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody includes: VH , the VH includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 5, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L bag Containing: LC-CDR1, which includes the amino acid sequence SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence SEQ ID NO:9, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:11, or the V L Variants containing up to about 5
  • the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof that is at least the same as the amino acid sequence SEQ ID NO: 13 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 18 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 18.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof that is at least the same as the amino acid sequence SEQ ID NO: 14 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 19.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof that is at least the same as the amino acid sequence SEQ ID NO: 15 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 19.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof that is at least the same as the amino acid sequence SEQ ID NO: 16 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 19.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant The defined region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:2, HC-CDR2, which includes the amino acid sequence SEQ ID NO:4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:6, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 8, LC- CDR2, which includes the amino acid sequence of SEQ ID NO:
  • VH heavy chain variable domain
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence shown in SEQ ID NO: 17 or a variant thereof, the variant being identical to SEQ ID NO :
  • the amino acid sequence shown in 17 has at least about 80% sequence identity; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:20 or a variant thereof, which variant is identical to SEQ ID NO:20
  • the amino acid sequences shown have at least about 80% sequence identity.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual with a disease associated with the Nogo-A signaling pathway comprising administering to the individual Contains an effective amount of anti-Nogo-A
  • Pharmaceutical compositions of antibodies e.g., full-length anti-Nogo-A antibodies
  • the antibodies comprise: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1, which contains SYGMH (SEQ ID NO:28); HC-CDR2, which contains VIWYHGSKKYYADSVKD (SEQ ID NO:48); and HC-CDR3, which contains SIAETTDYGLDS (SEQ ID NO:65); and light chain variable structures Domain (V L ), the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes RSSQSLLYRGGKTFLY (SEQ ID NO:85); LC-CDR2, which
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating a subject with a disease associated with the Nogo-A signaling pathway comprising administering to the subject an effective amount A composition comprising an anti-Nogo-A antibody, wherein the antibody comprises VH , and the VH comprises: HC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO:28, HC-CDR2, which comprises SEQ ID The amino acid sequence shown in NO:48, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:65, or a variant of the V H whose HC-CDRs include substitutions of up to about 5 amino acids; and VL , said VL comprising: LC-CDR1, which includes the amino acid sequence shown in SEQ ID NO:85, LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO:100, and LC-CDR3, which Comprising the amino acid sequence shown in SEQ ID NO: 111
  • a method for treating a subject with a disease associated with the Nogo-A signaling pathway comprising administering to the subject an effective amount A composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence shown in any one of SEQ ID NOs: 127-128 or a variant thereof, the variant being identical to SEQ ID NOs :
  • the amino acid sequence shown in any one of SEQ ID NOs: 127-128 has at least about 80% sequence identity; and VL , which includes the amino acid sequence shown in any one of SEQ ID NOs: 150-151 or a variant thereof, the variant
  • the entity has at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 150-151.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the heavy chain constant region comprises or It consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 127 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 127 Sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 150 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 150.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 128 Sequence identity; and VL comprising the amino acid sequence SEQ ID NO:151 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:151.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 128 Sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 150 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 150.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 29, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 49, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 66, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 86, LC- CDR2, which comprises the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 129 or a variant thereof, which variant is identical to that shown in SEQ ID NO: 129
  • the amino acid sequence shown has at least about 80% sequence identity
  • V L includes the amino acid sequence shown in SEQ ID NO: 152 or a variant thereof, which variant has the same amino acid sequence as the amino acid sequence shown in SEQ ID NO: 152 At least about 80% sequence identity.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:30, HC-CDR2, which includes the amino acid sequence SEQ ID NO:50, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:67, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 87, LC- CDR2, which comprises the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic disease of the head, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, cerebrospinal inflammation, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease, pontine myelmolysis, adrenoleukodystrophy, Pellizois-Metzbach disease, spongiform encephalopathy, Alexander disease, spongiform white matter Degenerative diseases, metachromatic leukodystrophy and Krabb's disease, degenerative visual
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 130 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 153 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 153.
  • V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 130 about 80% sequence identity
  • V L comprising the amino acid sequence SEQ ID NO: 153 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 153.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 31, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 68, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 131 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 154 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 154.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:32, HC-CDR2, which includes the amino acid sequence SEQ ID NO:51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:69, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic disease of the head, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pellizois-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof, the variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 132; and V L comprising the amino acid sequence SEQ ID NO: 155 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 155 80% sequence identity.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:33, HC-CDR2, which includes the amino acid sequence SEQ ID NO:52, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:70, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 89, LC- CDR2, which comprises the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 133 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 156 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 156.
  • V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 133 about 80% sequence identity
  • V L comprising the amino acid sequence SEQ ID NO: 156 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 156.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the heavy chain constant region comprises or It consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 34, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 71, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence
  • VH heavy chain variable domain
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 134 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 157 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 157.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain (V H ), the V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 35, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 54, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 72, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ), the V L comprising: LC-CDR1, which Comprising the amino acid sequence SEQ ID NO: 90, LC-CDR2 comprising the amino acid sequence
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 135 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 158 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 158.
  • V H comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 135 about 80% sequence identity
  • V L comprising the amino acid sequence SEQ ID NO: 158 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 158.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:36, HC-CDR2, which includes the amino acid sequence SEQ ID NO:55, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:73, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 91, LC- CDR2, which comprises the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 136 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 159 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 159.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 37, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 56, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 74, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 91, LC- CDR2, which includes the amino acid sequence
  • V H heavy chain variable domain
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenal white matter deoxygenation disease, Pellizois-Mertzbach disease, spongiform encephalopathies, Alexander disease, spongiform degeneration, metachromatic leukodystrophy, and Krabbe disease, degenerative visual diseases such as
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 137 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 159 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 159.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 31, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 57, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 75, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 92, LC- CDR2, which comprises the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 138 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 160 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 160.
  • V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 138 about 80% sequence identity
  • V L comprising the amino acid sequence SEQ ID NO: 160 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 160.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 38, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 58, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 76, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 93, LC- CDR2, which comprises the amino acid
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof, the variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 139; and V L comprising the amino acid sequence SEQ ID NO: 161 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 161 80% sequence identity.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 39, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 77, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence
  • VH heavy chain variable domain
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 140 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 162 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 162.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the heavy chain constant region comprises or It consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 40, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 59, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 78, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 94, LC- CDR2, which comprises the amino acid
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 141 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 141 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 163 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 163.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain (V H ), the V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 41, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 60, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 79, or a variant of the V H containing at most about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ), the V L comprising: LC-CDR1, which Comprising the amino acid sequence SEQ ID NO: 88, LC-CDR2 comprising the amino
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 142 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 164 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 164.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 42, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which includes the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 143 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 165 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 165.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 95, LC- CDR2, which comprises the amino acid sequence
  • VH heavy chain variable domain
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenal white matter deoxygenation disease, Pellizois-Mertzbach disease, spongiform encephalopathies, Alexander disease, spongiform degeneration, metachromatic leukodystrophy, and Krabbe disease, degenerative visual diseases such as
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 144 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 166 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 166.
  • V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 144 about 80% sequence identity
  • V L comprising the amino acid sequence SEQ ID NO: 166 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 166.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 44, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 62, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 82, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 96, LC- CDR2, which comprises the amino acid
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 145 about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:167 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:167.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 45, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 63, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 83, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 97, LC- CDR2, which comprises the amino acid
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof, the variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 146; and V L comprising the amino acid sequence SEQ ID NO: 168 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 168 80% sequence identity.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 46, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 98, LC- CDR2, which comprises the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 147 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 169 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 169.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21.
  • the heavy chain constant region comprises or It consists of the amino acid sequence SEQ ID NO:22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 47, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 64, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 84, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 99, LC- CDR2, which comprises the amino acid sequence S
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 148 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 170 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 170.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain (V H ), the V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ), the V L comprising: LC-CDR1, which Comprising the amino acid sequence SEQ ID NO: 95, LC-CDR2 comprising the amino
  • the anti-Nogo-A antibody is a full-length antibody.
  • the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody.
  • the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases
  • neurodegenerative diseases such as Alzheimer'
  • a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 149 about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:171 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:171.
  • an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
  • the subject is a mammal (eg, human, non-human primate, rat, mouse, cow, horse, porcine, sheep, goat, dog, cat, etc.).
  • the individual is a human.
  • the individual is a clinical patient, clinical trial volunteer, experimental animal, etc.
  • the individual is less than 60 years old (including, for example, less than 50, 40, 30, 25, 20, 15, or 10 years old).
  • the individual is older than 60 years old (including, for example, older than 70, 80, 90, or 100 years old).
  • the individual is diagnosed with or genetically predisposed to one or more diseases or conditions described herein (eg, central nervous system and/or peripheral nervous system disease or trauma).
  • the individual has one or more risk factors associated with one or more diseases or conditions described herein.
  • the application provides a method of delivering an anti-Nogo-A antibody (e.g., any of the anti-Nogo-A antibodies described herein, e.g., an isolated anti-Nogo-A antibody) to cells in an individual that express Nogo-A on their surface.
  • an anti-Nogo-A antibody e.g., any of the anti-Nogo-A antibodies described herein, e.g., an isolated anti-Nogo-A antibody
  • the method comprising administering to the individual a composition comprising an anti-Nogo-A antibody.
  • the anti-Nogo-A antibodies eg, full-length anti-Nogo-A antibodies
  • compositions described herein are combined with a second, third, or fourth agent (including, for example, corticosteroids, neurotrophic factors such as NGF, BDNF, or other drugs used for neurodegenerative diseases (such as Exelon TM , Levodopa) are used in combination to treat diseases related to the Nogo-A signaling pathway.
  • a second, third, or fourth agent including, for example, corticosteroids, neurotrophic factors such as NGF, BDNF, or other drugs used for neurodegenerative diseases (such as Exelon TM , Levodopa) are used in combination to treat diseases related to the Nogo-A signaling pathway.
  • Treatment of spinal cord injury is evaluated using, for example, neurite number, presence and density of regenerative sprouts, CST fiber number, cell spreading activity, protein expression levels and/or activity.
  • Methods of determining treatment efficacy may be employed, including, for example, detection of response by immunofluorescent staining, radiographic imaging, anatomical experiments, or behavioral experiments.
  • the effect of treatment is evaluated as a percent increase (%) in neurite number, calculated using the equation 100 - (T/C ⁇ 100), where T is the number of neurites in the treated spinal cord injury and C is Number of neurites in untreated spinal cord injury.
  • the percentage (%) is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94% , 95% or more than 95%.
  • therapeutic efficacy is assessed by the presence and density level of regenerative shoots in patients with spinal cord injury, calculated as the rate of change in the number of regenerative shoots compared to before administration of the antibody. In some embodiments, the presence and density of regenerated shoots is restored by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, or 35%.
  • therapeutic efficacy is assessed by CST fiber number in patients with spinal cord injury.
  • the CST fiber count is restored by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94% , 95% or more than 95%.
  • the dosage of an anti-Nogo-A antibody (eg, isolated anti-Nogo-A antibody) composition administered to an individual may vary depending on the particular composition, the mode of administration, and the type of disease being treated.
  • the amount of the composition e.g., a composition comprising an anti-Nogo-A antibody
  • an objective response e.g., a partial response or a complete response
  • the amount of anti-Nogo-A antibody composition is sufficient to produce a complete response in an individual.
  • the amount of anti-Nogo-A antibody composition is sufficient to produce a partial response in an individual.
  • the anti-Nogo-A antibody composition is administered at a dose (e.g., when administered alone) sufficient to produce greater than 20%, 25%, 30% in a population of individuals treated with the anti-Nogo-A antibody composition , 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90% overall response rate.
  • a dose e.g., when administered alone
  • An individual's response to the treatment methods described herein can be determined by, for example, sprouting at the site of nerve injury, regeneration of damaged axons, and neurite outgrowth of damaged neurites.
  • the amount of the composition is sufficient to prolong progression-free survival in an individual. In some embodiments, the amount of the composition is sufficient to prolong the overall survival of the subject. In some embodiments, using The amount of the composition (eg, when administered alone) is sufficient to produce greater than 50%, 60%, 70%, or 77% of the clinical benefit in a population of individuals treated with the anti-Nogo-A antibody composition.
  • the amount of a composition is before treatment. or an amount sufficient to control symptoms and reduce the risk of exacerbation of the condition as compared to the corresponding activity in other subjects not receiving treatment.
  • the magnitude of this effect can be measured using standard methods, such as in vitro assays of purified enzymes, cell-based assays, animal models, or human trials.
  • the amount of anti-Nogo-A antibody (e.g., full-length anti-Nogo-A antibody) in the composition is less than the amount that causes a toxic effect (i.e., an amount greater than clinically acceptable) when the composition is administered to an individual. Toxic levels of effects), or at a level where potential side effects can be controlled or tolerated.
  • the amount of the composition approximates the maximum tolerated dose (MTD) of the composition. In some embodiments, the amount of the composition is greater than 80%, 90%, 95%, or 98% of the MTD.
  • the amount of anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) in the composition ranges from 0.001 ⁇ g to 1000 ⁇ g.
  • the effective amount of anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) in the composition is in the range of 0.1 ⁇ g/kg to 100 mg/kg based on body weight. within.
  • Anti-Nogo-A antibody compositions can be administered to an individual (e.g., a human) by a variety of routes, including, for example, intravenous injection, intraarterial administration, intraperitoneal injection, intrapulmonary administration, oral administration, inhalation administration, intravascular administration medicine, intramuscular injection, intratracheal administration, subcutaneous injection, intraocular administration, intrathecal administration, mucosal administration or transdermal administration.
  • routes including, for example, intravenous injection, intraarterial administration, intraperitoneal injection, intrapulmonary administration, oral administration, inhalation administration, intravascular administration medicine, intramuscular injection, intratracheal administration, subcutaneous injection, intraocular administration, intrathecal administration, mucosal administration or transdermal administration.
  • a sustained release formulation of the composition is used.
  • the composition is administered intravenously.
  • the composition is administered intraarterially.
  • the composition is administered intraperitoneally.
  • the composition is administered intrahepatically.
  • the composition is administered by hepatic
  • an article of manufacture comprising a substance that can be used to treat diseases associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma), or for delivering an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody) to cells expressing Nogo-A on their surface.
  • the article of manufacture may include a container and a label or package insert on or accompanying the container. Suitable containers include, for example, bottles, vials, syringes, and the like. Containers can be made from a variety of materials, such as glass or plastic.
  • the container contains a composition effective for treating the disease or condition described herein and has a sterile port (eg, the container may be an IV bag or a vial with a hypodermic needle-pierceable cap). At least one active substance in the composition is the anti-Nogo-A antibody described in this application.
  • the label or package insert identifies the specific condition for which the composition is used to treat.
  • the label or package insert further contains instructions for administering the anti-Nogo-A antibody composition to a patient. Articles and kits including combination therapies are considered within the scope of this article.
  • Package insert means the instructions usually included in the commercial packaging of therapeutic products that contain information on indications, usage, dosage, administration, contraindications and/or warnings relevant to the use of these therapeutic products.
  • the package insert states that the composition can be used to treat diseases associated with the Nogo-A signaling pathway (eg, central nervous system and/or peripheral nervous system diseases or trauma).
  • the package insert states that the composition can be used to treat neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy Body-like diseases, other common dementias, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis , Marchiafava-Bignami disease, pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Metzbach disease, spongiform encephalopathies, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Gram Labware disease, degenerative visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (
  • the article of manufacture may further include a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffer, Green's solution, or dextrose solution.
  • a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffer, Green's solution, or dextrose solution.
  • kits that can be used for various purposes, such as for the treatment of diseases associated with the Nogo-A signaling pathway (such as central nervous system and/or peripheral nervous system diseases or trauma), or for the delivery of anti-Nogo-A antibodies. (e.g., full-length anti-Nogo-A antibody) into cells expressing Nogo-A on their surface, optionally in combination with a preparation.
  • Kits of the present application include one or more containers containing an anti-Nogo-A antibody composition (or single dose form and/or article of manufacture) and, in some embodiments, further comprising another agent (e.g., as described herein agent) and/or instructions for use consistent with any of the methods described herein.
  • the kit may further include instructions for selecting individuals suitable for treatment. Instructions for use accompanying the kit in this application are usually written instructions on the label or package insert (e.g., a sheet of paper included in the kit), machine-readable instructions (e.g., instructions on a magnetic or optical storage disc) Also acceptable.
  • the kit includes a composition comprising an anti-Nogo-A antibody (eg, a full-length anti-Nogo-A antibody).
  • a kit includes: a) a composition comprising any one of the anti-Nogo-A antibodies described herein, and b) an effective amount of at least one other agent capable of enhancing the anti-Nogo-A antibody's Effect (such as treatment effect, detection effect).
  • the kit includes: a) a composition comprising any one of the anti-Nogo-A antibodies described herein, and b) administering to the individual the anti-Nogo-A antibody composition for treating Nogo-A signaling Instructions for use in pathway-related disorders (e.g., central nervous system and/or peripheral nervous system disease or trauma).
  • pathway-related disorders e.g., central nervous system and/or peripheral nervous system disease or trauma.
  • a kit includes: a) a composition comprising any one of the anti-Nogo-A antibodies described herein, and b) an effective amount of at least one other agent capable of enhancing the anti-Nogo-A antibody's effects (e.g., therapeutic effects, detection effects) and c) administering anti-Nogo-A antibody compositions and other substances to individuals for the treatment of diseases associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system diseases or trauma) instructions for use.
  • the anti-Nogo-A antibody and other substances may be present in separate containers or in the same container.
  • the kit may include a specific A specific composition or two or more compositions, one of which includes an anti-Nogo-A antibody and the other of which includes another pharmaceutical agent.
  • the kit includes a nucleic acid (or a set of nucleic acids) encoding an anti-Nogo-A antibody (eg, a full-length anti-Nogo-A antibody).
  • the kit comprises: a) a nucleic acid (or a set of) encoding an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), and b) an expression nucleic acid (or a set of nucleic acid) host cells.
  • the kit comprises: a) one (or a set of) nucleic acids encoding an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), and b) instructions for use, suitable for: i) expressing an anti-Nogo-A antibody in a host cell, ii) preparing a composition comprising the anti-Nogo-A antibody, and iii) administering the composition comprising the anti-Nogo-A antibody to an individual to treat a disease associated with the Nogo-A signaling pathway (e.g. central nervous system and/or peripheral nervous system disease or trauma).
  • a disease associated with the Nogo-A signaling pathway e.g. central nervous system and/or peripheral nervous system disease or trauma.
  • the kit includes: a) a nucleic acid (or a set of nucleic acids) encoding an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), b) an expression nucleic acid (or a set of nucleic acids ), and c) instructions for use suitable for: i) expressing an anti-Nogo-A antibody in a host cell, ii) preparing a composition comprising an anti-Nogo-A antibody, and iii) administering to an individual a composition comprising an anti-Nogo-A antibody.
  • a composition of antibodies to treat diseases related to the Nogo-A signaling pathway such as central nervous system and/or peripheral nervous system diseases or trauma).
  • kits described in this application are packaged in a suitable form.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (eg, sealed mylar or plastic bags), and the like. Kits may optionally provide other components such as buffers and instructions. Accordingly, the present application also provides articles including vials, bottles, jars, flexible packaging (eg, sealed Mylar or plastic bags), and the like.
  • Containers may be unit dose, bulk (eg, multi-dose packaging) or subunit dose.
  • a kit is provided that contains a sufficient dose of an anti-Nogo-A antibody as described herein (e.g., a full-length anti-Nogo-A antibody) to effectively treat an individual for a long period of time, such as one week, 8 days, 9 days , 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months months or more.
  • the kit may also contain multiple unit doses of anti-Nogo-A antibody, a pharmaceutical composition, and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies, such as hospital pharmacies and compounding pharmacies.
  • Nogo-A Neurorite outgrowth inhibitor-A, neurite growth inhibitory factor A
  • Bavih-hNiG Biotin-hNiG-Avi-10His
  • Example 1 Preparation of recombinant NiG antigen and screening of Nogo-A antibody
  • Nogo-A with a molecular weight of 190kD, is the translation product of the reticuloendothelin RTN4 gene.
  • the protein composed of 818 amino acids (186-1004aa) encoded by the unique exon 3 of Nogo-A is called NiG.
  • Codon-optimized coding sequences of human NiG (hNiG, 186-1004aa), rhesus monkey NiG (mkNiG, 171-1049aa), and rat NiG (rNiG, 174-979aa) were synthesized and fused with His tags to construct In the eukaryotic cell expression vector pTTa1.
  • the following expression vectors were constructed respectively: pTTa1-hNiG-10His, pTTa1-mkNiG-10His, and pTTa1-rNiG-10His.
  • His or His represents the His tag
  • Avi represents the avidin tag.
  • the above recombinant NiG was expressed and purified according to the manufacturer's instructions. Briefly, the above expression vectors were transfected into 293F cells respectively, and the above cells were cultured at 37°C, 8% CO 2 , and 120 rpm for 5 days.
  • His-tag proteins For purification of His-tag proteins, collect the cell culture fluid, load the supernatant into a Histrap column, equilibrate with 20mM sodium phosphate buffer (pH7.4) containing 0.25M NaCl and 5mM imidazole (pH8.0), and use The column was washed with 20mM sodium phosphate buffer (pH7.4) containing 0.25M NaCl and 15mM imidazole (pH8.0), followed by 20mM sodium phosphate buffer (pH7.4) containing 0.25M NaCl and 100mM imidazole (pH8.0). Elute and collect the protein of interest.
  • biotinylation ligase B0101A (GeneCopoeia) was used to biotinylate hNiG-Avi-10His. Briefly, buffer A/B and BirA ligase were added to hNiG-Avi-10His antigen and incubated at 30°C for 2 hours. Biotinylated hNiG (ie Biotin-hNiG-Avi-10His) was named Bavih-hNiG. Biotinylation efficiency was detected by ELISA method.
  • the starting concentration of Bavih-hNiG was set to 500ng/ml, diluted at a ratio of 1:2, and then coated on the ELISA plate after dilution.
  • SA-HRP was used for detection and biotinylated standards were used as controls.
  • the Bavih-hNiG biotinylation labeling efficiency was 70%.
  • scFv antibody yeast display library hNiG-10His was used as antigen and cynomolgus monkeys were immunized with equal parts (v/v) of adjuvant.
  • the monkey serum after immunization was collected, and the total IgG titer in the above serum was detected by ELISA.
  • scFv anti-NiG single chain antibodies
  • CHO-IgG library that can both display and secrete IgG antibodies and screen IgG antibodies: Use the designed primers to perform two rounds of PCR amplification on the plasmid obtained from the yeast library, and then pass the obtained VL-CL-2A-VH fragment through AgeI and NheI digestion and cloned into the CHO-IgG display secretion vector pFLP-In-TM.
  • the ligated plasmid was co-transfected into CHO-FRT cells (Thermofisher, cat. #R75807), a CHO-IgG antibody display library was obtained through hygromycin (Sigma, cat#31282-04-9) screening.
  • IgG antibodies that specifically bind hNiG were isolated from the display library.
  • the cell population is obtained by FACS sorting by reducing the antigen concentration in each round, and then the final round of cell population is FACS monoclonal sorted and cultured in a 96-well plate. Two weeks later, the supernatant is taken for ELISA identification.
  • variable domain sequences of the heavy and light chains of candidate lead antibodies L82 and mkNG-22 are shown in Tables 2 and 3.
  • Candidate lead antibodies mkNG-3, mkNG-26, mkNG-38, mkNG-258, mkNG-267, mkNG-272, mkNG-325, mkNG-327, mkNG-333, mkNG-360, mkNG-362, mkNG-375 , variable structures of heavy and light chains of mkNG-378, mkNG-379, mkNG-381, mkNG-388, mkNG-398, mkNG-401, mkNG-405, mkNG-407, mkNG-412, mkNG-416 Domain sequences are shown in Table 2A and Table 3A.
  • the most promising Fab antibodies are constructed as human IgG1 or IgG4 antibody molecules with the heavy chain constant region of human IgG1 or IgG4 and the human kappa or lambda light chain constant region.
  • Plasmids expressing light and heavy chains were extracted respectively, co-transfected into 293F cells, cultured at 37°C, 5% CO 2 , and 120 rpm for 6 days, and the culture medium was purified using a protein A affinity chromatography column. Briefly, the protein A column was first equilibrated with 6 column volumes of PBS buffer (pH 7.2-7.4) at a flow rate of 150 cm/h. The culture supernatant (pH adjusted to 7.2) flows through the column at a flow rate of 150cm/h.
  • Anti-Nogo-A lead antibody full-length form including antibody L82, mkNG-22, mkNG-3, mkNG-26, mkNG-38, mkNG-258, mkNG-267, mkNG-272, mkNG-325, mkNG-327, mkNG-333, mkNG-360, mkNG-362, mkNG-375, mkNG-378, mkNG-379, mkNG-381, mkNG-388, mkNG-398, mkNG-401, mkNG-405, mkNG-407, mkNG-412, mkNG-416), including detection of affinity, neutralizing activity and biological activity, see the following examples for details.
  • Humanization of anti-Nogo-A antibody Based on the obtained typical VH / VL CDR structure of the lead antibody L82 (human IgG4 form), combine the heavy and light chain variable region sequences with those in the antibody germline database The sequences are compared to obtain a human germline template with high homology. The CDR regions of the chimeric antibody are grafted onto a selected human germline template to generate humanized variable regions, which are then recombined with the corresponding human IgG constant regions (preferably IgG4 heavy chain (LALA) and kappa light chain) .
  • IgG4 heavy chain (LALA) and kappa light chain preferably IgG4 heavy chain (LALA) and kappa light chain
  • the lead antibody mkNG-362 was also humanized to obtain the corresponding humanized molecules hum-mkNG362-1 and hum-mkNG362-2.
  • the variable domain sequences of the heavy chain and light chain of the above-mentioned humanized antibodies are shown in Table 2A and Table 3A.
  • ELISA experiment was used to evaluate the lead antibodies L82, mkNG-22, mkNG-3, mkNG-26, mkNG-38, mkNG-327, mkNG-333, mkNG-362, mkNG-378, mkNG-398, mkNG-401, mkNG- 405 and the affinity of humanized antibodies H-L82-1, H-L82-2, H-L82-3, hum-mkNG-362-1, hum-mkNG-362-2 (reconstituted as human IgG4) for hNiG. Briefly, a 96-well microplate was coated with 1 ⁇ g/mL hNiG antigen at 4°C overnight.
  • ATI-355 Novartis
  • Wash the plate three times add 100 ⁇ L/well HRP-labeled goat anti-human IgG Fab secondary antibody (1:16000 dilution, Jackson ImmunoResearch, cat#109-036-097), and react at 37°C for 1 hour. Wash 5 times with wash buffer.
  • the results of the binding activity of humanized molecules derived from the lead antibody mkNG-362 are shown in Table 5B.
  • the binding activities of humanized anti-Nogo-A antibodies hum-mkNG-362-1 and hum-mkNG-362-2 are similar to those of their parents.
  • Antibody mkNG-362 was comparable, indicating that humanization did not alter the binding activity of the anti-Nogo-A antibody.
  • Example 5 Anti-Nogo-A antibody inhibits the binding test of hNiG to Nogo-A receptors on cell membranes
  • Cell ELISA method was used to detect lead antibodies L82, mkNG-22, mkNG-360, mkNG-362 and humanized antibodies H-L82-1, H-L82-2, H-L82-3, hum-mkNG-362-1 , hum-mkNG-362-2 (reconstructed into human IgG4) blocks the binding test of hNiG to Nogo-A receptor on PC12 or NIH 3T3 cell membrane.
  • PC12 cells Concordia Cell Center, cat#1101RAT-PUMC000024
  • NIH 3T3 cells hereinafter referred to as 3T3, from Concordia Cell Center, cat#1101MOU-PUMC000018
  • exemplary anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 (Table 6A and Figure 2A), mkNG-360, mkNG -362 (Table 6C) can effectively block the binding of hNiG to the Nogo-A receptor on the PC12 cell membrane, and its blocking activity is better than the positive control antibody ATI-355.
  • Anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 (Table 6B and Figure 2B), mkNG-360, mkNG-362 (Table 6D) can effectively block hNiG Binding to the Nogo-A receptor on the 3T3 cell membrane, its blocking activity is better than the positive control antibody ATI-355.
  • mkNG-22, hum-mkNG-362-1, and hum-mkNG-362-2 can also effectively block the binding of hNiG to Nogo-A receptors on PC12 or 3T3 cell membranes, and their blocking activities are better than positive Control antibody ATI-355, and the blocking activities of hum-mkNG-362-1 and hum-mkNG-362-2 were basically equivalent to their parent antibody mkNG-362 (data not shown).
  • Example 6 Detection of cross-binding activity of anti-Nogo-A antibodies to Nogo-A of different species
  • the FACS method was used to detect the cross-binding activity of anti-Nogo-A antibodies to Nogo-A of different species (including humans, rhesus monkeys, mice and rats). Briefly, 293T cells were centrifuged and counted and seeded in a 6-well culture plate at 37°C and 5% CO 2 overnight until the density was approximately 80% to 90%.
  • the plasmids pcmv3-human RTN4, pcmv3-rhesus monkey RTN4, pcmv3-rat RTN4, and pcmv3-mouse RTN4 encoding Nogo-A proteins from different species were transfected into 293T cells respectively, and the cells were incubated at 37°C and 5% CO 2 Incubate for 48h.
  • anti-Nogo-A antibodies mkNG-360, mkNG-362, hum-mkNG-362-1, hum-mkNG-362-2 are related to rhesus monkey Nogo-A, rat Nogo-A, mouse Both Nogo-A have cross-binding activity (data not shown).
  • Biacore T200 was used to characterize the binding affinity of anti-Nogo-A antibodies (reconstituted as human IgG4).
  • the hNiG antigen was fixed on the sensor chip CM5, and anti-Nogo-A antibodies at different concentrations (including 0M, 5.208E-10M, 1.042E-9M, 2.083E-9M, 4.167E-9M, 8.333E-9M) were detected against hNiG Antigen affinity.
  • SPR technology is used to measure the binding and dissociation rates of antibodies and determine binding affinity.
  • Nogo-A is a protein that can inhibit nerve growth and regeneration, and has the activity of inhibiting the growth and extension of nerve cell axons.
  • GAP-43 is an axonal growth-related membrane protein that is closely related to neural development, synapse formation and plasticity, especially nerve regeneration.
  • the passaged PC12 cell line selected for the experiment is rat pheochromoma cells, a tumor derived from neuroectodermal chromaffin tissue. Under NGF stimulation, the cells can exhibit neuronal cell-like axonal growth, accompanied by an upregulation of GAP-43 mRNA and protein expression levels; while Nogo-A can inhibit axonal growth and promote a decrease in GAP-43mRNA levels.
  • This experiment is based on the biological activity mechanism of Nogo-A and the biological properties of GAP-43.
  • PC12 cells cultured in vitro were used to detect the inhibitory activity of Nogo-A on the transcription level of GAP-43, thereby evaluating the blocking effect of anti-Nogo-A antibodies. effect.
  • NGF, anti-Nogo-A antibody to be tested L82, H-L82-1, H-L82-2, H-L82-3, mkNG-22, mkNG-3, mkNG-26, mkNG-258 , mkNG-267, mkNG-272, mkNG-325, mkNG-327, mkNG-333, mkNG-360, mkNG-362, mkNG-375, mkNG-379, mkNG-381, mkNG-388, mkNG-405, mkNG -407, mkNG-412, mkNG-416, ATI-355 and Nogo-A were mixed, added to PC12 cells and incubated for 48 hours.
  • the blank control group did not add NGF (NGF-), and the negative control group did not add anti-Nogo-A antibodies.
  • NGF NGF
  • ATI-355 was used as a positive control.
  • the total RNA in each group of cells was extracted and reverse transcribed, and then the primers of GAP-43 and the housekeeping protein GAPDH were used respectively.
  • the primers were used for relative fluorescence quantitative PCR to quantitatively detect the change level of GAP-43 mRNA under the action of the antigen Nogo-A, thereby reflecting the in vitro activity of the anti-Nogo-A antibody.
  • Example 9 Restoration effect of anti-Nogo-A antibody on hNiG-inhibited neurite growth of N1E-115 cells
  • N1E-115 cells were used to evaluate the restoration effect of anti-Nogo-A antibody on hNiG-inhibited neurite growth. Briefly, N1E-115 cells (ATCC) were seeded into 96-well plates and cultured at 37°C overnight. Then, 0.05% DMSO was added to induce neurite growth, and hNiG and corresponding concentrations of the anti-Nogo-A antibody to be tested were added at the same time. After incubation for 48 hours, the cell morphology was observed under a microscope and photographed (Figure 5A), and Image J software was used to quantitatively analyze neurite growth ( Figures 5B-5C).
  • Example 10 Restorative effect of anti-Nogo-A antibody on the inhibition of neurite growth of N1E-115 cells by monkey spinal cord extract
  • Monkey spinal cord extract is rich in Nogo-A protein, which can inhibit the growth of neurites of N1E-115 cells.
  • the morphological changes of N1E-115 cells were used to evaluate the recovery of neurite growth inhibited by anti-Nogo-A antibody in monkey spinal cord extract (hereinafter referred to as Mk ex.) effect. Briefly, N1E-115 cells were seeded into 96-well plates and cultured at 37°C overnight. Then, 0.05% DMSO was added to induce neurite growth, and monkey spinal cord extract and corresponding concentrations of the anti-Nogo-A antibody to be tested were added. After incubation for 48 hours, the cell morphology was observed under a microscope and photographed ( Figure 6A), and the neurite growth was quantitatively analyzed using Image J software ( Figure 6B).
  • Monkey spinal cord extract has a significant inhibitory effect on the neurite growth of N1E-115 cells, while anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H- Both L82-3 and mkNG-22 (reconstituted into human IgG4) significantly restored neurite growth, and the recovery effect was better than that of the positive control antibody ATI-355.
  • Example 11 Restorative effect of anti-Nogo-A antibody on hNiG-inhibited neurite growth of PC12 cells
  • PC12 cells (Xiehe) were seeded into polylysine-coated 96-well plates and cultured at 37°C overnight. Then 20ng/ml NGF was added to induce neurite growth for 2 hours, and then hNiG and the corresponding concentration of the anti-Nogo-A antibody to be tested were added. After 5 days of incubation, the cell morphology was observed under a microscope and photographed (data not shown), and Image J software was used to quantitatively analyze neurite growth (Figure 6C).
  • exemplary anti-Nogo-A antibodies hum-mkNG-362-1 and hum-mkNG-362-2 also significantly restored the inhibition of neurite growth, and the restoration effects were basically equivalent to their parent antibody mkNG-362. , better than the positive control antibody ATI-355 (data not shown).
  • Example 12 In vivo pharmacodynamic study of anti-Nogo-A antibody in spinal cord injury mouse model
  • the constructed mouse model of spinal cord injury was used to verify the in vivo pharmacodynamics of anti-Nogo-A antibodies.
  • SCI mouse model Construction of spinal cord injury (SCI) mouse model . Briefly, according to the body weight measured before grouping, 13 quarantine-qualified 9-week-old C57BL/6 female mice (Beijing Huafukang Biotechnology Co., Ltd.) were randomly divided into two groups: model control group and test article. Group, 6 to 7 animals/group. The mice in each group were anesthetized and depilated and skin was prepared. The spine at T7 to T10 was exposed. The laminae at T7 and T10 were removed. A right transverse hemisection was performed at T7 to T8 thoracic cord, and a left transverse hemisection was performed at T10 to T11. Cut in half. The skin was sutured and kept in single cages. The day of surgery was defined as day 0.
  • Anti-Nogo-A antibody treatment The mice in the test group were injected with anti-Nogo-A antibody into the tail vein at a dose of 10 mg/kg, and the administration frequency was once on days 0, 3, 7, and 10.
  • the model control group was injected with an equal volume of PBS solution at the same administration frequency. Observe the survival status of the mice every day and record the death date of the mice.
  • a professional camera was used to capture videos of mice exploring in their natural state for no less than 4 minutes on days 7, 14, 21, 28, and 35. The same professionals analyzed the videos in accordance with the BMS scale scoring standards (see Table 8 for details). , and used statistical software SPSS and GraphPad Prism to draw animal BMS score curves.
  • anti-NogoA antibodies L82, H-L82-1, H-L82-2, mkNG-22, mkNG-362, hum-mkNG-362-1, hum-mkNG-362-2 also produced similar therapeutic effects in spinal cord injury. effects (data not shown).
  • Extremely poor body stability mainly exists in one of the following two aspects: (1) The hind limbs and hips show extremely abnormal postures (such as obvious tilt, stagger and/or during the test There is a clear tendency for the hind limbs and buttocks to collapse); (2) The buttocks hit the ground 5 or more times, muscle spasm and/or scoliosis occurs, causing the step to stop.

Abstract

The present invention relates to an antibody or an antigen-binding fragment specifically recognizing Nogo-A, a preparation method therefor, and use thereof.

Description

特异性识别Nogo-A的抗体及其应用Antibodies that specifically recognize Nogo-A and their applications
相关申请的交叉参考Cross-references to related applications
本申请要求申请号为202211006418.4，申请日为2022.08.22，发明名称为“特异性识别Nogo-A的抗体及其应用”的中国专利申请的优先权，且该申请的全部内容以引用方式并入本文中。This application requires the priority of the Chinese patent application with application number 202211006418.4, filing date 2022.08.22, and the invention title is "Antibodies that specifically recognize Nogo-A and applications thereof", and the entire content of this application is incorporated by reference. in this article.
以xml文件提交电子序列表Submit electronic sequence listing as xml file
电子序列表的内容通过整体引用并入本文中：(NOGOA_WIPO_2023.08.17.xml；大小:153KB；以及创建日期:2022.08.03)。The contents of the electronic sequence listing are incorporated herein by reference in their entirety: (NOGOA_WIPO_2023.08.17.xml; size: 153KB; and creation date: 2022.08.03).
技术领域Technical field
本发明涉及特异性识别NogoA的抗体，及其制备方法和用途，包括用其治疗Nogo-A信号通路失调导致的疾病和/或病症，例如中枢神经系统和/或外周神经系统疾病或创伤的方法。The present invention relates to antibodies that specifically recognize NogoA, preparation methods and uses thereof, including methods of using them to treat diseases and/or conditions caused by disorders of the Nogo-A signaling pathway, such as central nervous system and/or peripheral nervous system diseases or trauma. .
背景技术Background technique
成年人中枢神经系统(CNS)损伤后，由于包盖轴突的抑制性髓鞘质环境的存在和瘢痕组织的形成，神经再生受到限制。已有研究表明，抑制神经生长的因子在很大程度上影响了成人中枢神经系统损伤后的再生能力。这些因子在稳定成年高等脊椎动物中枢神经系统的复杂布线和在神经系统发育中建立神经元通路方面发挥着重要作用(Akbik FV et al.Exp Neurol.2012.；Schwab ME.te al.Nat Rev Neurosci.2010.)，其中包括Nogo-A、髓鞘质相关糖蛋白(MAG)和髓鞘质少突胶质细胞糖蛋白(OMGP)在内的分子已被描述为有效的神经突起抑制因子。After central nervous system (CNS) injury in adults, nerve regeneration is limited due to the presence of an inhibitory myelin environment that coats axons and the formation of scar tissue. Studies have shown that factors that inhibit nerve growth largely affect the regeneration capacity of the adult central nervous system after injury. These factors play an important role in stabilizing the complex wiring of the central nervous system of adult higher vertebrates and establishing neuronal pathways in nervous system development (Akbik FV et al. Exp Neurol. 2012.; Schwab ME.te al. Nat Rev Neurosci .2010.), molecules including Nogo-A, myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein (OMGP) have been described as potent neurite inhibitory factors.
研究最多的抑制因子之一是浆膜蛋白质家族成员Nogo-A，它发生在髓磷脂和某些神经元中，抑制中枢神经损伤后的轴突再生和可塑性(Filbin at al.Nat Rev Neurosci.2003；Yiu G et al.Nat Rev Neurosci.2006)。Nogo-A通过两个不同的胞外结构域Nogo-A-Δ20(鼠aa544-725)和Nogo-66(鼠aa1026-1091)发挥其抑制活性(Schwab ME等，Nat Rev Neurosci)。Anissa Kempf等人发现G蛋白偶联受体(GPCR)鞘氨醇1-磷酸受体2(S1PR2)是Nogo-A的Δ20结构域的功能性受体(Kempf A et al.PLoS Biol.2014.)。One of the most studied inhibitory factors is Nogo-A, a member of the serosal protein family, which occurs in myelin and certain neurons and inhibits axon regeneration and plasticity after central nervous system injury (Filbin at al. Nat Rev Neurosci. 2003 ; Yiu G et al. Nat Rev Neurosci. 2006). Nogo-A exerts its inhibitory activity through two different extracellular domains, Nogo-A-Δ20 (mouse aa544-725) and Nogo-66 (mouse aa1026-1091) (Schwab ME et al., Nat Rev Neurosci). Anissa Kempf et al. found that the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) is a functional receptor for the Δ20 domain of Nogo-A (Kempf A et al. PLoS Biol. 2014. ).
Nogo-A通过其抑制性Nogo-66结构域与受体NgR1结合，并与跨膜蛋白LINGO1、p75或TROY形成复合体，从而抑制神经突的生长。这种结合通过未知的中间体导致细胞内Ca2+的增加，以及Rho相关蛋白激酶(ROCK)信号通路的激活(Nash M等，Mol Neurobiol,2009；Fournier A.E.等,J.Neurosci.2003)。通过RhoA信号传递，肌动蛋白细胞骨架失稳，从而导致生长锥塌陷(Hsieh等，J.Neurosci,2006；Montani,L等，J.Biol.Chem,2009)。除了NgR1，Nogo-66还与辅助蛋白和配对的免疫球蛋白样受体B(PIRB)(Atwal JK等，Science.2008)相互作用，诱导生长抑制。 Nogo-A binds to the receptor NgR1 through its inhibitory Nogo-66 domain and forms a complex with the transmembrane protein LINGO1, p75 or TROY, thereby inhibiting neurite growth. This binding leads to an increase in intracellular Ca 2+ through an unknown intermediate and the activation of the Rho-related protein kinase (ROCK) signaling pathway (Nash M et al., Mol Neurobiol, 2009; Fournier AE et al., J. Neurosci. 2003). Through RhoA signaling, the actin cytoskeleton is destabilized, leading to growth cone collapse (Hsieh et al., J. Neurosci, 2006; Montani, L et al., J. Biol. Chem, 2009). In addition to NgR1, Nogo-66 also interacts with accessory proteins and paired immunoglobulin-like receptor B (PIRB) (Atwal JK et al., Science. 2008) to induce growth inhibition.
Nogo-A主要在神经系统中表达，在发育过程中有三个不同的表达窗口(Huber等，Trends Cell Biol,2007；Wang,X等，J.Neurosci.2002.)。首先在发育早期，Nogo-A在迁移的神经母细胞和神经管中未成熟的神经元中表达(Caltharp等，BMC Dev Biol,2007；Mathis等，Cereb Cortex,2010.)。第二，在中枢和外周神经元的主要生长阶段，Nogo-A在多种神经元类型中表达，特别是具有长轴突的神经元。这种表达在出生后下降到到通常无法检测的低水平。然而，一些神经元类型保留了高水平的Nogo-A表达，特别是嗅球、海马体的锥体细胞和中间神经元、脊髓运动神经元和背根神经节细胞(Mingorance,A等，Mol Cell Neurosci,2004；Richard,M等，Europ.J.Neurosci,2005)。这些类型的神经元的特点是其连接具有高度可塑性，表明神经元Nogo可能在突触可塑性中发挥作用。最后，在出生后的中枢神经系统中，Nogo-A主要在少突胶质细胞中表达。然而周围神经系统中的类细胞类型(施旺细胞)不表达Nogo-A(Huber等，J.Neurosci,2002)。在中枢神经系统之外，Nogo-A在发育中的皮肤、分化过程中的骨骼肌和心脏中表达。成年大鼠、小鼠和人类的心脏组织，以及小鼠和人类的某些免疫细胞特别是巨噬细胞，表达Nogo-A和Nogo受体复合物的成分如NgR1。Nogo-A is mainly expressed in the nervous system and has three different expression windows during development (Huber et al., Trends Cell Biol, 2007; Wang, X et al., J. Neurosci. 2002.). First, during early development, Nogo-A is expressed in migrating neuroblasts and immature neurons in the neural tube (Caltharp et al., BMC Dev Biol, 2007; Mathis et al., Cereb Cortex, 2010.). Second, during the main growth phase of central and peripheral neurons, Nogo-A is expressed in multiple neuron types, especially neurons with long axons. This expression decreases after birth to low levels that are often undetectable. However, some neuronal types retain high levels of Nogo-A expression, notably the olfactory bulb, pyramidal cells and interneurons of the hippocampus, spinal motor neurons, and dorsal root ganglion cells (Mingorance, A et al., Mol Cell Neurosci , 2004; Richard, M et al., Europ. J. Neurosci, 2005). These types of neurons are characterized by a high degree of plasticity in their connections, suggesting that neuronal Nogo may play a role in synaptic plasticity. Finally, in the postnatal central nervous system, Nogo-A is predominantly expressed in oligodendrocytes. However, a cell type in the peripheral nervous system (Schwann cells) does not express Nogo-A (Huber et al., J. Neurosci, 2002). Outside the central nervous system, Nogo-A is expressed in developing skin, skeletal muscle during differentiation, and heart. Heart tissue from adult rats, mice and humans, as well as certain immune cells in mice and humans, especially macrophages, express Nogo-A and components of the Nogo receptor complex such as NgR1.
在Nogo-A缺陷小鼠中，脊髓提取物对该缺陷型小鼠神经突起生长的抑制作用降低。成年鼠胸椎脊髓背侧切除两周后，与野生型小鼠相比，Nogo-A KO小鼠显示更多的皮质脊髓束(CST)纤维向病变部位生长。这一研究表明了髓鞘相关生长抑制剂Nogo-A的系统性缺失能够改善脊髓损伤后的再生和可塑性反应(M Simonen等,Neuron,2003)。另外，已证明中和Nogo-A能促进轴突生长和成人脊髓和大脑的代偿性萌发，并能改善中枢神经系统损伤后的功能恢复(Schwab ME et al.Curr Opin Neurobiol.2004.；Kempf et al.Physiology.2013.)。最近的研究显示，Nogo-A信号在抑制成熟神经元网络的突触可塑性方面发挥了新的重要作用，表明Nogo-A的抑制潜力远远超过其已被研究的对轴突生长的限制(Kempf A et al.PLoS Biol.2014.；Delekate et al.Proc Natl Acad Sci.2011.；Tews B et al.Proc Natl Acad Sci.2013.)。除了对成人中枢神经系统轴突再生的抑制作用，研究人员还发现Nogo-A调节小鼠胚胎期皮层的神经前体的迁移。在Nogo-A-/-小鼠中以及在抗Nogo-A、NgR1或LINGO-1抗体中培养的野生型神经元中，皮质神经前体的迁移增强，表明细胞表面的Nogo-A通过含NgR1-LINGO1受体复合物调控早期发育的CNS的神经元迁移(Mathis,C等，Cereb Cortex,2010)。In Nogo-A-deficient mice, the inhibitory effect of spinal cord extracts on neurite growth in the deficient mice was reduced. Two weeks after dorsal resection of the thoracic spinal cord in adult mice, Nogo-A KO mice showed more corticospinal tract (CST) fibers growing towards the lesion site compared with wild-type mice. This study shows that systemic deletion of the myelin-associated growth inhibitor Nogo-A can improve regeneration and plasticity responses after spinal cord injury (M Simonen et al., Neuron, 2003). Additionally, neutralizing Nogo-A has been shown to promote axonal growth and compensatory sprouting in the adult spinal cord and brain and improve functional recovery after central nervous system injury (Schwab ME et al. Curr Opin Neurobiol. 2004.; Kempf et al. Physiology. 2013.). Recent studies have shown that Nogo-A signaling plays a new important role in inhibiting synaptic plasticity in mature neuronal networks, suggesting that the inhibitory potential of Nogo-A far exceeds its already studied limitation on axonal growth (Kempf A et al. PLoS Biol. 2014.; Delekate et al. Proc Natl Acad Sci. 2011.; Tews B et al. Proc Natl Acad Sci. 2013.). In addition to its inhibitory effect on axonal regeneration in the adult central nervous system, the researchers also found that Nogo-A regulates the migration of neural precursors in the mouse embryonic cortex. Migration of cortical neural precursors is enhanced in Nogo-A-/- mice and in wild-type neurons cultured in anti-Nogo-A, NgR1, or LINGO-1 antibodies, suggesting that cell surface Nogo-A is transported through NgR1-containing -LINGO1 receptor complex regulates neuronal migration in the early developing CNS (Mathis, C et al., Cereb Cortex, 2010).
专利申请WO2004052932A2公开了一种结合人Nogo-A多肽的单克隆抗体或其片段，以及使用这些抗体来治疗与神经修复相关的疾病等。WO2009056509A1公开了一种人Nogo-A多肽的单克隆抗体或其片段，以及此类结合分子作为药物的用途，特别是在外周和/或中枢神经系统疾病治疗中的用途。Patent application WO2004052932A2 discloses a monoclonal antibody or fragment thereof that binds human Nogo-A polypeptide, and the use of these antibodies to treat diseases related to nerve repair. WO2009056509A1 discloses a monoclonal antibody of human Nogo-A polypeptide or a fragment thereof, as well as the use of such binding molecules as drugs, especially in the treatment of peripheral and/or central nervous system diseases.
因此，本领域仍然需要有效抑制或以其他方式拮抗Nogo-A的治疗性抗体，以及治疗Nogo-A介导的疾病或病症的相关方法，例如中枢神经系统损伤和/或修复、脊髓损伤、阿尔兹海默症等疾病。 Therefore, there remains a need in the art for therapeutic antibodies that effectively inhibit or otherwise antagonize Nogo-A, as well as related methods for treating Nogo-A-mediated diseases or conditions, such as central nervous system injury and/or repair, spinal cord injury, Alzheimer's disease Alzheimer's disease and other diseases.
本文提及的所有出版物、专利、专利申请和已公开的专利申请中披露的内容，以引用方式全部并入本文中。The disclosures in all publications, patents, patent applications, and published patent applications mentioned herein are hereby incorporated by reference in their entirety.
申请概述Application Overview
在一些实施例中，提供一种分离的抗Nogo-A抗体，包含重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYGMH(SEQ ID NO:1)；HC-CDR2，其包含SISHTGKTVFYGESVKG(SEQ ID NO:3)；和HC-CDR3，其包含TELGGDNWFDV(SEQ ID NO:5)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含TGSSSNIGGYDVY(SEQ ID NO:7)；LC-CDR2，其包含DNNKRPS(SEQ ID NO:9)；和LC-CDR3，其包含AAWDDSLYGYI(SEQ ID NO:11)。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising a heavy chain variable domain (V H ), the V H comprising: heavy chain complementarity determining region (HC-CDR) 1 comprising DYGMH (SEQ ID NO: 1); HC-CDR2 comprising SISHTGKTVFYGESVKG (SEQ ID NO: 3); and HC-CDR3 comprising TELGGDNWFDV (SEQ ID NO: 5); and light chain variable domain (V L ) , the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes TGSSSNIGGYDVY (SEQ ID NO: 7); LC-CDR2, which includes DNKRPS (SEQ ID NO: 9); and LC-CDR3, It contains AAWDDSLYGYI (SEQ ID NO: 11).
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:1所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；HC-CDR2，其包含SEQ ID NO:3所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:5所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:7所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；LC-CDR2，其包含SEQ ID NO:9所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和LC-CDR3，其包含SEQ ID NO:11所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, which includes VH , and the VH includes: HC-CDR1, which includes the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, wherein The variants comprise substitutions of up to about 3 amino acids; HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 3 or a variant thereof, the variants comprising substitutions of up to about 3 amino acids; and HC-CDR3 , which comprises the amino acid sequence shown in SEQ ID NO: 5 or a variant thereof, said variant comprising a substitution of up to about 3 amino acids; and V L , said V L comprising: LC-CDR1, which comprises SEQ ID NO : The amino acid sequence shown in SEQ ID NO: 9 or a variant thereof, the variant comprising a substitution of at most about 3 amino acids; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 9 or a variant thereof, the variant Comprised of substitutions of up to about 3 amino acids; and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 11 or a variant thereof, said variant comprising substitutions of up to about 3 amino acids.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：VH，所述VH包含如SEQ ID NOs:13-16中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3，以及VL，所述VL包含如SEQ ID NOs:18-19中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: VH , the VH comprising a VH comprising HC- as shown in any of the amino acid sequences of SEQ ID NOs: 13-16 CDR1, HC- CDR2 and HC-CDR3, and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in any one of the amino acid sequences of SEQ ID NOs: 18-19 .
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:13所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:18所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(ii)VH，其包含如氨基酸序列SEQ ID NO:14所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:19所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(iii)VH，其包含如氨基酸序列SEQ ID NO:15所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:19所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(iv)VH，其包含如氨基酸序列SEQ ID NO:16所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:19所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 13 and HC-CDR3; and V L comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by V L as shown in the amino acid sequence SEQ ID NO: 18; (ii) V H comprising the amino acid sequence SEQ V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in ID NO :14; and V L comprising LC-CDR1, LC- CDR2 and LC-CDR3; (iii) VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence SEQ ID NO: 15; and VL comprising the amino acid sequence as shown LC-CDR1, LC-CDR2 and LC-CDR3 included in the V L shown in SEQ ID NO: 19; (iv) V H including HC-CDR1 included in the V H shown in the amino acid sequence SEQ ID NO: 16 , HC-CDR2 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 19.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:3，和HC-CDR3，其包含氨基酸序列SEQ ID NO:5，或者所述VH的变体，其HC-CDRs中包含至多约5个氨 基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:7，LC-CDR2，其包含氨基酸序列SEQ ID NO:9，和LC-CDR3，其包含氨基酸序列SEQ ID NO:11，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2, It contains the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which contains the amino acid sequence SEQ ID NO: 5, or a variant of the V H containing up to about 5 amino acids in its HC-CDRs. Substitution of amino acid; and VL , the VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence SEQ ID NO:9, and LC-CDR3, which includes The amino acid sequence SEQ ID NO: 11, or a variant of said V L , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，如上所述任一种分离的抗Nogo-A抗体，其包含：VH，其包含SEQ ID NOs:13-16中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:13-16中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NOs:18-19中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:18-19中任一所示的氨基酸序列具有至少约80％序列同一性。In some embodiments, any of the isolated anti-Nogo-A antibodies as described above, which includes: VH , which includes the amino acid sequence shown in any one of SEQ ID NOs: 13-16 or a variant thereof, said A variant having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 13-16; and a VL comprising an amino acid sequence set forth in any one of SEQ ID NOs: 18-19 or a V L thereof Variants having at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 18-19.
在一些实施例中，提供一种分离的抗Nogo-A抗体包含：(i)VH，其包含氨基酸序列SEQ ID NO:13或其变体，所述变体与氨基酸序列SEQ ID NO:13具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:18或其变体，所述变体与氨基酸序列SEQ ID NO:18具有至少约80％序列同一性；(ii)VH，其包含氨基酸序列SEQ ID NO:14或其变体，所述变体与氨基酸序列SEQ ID NO:14具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性；(iii)VH，其包含氨基酸序列SEQ ID NO:15或其变体，所述变体与氨基酸序列SEQ ID NO:15具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性；(iv)VH，其包含氨基酸序列SEQ ID NO:16或其变体，所述变体与氨基酸序列SEQ ID NO:16具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO: 13 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 18 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 18; (ii ) V H comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 14; and V L comprising the amino acid sequence SEQ ID NO : 19 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 19; (iii) V H comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof, the A variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 15; and a V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having the amino acid sequence SEQ ID NO: 19 and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 19.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:17所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:20所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 17 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO:20.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:4，和HC-CDR3，其包含氨基酸序列SEQ ID NO:6，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:8，LC-CDR2，其包含氨基酸序列SEQ ID NO:10，和LC-CDR3，其包含氨基酸序列SEQ ID NO:12，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 2, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 6, or a variant of said V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 8, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 10, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 12 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，如上所述任一种分离的抗Nogo-A抗体，其包含：VH，其包含SEQ ID NO:17所示的氨基酸序列或其变体，所述变体与SEQ ID NO:17所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:20所示的氨基酸序列或其变体，所述变体与SEQ ID NO:20所示的氨基酸序列具有至少约80％序列同一性。In some embodiments, any of the isolated anti-Nogo-A antibodies as described above includes: VH , which includes the amino acid sequence shown in SEQ ID NO: 17 or a variant thereof, which variant is identical to SEQ ID NO. The amino acid sequence shown in NO:17 has at least about 80% sequence identity; and VL , which includes the amino acid sequence shown in SEQ ID NO:20 or a variant thereof, which is identical to the amino acid sequence shown in SEQ ID NO:20 The amino acid sequences have at least about 80% sequence identity.
在一些实施例中，提供一种分离的抗Nogo-A抗体，包含重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYGMH(SEQ ID NO:28)；HC-CDR2，其包含VIWYHGSKKYYADSVKD(SEQ ID NO:48)；和HC-CDR3，其包含SIAETTDYGLDS(SEQ ID  NO:65)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLLYRGGKTFLY(SEQ ID NO:85)；LC-CDR2，其包含ELSNRAS(SEQ ID NO:100)；和LC-CDR3，其包含MQGIQLPWT(SEQ ID NO:111)。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising a heavy chain variable domain ( VH ), the VH comprising: heavy chain complementarity determining region (HC-CDR) 1 comprising SYGMH (SEQ ID NO:28); HC-CDR2, which contains VIWYHGSKKYYADSVKD (SEQ ID NO:48); and HC-CDR3, which contains SIAETTDYGLDS (SEQ ID NO: 65); and a light chain variable domain (V L ), the V L comprising: light chain complementarity determining region (LC-CDR) 1, which includes RSSQSLLYRGGKTFLY (SEQ ID NO: 85); LC-CDR2, It contains ELSNRAS (SEQ ID NO:100); and LC-CDR3, which contains MQGIQLPWT (SEQ ID NO:111).
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:28所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；HC-CDR2，其包含SEQ ID NO:48所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:65所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:85所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；LC-CDR2，其包含SEQ ID NO:100所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和LC-CDR3，其包含SEQ ID NO:111所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising a V H comprising: HC- CDR1 comprising the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof, wherein The variants comprise substitutions of up to about 3 amino acids; HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 48 or a variant thereof, the variants comprising substitutions of up to about 3 amino acids; and HC-CDR3 , which comprises the amino acid sequence set forth in SEQ ID NO: 65 or a variant thereof, said variant comprising a substitution of up to about 3 amino acids; and V L , said V L comprising: LC-CDR1, which comprises SEQ ID NO : The amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, the variant comprising a substitution of at most about 3 amino acids; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, the variant Comprising a substitution of up to about 3 amino acids; and an LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 111 or a variant thereof, the variant comprising a substitution of up to about 3 amino acids.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：VH，所述VH包含如SEQ ID NOs:127-128中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3，以及VL，所述VL包含如SEQ ID NOs:150-151中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: VH , the VH comprising a VH comprising HC- as shown in any one of the amino acid sequences of SEQ ID NOs: 127-128 CDR1, HC-CDR2 and HC-CDR3, and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in any one of the amino acid sequences of SEQ ID NOs : 150-151 .
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:127所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:150所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(ii)VH，其包含如氨基酸序列SEQ ID NO:128所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:151所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(iii)VH，其包含如氨基酸序列SEQ ID NO:128所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:150所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 127 and HC-CDR3; and V L comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by V L as set forth in the amino acid sequence SEQ ID NO: 150; (ii) V H comprising the amino acid sequence SEQ V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in ID NO : 128; and V L comprising LC-CDR1, LC- as shown in amino acid sequence SEQ ID NO: 151. CDR2 and LC-CDR3; (iii) VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence SEQ ID NO: 128 of VH ; and VL comprising the amino acid sequence VL shown in SEQ ID NO:150 contains LC-CDR1, LC-CDR2 and LC-CDR3.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:28，HC-CDR2，其包含氨基酸序列SEQ ID NO:48，和HC-CDR3，其包含氨基酸序列SEQ ID NO:65，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:85，LC-CDR2，其包含氨基酸序列SEQ ID NO:100，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 28, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 48, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 65, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 85, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 100, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 111 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，如上所述任一种分离的抗Nogo-A抗体，其包含：VH，其包含SEQ ID NOs:127-128中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:127-128中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NOs:150-151中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:150-151中任一所示的氨基酸序列具有至少约80％序列同一性。 In some embodiments, any of the isolated anti-Nogo-A antibodies as described above, which includes: VH , which includes the amino acid sequence shown in any one of SEQ ID NOs: 127-128 or a variant thereof, said A variant having at least about 80% sequence identity with the amino acid sequence set forth in any of SEQ ID NOs: 127-128; and a VL comprising the amino acid sequence set forth in any of SEQ ID NOs: 150-151 or its Variants having at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 150-151.
在一些实施例中，提供一种分离的抗Nogo-A抗体包含：(i)VH，其包含氨基酸序列SEQ ID NO:127或其变体，所述变体与氨基酸序列SEQ ID NO:127具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性；(ii)VH，其包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:151或其变体，所述变体与氨基酸序列SEQ ID NO:151具有至少约80％序列同一性；(iii)VH，其包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 127 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO: 127 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 150 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 150; (ii ) V H comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 128; and V L comprising the amino acid sequence SEQ ID NO :151 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:151; (iii) V H comprising the amino acid sequence SEQ ID NO:128 or a variant thereof, the A variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 128; and a V L comprising the amino acid sequence SEQ ID NO: 150 or a variant thereof having the amino acid sequence SEQ ID NO: 150 At least about 80% sequence identity.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:129所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:152所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 129 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 152.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:29，HC-CDR2，其包含氨基酸序列SEQ ID NO:49，和HC-CDR3，其包含氨基酸序列SEQ ID NO:66，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:86，LC-CDR2，其包含氨基酸序列SEQ ID NO:101，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 29, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 49, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 66, or a variant of the V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 86, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 101, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 112 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，如上所述任一种分离的抗Nogo-A抗体，其包含：VH，其包含SEQ ID NO:129所示的氨基酸序列或其变体，所述变体与SEQ ID NO:129所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:152所示的氨基酸序列或其变体，所述变体与SEQ ID NO:152所示的氨基酸序列具有至少约80％序列同一性。In some embodiments, any of the isolated anti-Nogo-A antibodies as described above includes: VH , which includes the amino acid sequence shown in SEQ ID NO: 129 or a variant thereof, which variant is identical to SEQ ID NO. The amino acid sequence shown in NO:129 has at least about 80% sequence identity; and VL , which includes the amino acid sequence shown in SEQ ID NO:152 or a variant thereof, which is identical to the amino acid sequence shown in SEQ ID NO:152 The amino acid sequences have at least about 80% sequence identity.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:130所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:153所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 130 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 153.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:30，HC-CDR2，其包含氨基酸序列SEQ ID NO:50，和HC-CDR3，其包含氨基酸序列SEQ ID NO:67，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:87，LC-CDR2，其包含氨基酸序列SEQ ID NO:102，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 30, HC-CDR2, It includes the amino acid sequence SEQ ID NO: 50, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 67, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 87, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 102, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 113 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％序列同一性；以及 VL，其包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:153具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :130 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 153 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 153.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:131所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:154所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 131 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 154.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:68，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 68, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:131或其变体，所述变体与氨基酸序列SEQ ID NO:131具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:154或其变体，所述变体与氨基酸序列SEQ ID NO:154具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :131 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:154 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:154.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:132所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:155所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 132 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 155.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:32，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:69，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 32, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 69, or a variant of the V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:132或其变体，所述变体与氨基酸序列SEQ ID NO:132具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:155或其变体，所述变体与氨基酸序列SEQ ID NO:155具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :132 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:155 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:155.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:133所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:156所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 133 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 156.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:33，HC-CDR2，其包含氨基酸序列SEQ ID NO:52，和HC-CDR3，其包含氨基酸序列SEQ ID NO:70，或者所述VH的变体，其HC-CDRs中包含至多约5 个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:89，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:115，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 33, HC-CDR2, It contains the amino acid sequence SEQ ID NO: 52, and HC-CDR3, which contains the amino acid sequence SEQ ID NO: 70, or a variant of the V H containing up to about 5 in its HC-CDRs substitutions of amino acids; and V L comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 89, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 104, and LC-CDR3 comprising The amino acid sequence SEQ ID NO: 115, or a variant of the V L containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:133或其变体，所述变体与氨基酸序列SEQ ID NO:133具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:156或其变体，所述变体与氨基酸序列SEQ ID NO:156具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :133 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:156 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:156.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:134所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:157所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 134 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 157.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:34，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:71，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 34, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 71, or a variant of the V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:134或其变体，所述变体与氨基酸序列SEQ ID NO:134具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:157或其变体，所述变体与氨基酸序列SEQ ID NO:157具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :134 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:157 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:157.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:135所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:158所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 135. and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 158.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:35，HC-CDR2，其包含氨基酸序列SEQ ID NO:54，和HC-CDR3，其包含氨基酸序列SEQ ID NO:72，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:90，LC-CDR2，其包含氨基酸序列SEQ ID NO:105，和LC-CDR3，其包含氨基酸序列SEQ ID NO:116，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 35, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 54, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 72, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 90, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 105, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 116 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:135或其变体，所述变体与氨基酸序列SEQ ID NO:135具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:158或其变体，所述变体与氨基酸序列SEQ ID NO:158具有至少约80％序列同一性。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :135 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:158 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:158.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:136所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:159所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 136 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 159.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:36，HC-CDR2，其包含氨基酸序列SEQ ID NO:55，和HC-CDR3，其包含氨基酸序列SEQ ID NO:73，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 36, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 55, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 73, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 91, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 117 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :136 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:137所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:159所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 137 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 159.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:37，HC-CDR2，其包含氨基酸序列SEQ ID NO:56，和HC-CDR3，其包含氨基酸序列SEQ ID NO:74，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 37, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 56, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 74, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 91, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 117 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :137 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:138所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:160所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 138 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 160.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:57，和HC-CDR3，其包含氨基酸序列SEQ ID NO:75，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:92，LC- CDR2，其包含氨基酸序列SEQ ID NO:107，和LC-CDR3，其包含氨基酸序列SEQ ID NO:118，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 57, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 75, or a variant of the V H comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 92, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 107, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 118, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:138或其变体，所述变体与氨基酸序列SEQ ID NO:138具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:160或其变体，所述变体与氨基酸序列SEQ ID NO:160具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :138 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:160 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:160.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:139所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:161所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 139 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 161.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:38，HC-CDR2，其包含氨基酸序列SEQ ID NO:58，和HC-CDR3，其包含氨基酸序列SEQ ID NO:76，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:93，LC-CDR2，其包含氨基酸序列SEQ ID NO:108，和LC-CDR3，其包含氨基酸序列SEQ ID NO:119，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 38, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 58, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 76, or a variant of said V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 93, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 108, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 119 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:139或其变体，所述变体与氨基酸序列SEQ ID NO:139具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:161或其变体，所述变体与氨基酸序列SEQ ID NO:161具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :139 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:161 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:161.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:140所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:162所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 140 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 162.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:39，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:77，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 39, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 77, or a variant of said V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 120 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:140或其变体，所述变体与氨基酸序列SEQ ID NO:140具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:162或其变体，所述变体与氨基酸序列SEQ ID NO:162具有至少约80％序列同一性。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :140 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:162 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:162.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:141所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:163所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 141 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 163.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:40，HC-CDR2，其包含氨基酸序列SEQ ID NO:59，和HC-CDR3，其包含氨基酸序列SEQ ID NO:78，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:94，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:121，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 40, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 59, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 78, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 94, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 121 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:141或其变体，所述变体与氨基酸序列SEQ ID NO:141具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:163或其变体，所述变体与氨基酸序列SEQ ID NO:163具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 141 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :141 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:163 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:163.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:142所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:164所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 comprised by the V H as shown in the amino acid sequence SEQ ID NO: 142 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 164.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:41，HC-CDR2，其包含氨基酸序列SEQ ID NO:60，和HC-CDR3，其包含氨基酸序列SEQ ID NO:79，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 41, HC-CDR2, It includes the amino acid sequence SEQ ID NO: 60, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 79, or a variant of the V H , including up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:142或其变体，所述变体与氨基酸序列SEQ ID NO:142具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:164或其变体，所述变体与氨基酸序列SEQ ID NO:164具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :142 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:164 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:164.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:143所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:165所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 143 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 165.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:42，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC- CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 42, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 120, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:143或其变体，所述变体与氨基酸序列SEQ ID NO:143具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:165或其变体，所述变体与氨基酸序列SEQ ID NO:165具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :143 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:165 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:165.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:144所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:166所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 144 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 166.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:122，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2, It includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81, or a variant of the V H , including up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 95, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 122 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:144或其变体，所述变体与氨基酸序列SEQ ID NO:144具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:166或其变体，所述变体与氨基酸序列SEQ ID NO:166具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :144 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:166 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:166.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:145所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:167所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 145 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 167.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:44，HC-CDR2，其包含氨基酸序列SEQ ID NO:62，和HC-CDR3，其包含氨基酸序列SEQ ID NO:82，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:96，LC-CDR2，其包含氨基酸序列SEQ ID NO:110，和LC-CDR3，其包含氨基酸序列SEQ ID NO:123，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 44, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 62, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 82, or a variant of the V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 96, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 110, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 123 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:145或其变体，所述变体与氨基酸序列SEQ ID NO:145具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:167或其变体，所述变体与氨基酸序列SEQ ID NO:167具有至少约80％序列同一性。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :145 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:167 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:167.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:146所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:168所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 146 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 168.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:45，HC-CDR2，其包含氨基酸序列SEQ ID NO:63，和HC-CDR3，其包含氨基酸序列SEQ ID NO:83，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:97，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:124，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 45, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 63, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 83, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 97, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 124 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:168或其变体，所述变体与氨基酸序列SEQ ID NO:168具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :146 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:168 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:168.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:147所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:169所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 147 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 169.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:46，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:98，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 46, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V H , the HC-CDRs of which comprise up to about 5 amino acid substitutions; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 98, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:169或其变体，所述变体与氨基酸序列SEQ ID NO:169具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :147 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:169 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:169.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:148所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:170所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 148 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 170.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:47，HC-CDR2，其包含氨基酸序列SEQ ID NO:64，和HC-CDR3，其包含氨基酸序列SEQ ID NO:84，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:99，LC- CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:125，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 47, HC-CDR2, It comprises the amino acid sequence SEQ ID NO: 64, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 84, or a variant of said V H , comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 99, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 125, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:170或其变体，所述变体与氨基酸序列SEQ ID NO:170具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :148 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:170 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:170.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:149所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:171所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。 In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising HC-CDR1, HC-CDR2 as shown in the amino acid sequence of SEQ ID NO: 149 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as set forth in the amino acid sequence SEQ ID NO: 171.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:126，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2, It includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81, or a variant of the V H , including up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 95, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 126 , or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其包含：(i)VH，其包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:171或其变体，所述变体与氨基酸序列SEQ ID NO:171具有至少约80％序列同一性。In some embodiments, an isolated anti-Nogo-A antibody is provided, comprising: (i) V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof that is consistent with the amino acid sequence SEQ ID NO :149 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:171 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:171.
在一些实施例中，分离的抗Nogo-A抗体与人Nogo-A的结合的Kd值为0.1pM至约10nM。In some embodiments, the isolated anti-Nogo-A antibody binds to human Nogo-A with a Kd value of 0.1 pM to about 10 nM.
在一些实施例中，提供一种分离的抗Nogo-A抗体，其与上述任一种分离的抗Nogo-A抗体竞争与Nogo-A的特异性结合。在一些实施例中，提供一种分离的抗Nogo-A抗体，其与上述任一种分离的抗Nogo-A抗体特异性地结合相同的表位。In some embodiments, an isolated anti-Nogo-A antibody is provided that competes with any of the above-described isolated anti-Nogo-A antibodies for specific binding to Nogo-A. In some embodiments, an isolated anti-Nogo-A antibody is provided that specifically binds to the same epitope as any of the isolated anti-Nogo-A antibodies described above.
在一些实施例中，如上所述任一种分离的抗Nogo-A抗体，所述分离的抗Nogo-A抗体包含Fc片段。在一些实施例中，所述分离的抗Nogo-A抗体是全长的IgG抗体。在一些实施例中，所述分离的抗Nogo-A抗体是全长的IgG1、IgG2、IgG3或IgG4抗体。在一些实施例中，所述分离的抗Nogo-A抗体是嵌合的、全人的或人源化的抗体。在一些实施例中，所述分离的抗Nogo-A抗体是抗原结合片段，所述抗原结合片段选自Fab、Fab’、F(ab)’2、Fab’-SH、单链Fv(scFv)、Fv片段、dAb、Fd、纳米抗体(nanobody)、双链抗体(diabody)和线性抗体。In some embodiments, any of the isolated anti-Nogo-A antibodies described above, the isolated anti-Nogo-A antibody comprises an Fc fragment. In some embodiments, the isolated anti-Nogo-A antibody is a full-length IgG antibody. In some embodiments, the isolated anti-Nogo-A antibody is a full-length IgGl, IgG2, IgG3 or IgG4 antibody. In some embodiments, the isolated anti-Nogo-A antibody is a chimeric, fully human, or humanized antibody. In some embodiments, the isolated anti-Nogo-A antibody is an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab)' 2 , Fab'-SH, single chain Fv (scFv) , Fv fragments, dAb, Fd, nanobodies, diabodies and linear antibodies.
在一些实施例中，提供一种分离的核酸分子，所述核酸分子编码如上所述任一种抗Nogo-A抗体。在一些实施例中，提供一种载体，所述载体包含如上所述任一种核酸分子。在一些实施例中，提供一种宿主细胞，所述宿主细胞包含如上所述任一种抗Nogo-A抗体、如上所述任一种核酸分子或如上所述任一种载体。在一些实施例中，提供一种制备抗Nogo-A抗体的方法，其包含：a) 在能有效表达抗Nogo-A抗体的条件下培养上述任一种宿主细胞；和b)从宿主细胞中获得表达的抗Nogo-A抗体。In some embodiments, an isolated nucleic acid molecule encoding any of the anti-Nogo-A antibodies described above is provided. In some embodiments, a vector is provided comprising any of the nucleic acid molecules described above. In some embodiments, a host cell is provided, the host cell comprising any one of the anti-Nogo-A antibodies described above, any one of the nucleic acid molecules described above, or any one of the vectors described above. In some embodiments, a method of preparing an anti-Nogo-A antibody is provided, comprising: a) Cultivate any of the above host cells under conditions that can effectively express anti-Nogo-A antibodies; and b) obtain expressed anti-Nogo-A antibodies from the host cells.
在一些实施例中，提供一种治疗所需个体疾病或病症的方法，包括向所述个体施用有效量的如上所述的任一种抗Nogo-A抗体。在一些实施例中，提供如上所述的任一种抗Nogo-A抗体在制备用于治疗所需个体疾病或病症的药物组合物中的用途。在一些实施例中，提供如上所述的任一种抗Nogo-A抗体或包含抗Nogo-A抗体的药物组合物在制备用于治疗疾病或病症的药物中的用途。在一些实施例中，所述疾病或病症与Nogo-A信号通路有关，包括中枢神经系统和/或外周神经系统疾病或创伤或病症。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。In some embodiments, a method of treating a disease or condition in a desired individual is provided, comprising administering to the individual an effective amount of any of the anti-Nogo-A antibodies described above. In some embodiments, provided is the use of any of the anti-Nogo-A antibodies described above in the preparation of a pharmaceutical composition for treating a disease or condition in a desired individual. In some embodiments, the use of any of the anti-Nogo-A antibodies described above or a pharmaceutical composition comprising an anti-Nogo-A antibody in the preparation of a medicament for treating a disease or condition is provided. In some embodiments, the disease or disorder is associated with the Nogo-A signaling pathway, including central nervous system and/or peripheral nervous system disease or trauma or disorder. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression.
同时还提供包含如上所述的任一种抗Nogo-A抗体的药物组合物、试剂盒以及生产制品。Pharmaceutical compositions, kits and manufactured products containing any of the anti-Nogo-A antibodies mentioned above are also provided.
附图说明Description of drawings
图1所示为ELISA分析的抗Nogo-A抗体与hNiG的结合亲和力。图1A所示为ELISA分析的示例性抗体mkNG-22与hNiG的结合亲和力。图1B所示为ELISA分析的示例性抗体L82、H-L82-1、H-L82-2及H-L82-3与hNiG的结合亲和力。Figure 1 shows the binding affinity of anti-Nogo-A antibody to hNiG analyzed by ELISA. Figure 1A shows the binding affinity of exemplary antibody mkNG-22 to hNiG analyzed by ELISA. Figure 1B shows the binding affinity of exemplary antibodies L82, H-L82-1, H-L82-2, and H-L82-3 to hNiG analyzed by ELISA.
图2所示为ELISA分析的抗Nogo-A抗体对hNiG和细胞膜表面Nogo-A受体结合的抑制活性。图2A所示为ELISA分析的示例性抗体L82、H-L82-1、H-L82-2及H-L82-3对hNiG和PC12细胞膜上Nogo-A受体结合的抑制活性。图2B所示为ELISA分析的示例性抗体L82、H-L82-1、H-L82-2及H-L82-3对hNiG和3T3细胞膜上Nogo-A受体结合的抑制活性。Figure 2 shows the inhibitory activity of anti-Nogo-A antibodies on the binding of hNiG to Nogo-A receptors on the cell membrane surface analyzed by ELISA. Figure 2A shows the inhibitory activity of exemplary antibodies L82, H-L82-1, H-L82-2 and H-L82-3 on the binding of hNiG and Nogo-A receptors on PC12 cell membranes analyzed by ELISA. Figure 2B shows the inhibitory activity of exemplary antibodies L82, H-L82-1, H-L82-2 and H-L82-3 on the binding of hNiG and Nogo-A receptors on 3T3 cell membranes analyzed by ELISA.
图3所示为FACS分析的抗Nogo-A抗体与不同种属包括人、恒河猴、大鼠和小鼠的Nogo-A的交叉结合活性。图3A所示为FACS分析的抗Nogo-A抗体mkNG-22、L82、H-L82-1、H-L82-2及H-L82-3与人Nogo-A的结合活性。图3B所示为FACS分析的抗Nogo-A抗体mkNG-22、L82、H-L82-1、H-L82-2及H-L82-3与恒河猴Nogo-A的交叉结合活性。图3C所示为FACS分析的抗Nogo-A抗体mkNG-22、L82、H-L82-1、H-L82-2及H-L82-3与大鼠Nogo-A的交叉结合活性。图3D所示为FACS分析的抗Nogo-A抗体mkNG-22、L82、H-L82-1、H-L82-2及H-L82-3与小鼠Nogo-A的交叉结合活性。 Figure 3 shows the cross-binding activity of anti-Nogo-A antibodies analyzed by FACS with Nogo-A of different species including humans, rhesus monkeys, rats and mice. Figure 3A shows the binding activity of anti-Nogo-A antibodies mkNG-22, L82, H-L82-1, H-L82-2 and H-L82-3 to human Nogo-A analyzed by FACS. Figure 3B shows the cross-binding activity of anti-Nogo-A antibodies mkNG-22, L82, H-L82-1, H-L82-2 and H-L82-3 with rhesus monkey Nogo-A analyzed by FACS. Figure 3C shows the cross-binding activity of anti-Nogo-A antibodies mkNG-22, L82, H-L82-1, H-L82-2 and H-L82-3 with rat Nogo-A analyzed by FACS. Figure 3D shows the cross-binding activity of anti-Nogo-A antibodies mkNG-22, L82, H-L82-1, H-L82-2 and H-L82-3 with mouse Nogo-A analyzed by FACS.
图4所示为相对荧光定量PCR分析的抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3及mkNG-22对Nogo-A抑制GAP-43转录水平的阻断活性。Figure 4 shows the relative fluorescence quantitative PCR analysis of the effects of anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 on Nogo-A's inhibition of GAP-43 transcription levels. Blocking activity.
图5所示为抗Nogo-A抗体对hNiG抑制N1E-115细胞神经突生长的恢复作用。图5A所示为显微镜观察的抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3及mkNG-22对hNiG抑制N1E-115细胞神经突生长形态的恢复作用。图5B所示为定量分析的抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3及mkNG-22对hNiG抑制N1E-115细胞神经突生长比例的恢复作用。图5C所示为定量分析的抗Nogo-A抗体mkNG-362对hNiG抑制N1E-115细胞神经突生长比例的恢复作用。Figure 5 shows the recovery effect of anti-Nogo-A antibody on hNiG-inhibited neurite growth of N1E-115 cells. Figure 5A shows the restoration effect of anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 on hNiG-inhibited N1E-115 cell neurite growth morphology observed under a microscope. . Figure 5B shows the quantitative analysis of the restoration effect of anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 on the proportion of hNiG-inhibited neurite growth of N1E-115 cells. . Figure 5C shows the quantitative analysis of the restoration effect of anti-Nogo-A antibody mkNG-362 on the proportion of hNiG inhibiting neurite growth of N1E-115 cells.
图6所示为抗Nogo-A抗体对猴脊髓提取液抑制N1E-115细胞神经突生长的恢复作用。图6A所示为显微镜观察的抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3及mkNG-22对猴脊髓提取液抑制N1E-115细胞神经突生长形态的恢复作用。图6B所示为定量分析的抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3及mkNG-22对猴脊髓提取液抑制N1E-115细胞神经突生长形态比例的恢复作用。图6C所示为定量分析的示例性抗Nogo-A抗体mkNG-360、mkNG-362对hNiG抑制PC12细胞神经突生长比例的恢复作用。Figure 6 shows the recovery effect of anti-Nogo-A antibody on the inhibition of neurite growth of N1E-115 cells by monkey spinal cord extract. Figure 6A shows the inhibition of N1E-115 cell neurite growth morphology by anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 on monkey spinal cord extracts observed under a microscope. restorative effect. Figure 6B shows the quantitative analysis of anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 inhibiting the neurite growth morphology of N1E-115 cells in monkey spinal cord extracts. The restorative effect of proportion. Figure 6C shows the quantitative analysis of the restoration effect of exemplary anti-Nogo-A antibodies mkNG-360 and mkNG-362 on the proportion of hNiG inhibiting neurite growth of PC12 cells.
图7所示为示例性抗Nogo-A抗体H-L82-3在脊髓损伤小鼠模型中具有治疗脊髓损伤的作用。Figure 7 shows that exemplary anti-Nogo-A antibody H-L82-3 has the effect of treating spinal cord injury in a mouse model of spinal cord injury.
本申请的详细描述Detailed description of this application
本申请一方面提供抗Nogo-A抗体分子。通过scFv抗体酵母库筛选、scFv噬菌体库筛选、CHO-IgG抗体展示文库筛选、人源化、亲和力成熟以及适当设计的生物化学及生物学实验的组合，已经鉴定出能够结合人Nogo-A并抑制人Nogo-A与其受体作用的高效抗体分子。本文给出的结果表明，与已知抗Nogo-A抗体ATI-355、或11C7(诺华)相比，本申请中的抗体结合Nogo-A，并且令人惊讶地是，在各种生物学实验中证明了本申请中的抗体甚至比ATI-355更有效。In one aspect, the present application provides anti-Nogo-A antibody molecules. Through a combination of scFv antibody yeast library screening, scFv phage library screening, CHO-IgG antibody display library screening, humanization, affinity maturation, and appropriately designed biochemical and biological experiments, individuals capable of binding to and inhibiting human Nogo-A have been identified A highly effective antibody molecule that interacts with human Nogo-A and its receptor. The results presented here demonstrate that the antibody in this application binds Nogo-A compared to the known anti-Nogo-A antibodies ATI-355, or 11C7 (Novartis), and surprisingly, in various biological experiments The antibody in this application was demonstrated to be even more effective than ATI-355.
本申请所提供的抗Nogo-A抗体包括，例如，全长抗Nogo-A抗体、抗Nogo-A单链抗体(scFvs)、抗Nogo-A Fc融合蛋白、多特异性(如双特异性)抗Nogo-A抗体、抗Nogo-A免疫偶联物以及诸如此类的。Anti-Nogo-A antibodies provided by the application include, for example, full-length anti-Nogo-A antibodies, anti-Nogo-A single chain antibodies (scFvs), anti-Nogo-A Fc fusion proteins, multispecific (such as bispecific) Anti-Nogo-A antibodies, anti-Nogo-A immunoconjugates, and the like.
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYGMH(SEQ ID NO:1)；HC-CDR2，其包含SISHTGKTVFYGESVKG(SEQ ID NO:3)；和HC-CDR3，其包含TELGGDNWFDV(SEQ ID NO:5)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含TGSSSNIGGYDVY(SEQ ID NO:7)；LC-CDR2，其包含DNNKRPS(SEQ ID NO:9)；和LC-CDR3，其包含AAWDDSLYGYI(SEQ ID NO:11)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYGMH (SEQ ID NO: 1); HC-CDR2, which includes SISHTGKTVFYGESVKG (SEQ ID NO: 3); and HC-CDR3, which includes TELGGDNWFDV (SEQ ID NO: 5); and the light chain variable domain and _ LC-CDR3 containing AAWDDSLYGYI (SEQ ID NO: 11).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SHGMN(SEQ ID NO:2)；HC-CDR2，其包含YISNGGDSTYYADSVKG(SEQ ID NO:4)；和HC-CDR3，其包含TFSH(SEQ ID NO:6)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含 RSSQSLLHSNGNTYLH(SEQ ID NO:8)；LC-CDR2，其包含GGSNRAS(SEQ ID NO:10)；和LC-CDR3，其包含VQAIAFPYS(SEQ ID NO:12)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SHGMN (SEQ ID NO:2); HC-CDR2, which includes YISNGGDSTYYADSVKG (SEQ ID NO:4); and HC-CDR3, which includes TFSH (SEQ ID NO:6); and the light chain variable domain (V L ), the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes RSSQSLLHSNGNTYLH (SEQ ID NO:8); LC-CDR2, which contains GGSNRAS (SEQ ID NO:10); and LC-CDR3, which contains VQAIAFPYS (SEQ ID NO:12).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYGMH(SEQ ID NO:28)；HC-CDR2，其包含VIWYHGSKKYYADSVKD(SEQ ID NO:48)；和HC-CDR3，其包含SIAETTDYGLDS(SEQ ID NO:65)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLLYRGGKTFLY(SEQ ID NO:85)；LC-CDR2，其包含ELSNRAS(SEQ ID NO:100)；和LC-CDR3，其包含MQGIQLPWT(SEQ ID NO:111)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SYGMH (SEQ ID NO:28); HC-CDR2, which includes VIWYHGSKKYYADSVKD (SEQ ID NO:48); and HC-CDR3, which includes SIAETTDYGLDS (SEQ ID NO:65); and light chain variable domains and _ LC-CDR3 comprising MQGIQLPWT (SEQ ID NO: 111).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DHYMD(SEQ ID NO:29)；HC-CDR2，其包含FIRNKAKGGTTEYAASVKG(SEQ ID NO:49)；和HC-CDR3，其包含LYGAYY(SEQ ID NO:66)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RASQSISGWLA(SEQ ID NO:86)；LC-CDR2，其包含KASSLQS(SEQ ID NO:101)；和LC-CDR3，其包含QQYNSAPPT(SEQ ID NO:112)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DHYMD (SEQ ID NO:29); HC-CDR2, which includes FIRNKAKGGTTEYAASVKG (SEQ ID NO:49); and HC-CDR3, which includes LYGAYY (SEQ ID NO:66); and the light chain variable domain and _ LC-CDR3 comprising QQYNSAPPT (SEQ ID NO: 112).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYAMS(SEQ ID NO:30)；HC-CDR2，其包含YIRTKSHNSAAEYAASVKG(SEQ ID NO:50)；和HC-CDR3，其包含VGGY(SEQ ID NO:67)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLLHSNGNTYLS(SEQ ID NO:87)；LC-CDR2，其包含QVSNRYS(SEQ ID NO:102)；和LC-CDR3，其包含GQGAHFPFT(SEQ ID NO:113)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYAMS (SEQ ID NO:30); HC-CDR2, which includes YIRTKSHNSAAEYAASVKG (SEQ ID NO:50); and HC-CDR3, which includes VGGY (SEQ ID NO:67); and the light chain variable domain and _ LC-CDR3 comprising GQGAHFPFT (SEQ ID NO: 113).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYYMQ(SEQ ID NO:31)；HC-CDR2，其包含RINPKTGGTNYAQKFQG(SEQ ID NO:51)；和HC-CDR3，其包含GSAAVRD(SEQ ID NO:68)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含KSSQSLLYSSNNKNYLA(SEQ ID NO:88)；LC-CDR2，其包含WASTRES(SEQ ID NO:103)；和LC-CDR3，其包含QQYYSTPLT(SEQ ID NO:114)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYMQ (SEQ ID NO:31); HC-CDR2, which includes RINPKTGGTNYAQKFQG (SEQ ID NO:51); and HC-CDR3, which includes GSAAVRD (SEQ ID NO:68); and light chain variable domain and _ LC-CDR3 containing QQYYSTPLT (SEQ ID NO: 114).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含NYYIQ(SEQ ID NO:32)；HC-CDR2，其包含RINPKTGGTNYAQKFQG(SEQ ID NO:51)；和HC-CDR3，其包含GAAAAY(SEQ ID NO:69)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含KSSQSLLYSSNNKNYLA(SEQ ID NO:88)；LC-CDR2，其包含WASTRES(SEQ ID NO:103)；和LC-CDR3，其包含QQYYSTPLT(SEQ ID NO:114)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes NYYIQ (SEQ ID NO:32); HC-CDR2, which includes RINPKTGGTNYAQKFQG (SEQ ID NO:51); and HC-CDR3, which includes GAAAAY (SEQ ID NO:69); and the light chain variable domain and _ LC-CDR3 containing QQYYSTPLT (SEQ ID NO: 114).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含NYDIH(SEQ ID NO:33)；HC-CDR2， 其包含LVRNKANTYTTEYAAAVKG(SEQ ID NO:52)；和HC-CDR3，其包含PGTYSGSLDV(SEQ ID NO:70)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RASQGIINYLA(SEQ ID NO:89)；LC-CDR2，其包含KASTLQS(SEQ ID NO:104)；和LC-CDR3，其包含QQHNSYPLT(SEQ ID NO:115)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which contains NYDIH (SEQ ID NO:33); HC-CDR2, It includes LVRNKANTYTTEYAAAVKG (SEQ ID NO:52); and HC-CDR3, which includes PGTYSGSLDV (SEQ ID NO:70); and a light chain variable domain ( VL ), which VL includes: a light chain complementarity determining region (LC-CDR)1, which contains RASQGIINYLA (SEQ ID NO:89); LC-CDR2, which contains KASTLQS (SEQ ID NO:104); and LC-CDR3, which contains QQHNSYPLT (SEQ ID NO:115).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYYIQ(SEQ ID NO:34)；HC-CDR2，其包含RINPRTGGTNYAQKFQG(SEQ ID NO:53)；和HC-CDR3，其包含GAAAVSY(SEQ ID NO:71)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含KSSQSLLYSSNNKNYLA(SEQ ID NO:88)；LC-CDR2，其包含WASTRES(SEQ ID NO:103)；和LC-CDR3，其包含QQYYSTPLT(SEQ ID NO:114)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYIQ (SEQ ID NO:34); HC-CDR2, which includes RINPRTGGTNYAQKFQG (SEQ ID NO:53); and HC-CDR3, which includes GAAAVSY (SEQ ID NO:71); and the light chain variable domain and _ LC-CDR3 containing QQYYSTPLT (SEQ ID NO: 114).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含GSAMH(SEQ ID NO:35)；HC-CDR2，其包含RIRSKSNNYATEYAASVKG(SEQ ID NO:54)；和HC-CDR3，其包含GKIGTTPKFGSY(SEQ ID NO:72)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RASESVSVFGINLIY(SEQ ID NO:90)；LC-CDR2，其包含QASNKDT(SEQ ID NO:105)；和LC-CDR3，其包含LQSKNSPLT(SEQ ID NO:116)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes GSAMH (SEQ ID NO:35); HC-CDR2, which includes RIRSKSNNYATEYAASVKG (SEQ ID NO:54); and HC-CDR3, which includes GKIGTTPKFGSY (SEQ ID NO:72); and the light chain variable domain and _ LC-CDR3 comprising LQSKNSPLT (SEQ ID NO: 116).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SHGMN(SEQ ID NO:36)；HC-CDR2，其包含YISNGGDSTYYADSVKG(SEQ ID NO:55)；和HC-CDR3，其包含TFSH(SEQ ID NO:73)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLLHSNGNTYLH(SEQ ID NO:91)；LC-CDR2，其包含GGSNRAS(SEQ ID NO:106)；和LC-CDR3，其包含VQAIAFPRT(SEQ ID NO:117)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SHGMN (SEQ ID NO:36); HC-CDR2, which includes YISNGGDSTYYADSVKG (SEQ ID NO:55); and HC-CDR3, which includes TFSH (SEQ ID NO:73); and the light chain variable domain and _ LC-CDR3 containing VQAIAFPRT (SEQ ID NO: 117).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYTMH(SEQ ID NO:37)；HC-CDR2，其包含TIHSGGDTTYYTDSVKG(SEQ ID NO:56)；和HC-CDR3，其包含SDV(SEQ ID NO:74)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLLHSNGNTYLH(SEQ ID NO:91)；LC-CDR2，其包含GGSNRAS(SEQ ID NO:106)；和LC-CDR3，其包含VQAIAFPRT(SEQ ID NO:117)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SYTMH (SEQ ID NO:37); HC-CDR2, which includes TIHSGGDTTYYTDSVKG (SEQ ID NO:56); and HC-CDR3, which includes SDV (SEQ ID NO:74); and the light chain variable domain and _ LC-CDR3 containing VQAIAFPRT (SEQ ID NO: 117).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYYMQ(SEQ ID NO:31)；HC-CDR2，其包含FIRNKPNGGTAEYAASVKG(SEQ ID NO:57)；和HC-CDR3，其包含ADYYGSGLLFNY(SEQ ID NO:75)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLLDSEDGNTYLE(SEQ ID NO:92)；LC-CDR2，其包含EVSNRAS(SEQ ID NO:107)；和LC-CDR3，其包含LQSLEYPFT(SEQ ID NO:118)。 On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYMQ (SEQ ID NO:31); HC-CDR2, which includes FIRNKPNGGTAEYAASVKG (SEQ ID NO:57); and HC-CDR3, which includes ADYYGSGLLFNY (SEQ ID NO:75); and the light chain variable domain and _ LC-CDR3 containing LQSLEYPFT (SEQ ID NO: 118).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYAMT(SEQ ID NO:38)；HC-CDR2，其包含YIRSKSNNYATVYAASVKG(SEQ ID NO:58)；和HC-CDR3，其包含GLTATN(SEQ ID NO:76)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含KSSQSLLYNSNNKNYLA(SEQ ID NO:93)；LC-CDR2，其包含WASTRGS(SEQ ID NO:108)；和LC-CDR3，其包含QQYYGPPLT(SEQ ID NO:119)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYAMT (SEQ ID NO:38); HC-CDR2, which includes YIRSKSNNYATVYAASVKG (SEQ ID NO:58); and HC-CDR3, which includes GLTATN (SEQ ID NO:76); and the light chain variable domain and _ LC-CDR3 containing QQYYGPPLT (SEQ ID NO: 119).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含HYYIQ(SEQ ID NO:39)；HC-CDR2，其包含RINPKTGGTNYAQKFQG(SEQ ID NO:51)；和HC-CDR3，其包含GPAAISD(SEQ ID NO:77)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含KSSQSLLYSSNNKNYLA(SEQ ID NO:88)；LC-CDR2，其包含WASTRES(SEQ ID NO:103)；和LC-CDR3，其包含HQYYSTPLT(SEQ ID NO:120)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes HYYIQ (SEQ ID NO:39); HC-CDR2, which includes RINPKTGGTNYAQKFQG (SEQ ID NO:51); and HC-CDR3, which includes GPAAISD (SEQ ID NO:77); and light chain variable domain and _ LC-CDR3 containing HQYYSTPLT (SEQ ID NO: 120).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYYVQ(SEQ ID NO:40)；HC-CDR2，其包含RINPRTGGTNYAQKFRG(SEQ ID NO:59)；和HC-CDR3，其包含GPAAVAY(SEQ ID NO:78)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含KSSQNLLYSSNNKNYLA(SEQ ID NO:94)；LC-CDR2，其包含WASTRES(SEQ ID NO:103)；和LC-CDR3，其包含QQFYSTPLT(SEQ ID NO:121)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYVQ (SEQ ID NO:40); HC-CDR2, which includes RINPRTGGTNYAQKFRG (SEQ ID NO:59); and HC-CDR3, which includes GPAAVAY (SEQ ID NO:78); and the light chain variable domain and _ LC-CDR3 containing QQFYSTPLT (SEQ ID NO: 121).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含重链互补决定区(HC-CDR)1：，其包含SYYIQ(SEQ ID NO:41)；HC-CDR2，其包含RINPKTGGTNFAQKFQG(SEQ ID NO:60)；和HC-CDR3，其包含GVAAASY(SEQ IDNO:79)；以及轻链可变结构域(VL)，所述VL包含轻链互补决定区(LC-CDR)1：，其包含KSSQSLLYSSNNKNYLA(SEQ ID NO:88)；LC-CDR2，其包含WASTRES(SEQ ID NO:103)；和LC-CDR3，其包含QQYYSTPLT(SEQ ID NO:114)。In another aspect, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising a heavy chain complementarity determining region (HC-CDR) 1: , which includes SYYIQ (SEQ ID NO:41); HC-CDR2, which includes RINPKTGGTNFAQKFQG (SEQ ID NO:60); and HC-CDR3, which includes GVAAASY (SEQ ID NO:79); and the light chain variable domain ( V L ), said V L comprising light chain complementarity determining region (LC-CDR) 1:, comprising KSSQSLLYSSNNKNYLA (SEQ ID NO:88); LC-CDR2, comprising WASTRES (SEQ ID NO:103); and LC - CDR3 comprising QQYYSTPLT (SEQ ID NO: 114).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含AYYIQ(SEQ ID NO:42)；HC-CDR2，其包含RINPKTGGTNYAQKFQG(SEQ ID NO:51)；和HC-CDR3，其包含GAAAVNY(SEQ ID NO:80)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含KSSQSLLYSSNNKNYLA(SEQ ID NO:88)；LC-CDR2，其包含WASTRES(SEQ ID NO:103)；和LC-CDR3，其包含HQYYSTPLT(SEQ ID NO:120)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes AYYIQ (SEQ ID NO:42); HC-CDR2, which includes RINPKTGGTNYAQKFQG (SEQ ID NO:51); and HC-CDR3, which includes GAAAVNY (SEQ ID NO:80); and the light chain variable domain and _ LC-CDR3 containing HQYYSTPLT (SEQ ID NO: 120).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYYLQ(SEQ ID NO:43)；HC-CDR2，其包含RINPKTGATNYTQKFQG(SEQ ID NO:61)；和HC-CDR3，其包含VVY(SEQ ID NO:81)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含 RASQGITNDLL(SEQ ID NO:95)；LC-CDR2，其包含EASSLQG(SEQ ID NO:109)；和LC-CDR3，其包含QQYKGAPYS(SEQ ID NO:122)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYLQ (SEQ ID NO:43); HC-CDR2, which includes RINPKTGATNYTQKFQG (SEQ ID NO:61); and HC-CDR3, which includes VVY (SEQ ID NO:81); and the light chain variable domain (V L ), the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes RASQGITNDLL (SEQ ID NO:95); LC-CDR2, which contains EASSLQG (SEQ ID NO:109); and LC-CDR3, which contains QQYKGAPYS (SEQ ID NO:122).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含TYWWG(SEQ ID NO:44)；HC-CDR2，其包含EINTNSGSTSYNPSLKS(SEQ ID NO:62)；和HC-CDR3，其包含AAAYYYALDS(SEQ ID NO:82)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RASQNVSSWLA(SEQ ID NO:96)；LC-CDR2，其包含KTSSLRS(SEQ ID NO:110)；和LC-CDR3，其包含QQYNCAPLT(SEQ ID NO:123)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes TYWWG (SEQ ID NO:44); HC-CDR2, which includes EINTNSGSTSYNPSLKS (SEQ ID NO:62); and HC-CDR3, which includes AAAYYYALDS (SEQ ID NO:82); and light chain variable domains (V L ), said V L comprising: light chain complementarity determining region (LC-CDR) 1, comprising RASQNVSSWLA (SEQ ID NO: 96); LC-CDR2, comprising KTSSLRS (SEQ ID NO: 110); and LC-CDR3 comprising QQYNCAPLT (SEQ ID NO: 123).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DSYMH(SEQ ID NO:45)；HC-CDR2，其包含LVRNKDKSYTTEYAAAVKG(SEQ ID NO:63)；和HC-CDR3，其包含FNH(SEQ ID NO:83)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RASQDISIWLA(SEQ ID NO:97)；LC-CDR2，其包含KASTLQS(SEQ ID NO:104)；和LC-CDR3，其包含QQYKSAPYN(SEQ ID NO:124)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DSYMH (SEQ ID NO:45); HC-CDR2, which includes LVRNKDKSYTTEYAAAVKG (SEQ ID NO:63); and HC-CDR3, which includes FNH (SEQ ID NO:83); and the light chain variable domain and _ LC-CDR3 comprising QQYKSAPYN (SEQ ID NO: 124).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含NFYIQ(SEQ ID NO:46)；HC-CDR2，其包含RINPRTGGTNYAQKFQG(SEQ ID NO:53)；和HC-CDR3，其包含GAAAVNY(SEQ ID NO:80)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含KSSQSLFYSSNNKTYLA(SEQ ID NO:98)；LC-CDR2，其包含WASTRES(SEQ ID NO:103)；和LC-CDR3，其包含QQYYSTPLT(SEQ ID NO:114)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes NFYIQ (SEQ ID NO:46); HC-CDR2, which includes RINPRTGGTNYAQKFQG (SEQ ID NO:53); and HC-CDR3, which includes GAAAVNY (SEQ ID NO:80); and the light chain variable domain and _ LC-CDR3 containing QQYYSTPLT (SEQ ID NO: 114).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYSMQ(SEQ ID NO:47)；HC-CDR2，其包含AINSGGGTTYYADSVKG(SEQ ID NO:64)；和HC-CDR3，其包含GGGNHDAIDF(SEQ ID NO:84)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含KSGQSLLYRSNNKNYLA(SEQ ID NO:99)；LC-CDR2，其包含WASTRES(SEQ ID NO:103)；和LC-CDR3，其包含QHYYSIPWT(SEQ ID NO:125)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes SYSMQ (SEQ ID NO:47); HC-CDR2, which includes AINSGGGTTYYADSVKG (SEQ ID NO:64); and HC-CDR3, which includes GGGNHDAIDF (SEQ ID NO:84); and the light chain variable domain and _ LC-CDR3 comprising QHYYSIPWT (SEQ ID NO: 125).
另一方面，本申请提供抗Nogo-A抗体，所述抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYYLQ(SEQ ID NO:43)；HC-CDR2，其包含RINPKTGATNYTQKFQG(SEQ ID NO:61)；和HC-CDR3，其包含VVY(SEQ ID NO:81)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RASQGITNDLL(SEQ ID NO:95)；LC-CDR2，其包含EASSLQG(SEQ ID NO:109)；和LC-CDR3，其包含QHYYTTPFT(SEQ ID NO:126)。On the other hand, the application provides an anti-Nogo-A antibody, the anti-Nogo-A antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 , which includes DYYLQ (SEQ ID NO:43); HC-CDR2, which includes RINPKTGATNYTQKFQG (SEQ ID NO:61); and HC-CDR3, which includes VVY (SEQ ID NO:81); and the light chain variable domain (V L ), said V L comprising: light chain complementarity determining region (LC-CDR) 1, comprising RASQGITNDLL (SEQ ID NO: 95); LC-CDR2, comprising EASSLQG (SEQ ID NO: 109); and LC-CDR3 containing QHYYTTPFT (SEQ ID NO: 126).
同时还提供编码抗Nogo-A抗体的核酸，包含抗Nogo-A抗体的组合物，以及制备和使用抗Nogo-A抗体的方法。 Also provided are nucleic acids encoding anti-Nogo-A antibodies, compositions containing anti-Nogo-A antibodies, and methods of preparing and using anti-Nogo-A antibodies.
定义definition
如本文所述，“治疗(treatment)”或“治疗(treating)是一种获得有益的或期望的结果的方法，包括临床结果。鉴于本申请的目的，所述有益的或期望的临床结果，包括但不限于以下一种或多种：缓解由疾病引起的一种或多种症状，减轻疾病程度，稳定疾病(例如，预防或延迟疾病恶化)，预防或延迟疾病的扩散(例如，转移)，预防或延迟疾病复发，延迟或减缓疾病进展，改善疾病状态，缓解疾病(部分或全部)，减少治疗疾病所需的一种或多种其他药物的剂量，延迟疾病进展，改善或提高生活质量，增加体重，和/或延长生存期。同时，“治疗”还包括疾病病理结果的减少(例如，对神经损伤而言，神经突生长抑制)。本申请的方法考虑了这些治疗的任何一个或多个方面。As used herein, "treatment" or "treating" is a method of obtaining beneficial or desired results, including clinical results. For the purposes of this application, said beneficial or desired clinical results, Including but not limited to one or more of the following: alleviating one or more symptoms caused by the disease, reducing the severity of the disease, stabilizing the disease (e.g., preventing or delaying the progression of the disease), preventing or delaying the spread of the disease (e.g., metastasis) , prevent or delay disease recurrence, delay or slow disease progression, improve disease status, alleviate disease (partial or complete), reduce the dose of one or more other drugs required to treat the disease, delay disease progression, improve or improve quality of life , increased body weight, and/or prolonged survival. Also, "treatment" includes reduction of the pathological consequences of the disease (e.g., for nerve damage, inhibition of neurite growth). The methods of the present application contemplate any of these treatments or Many aspects.
术语“抗体”包括全长抗体及其抗原结合片段。全长抗体包括两条重链和两条轻链。轻链和重链的可变区负责抗原的结合。两条链中的可变区通常包括3个高变的环，被称为互补决定区(CDRs)(轻链(LC)CDRs包括LC-CDR1、LC-CDR2和LC-CDR3，重链(HC)CDRs包括HC-CDR1、HC-CDR2和HC-CDR3)。本文所披露的抗体或抗原结合片段的CDR边界可以通过Kabat，Chothia或Al-Lazikani惯例来定义或识别(Al-Lazikani 1997；Chothia 1985；Chothia 1987；Chothia 1989；Kabat 1987；Kabat 1991)。重链或轻链的3个CDR区插入到被称为框架区(FRs)的侧翼区段之间，所述框架区比CDR区具有更高的保守性，并形成支撑高变环的支架。重链和轻链的恒定区并不参与抗原结合，但展示出多种效应功能。抗体是基于它们重链恒定区的氨基酸序列进行分类的。抗体的五种主要类别或同种型是IgA、IgD、IgE、IgG和IgM，其特征在于分别具有α、δ、ε、γ和μ型重链。几种主要的抗体类别被分为亚类，如IgG1(γ1重链)、IgG2(γ2重链)、IgG3(γ3重链)、IgG4(γ4重链)、IgA1(α1重链)或IgA2(α2重链)。The term "antibody" includes full-length antibodies and antigen-binding fragments thereof. Full-length antibodies include two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable regions in the two chains usually include three hypervariable loops, called complementarity determining regions (CDRs) (light chain (LC) CDRs include LC-CDR1, LC-CDR2 and LC-CDR3, heavy chain (HC) )CDRs include HC-CDR1, HC-CDR2 and HC-CDR3). The CDR boundaries of the antibodies or antigen-binding fragments disclosed herein may be defined or identified by the Kabat, Chothia or Al-Lazikani conventions (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDR regions of the heavy or light chain are inserted between flanking segments called framework regions (FRs), which are more conserved than the CDR regions and form a scaffold supporting the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding but exhibit a variety of effector functions. Antibodies are classified based on the amino acid sequence of their heavy chain constant region. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by heavy chains of the alpha, delta, epsilon, gamma, and mu types, respectively. Several major antibody classes are divided into subclasses, such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain), or IgA2 ( α2 heavy chain).
如本文所述，术语“抗原结合片段”包括抗体片段，例如，双链抗体(diabody)、Fab、Fab’、F(ab’)2、Fv片段、二硫键稳定的Fv片段(dsFv)、(dsFv)2、双特异性dsFv(dsFv-dsFv’)、二硫键稳定的双链抗体(ds双链抗体)、单链Fv(scFv)、scFv二聚体(二价双链抗体)，由包含一个或多个CDRs的抗体片段组成的多特异性抗体、单域抗体、纳米抗体(nanobody)、域抗体、二价域抗体或者能够与抗原结合但不包含完整抗体结构的任何其他抗体片段。抗原结合片段能够与亲本抗体或亲本抗体片段(如亲本scFv)结合相同的抗原。抗原结合片段还包括包含上述抗体片段的融合蛋白。在一些实施例中，抗原结合片段可能包括来自特定人抗体的一个或多个CDRs，该CDRs被移植到来自一个或多个不同人抗体的框架区。As used herein, the term "antigen-binding fragment" includes antibody fragments, e.g., diabodies, Fab, Fab', F(ab') 2 , Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv) 2. Bispecific dsFv (dsFv-dsFv'), disulfide bond-stabilized diabody (ds diabody), single-chain Fv (scFv), scFv dimer (bivalent diabody), Multispecific antibodies consisting of antibody fragments containing one or more CDRs, single domain antibodies, nanobodies, domain antibodies, bivalent domain antibodies, or any other antibody fragment capable of binding to an antigen but not containing a complete antibody structure . The antigen-binding fragment is capable of binding to the same antigen as the parent antibody or parent antibody fragment (eg, parent scFv). Antigen-binding fragments also include fusion proteins containing the above-described antibody fragments. In some embodiments, the antigen-binding fragment may include one or more CDRs from a specific human antibody grafted to framework regions from one or more different human antibodies.
如本文所述，术语“表位”是指抗体或抗体部分结合的抗原上特定的原子或氨基酸组。如果两种抗体或抗体部分表现出与某抗原竞争性结合，则它们可能结合抗原上的相同表位。As used herein, the term "epitope" refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they may bind to the same epitope on the antigen.
如本文所用，当第一抗体在等摩尔浓度下抑制第二抗体与Nogo-A靶标结合至少50％(例如至少55％、60％、65％、70％、75％、80％、85％、90％、95％、98％或99％)时，第一抗体与第二抗体“竞争”结合Nogo-A靶标，反之亦然。PCT出版物WO 03/48731描述了基于交叉竞争的高通量抗体“表位归类”方法。 As used herein, a first antibody inhibits binding of a second antibody to a Nogo-A target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99%), the first antibody "competes" with the second antibody for binding to the Nogo-A target, and vice versa. PCT publication WO 03/48731 describes a cross-competition based high-throughput antibody "epitope classification" approach.
如本文所述，术语“特异性地结合”、“特异性地识别”或“对..来说是特异性的”是指可测量的和可再现的相互作用，例如抗体与靶标的结合可以确定在异质分子群，包括生物分子中存在该靶标。例如，抗体能够特异性地识别某靶标(可以是表位)是指，与其它靶标结合相比，该抗体与该靶标的结合具有更高的亲和力，亲合力，更容易和/或更持久。在一些实施例中，特异性地识别抗原的抗体与抗原的一个或多个抗原决定簇反应，其结合亲和力是其与其它靶标结合亲和力的至少10倍。As used herein, the terms "specifically bind," "specifically recognize," or "specific for" refer to a measurable and reproducible interaction, e.g., binding of an antibody to a target can The presence of the target in a heterogeneous population of molecules, including biomolecules, is determined. For example, the ability of an antibody to specifically recognize a target (which may be an epitope) means that the antibody binds to the target with higher affinity, avidity, easier and/or longer duration than to other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more epitopes of the antigen with a binding affinity that is at least 10 times greater than its binding affinity to other targets.
如本文所述，一种“分离的”抗Nogo-A抗体是指一种抗Nogo-A抗体，其(1)与天然存在的蛋白无关，(2)不含相同来源的其他蛋白，(3)由不同种属的细胞所表达，或(4)自然界中不存在。As used herein, an "isolated" anti-Nogo-A antibody is an anti-Nogo-A antibody that (1) is not associated with naturally occurring proteins, (2) does not contain other proteins from the same source, (3 ) is expressed by cells of different species, or (4) does not exist in nature.
如本文所述，术语“分离的核酸”，是指基因组、cDNA或合成来源的核酸或其组合。根据其来源，所述“分离的核酸”是指(1)与自然界中发现的“分离的核酸”中的全部或部分多核苷酸无关，(2)可与自然状态下不与之相连的多核苷酸可操作性地连接，或(3)在自然界中不作为较长序列的一部分而存在。As used herein, the term "isolated nucleic acid" refers to nucleic acids of genomic, cDNA or synthetic origin, or combinations thereof. Depending on its source, the "isolated nucleic acid" refers to (1) not related to all or part of the polynucleotides in the "isolated nucleic acid" found in nature, (2) may not be related to polynucleotides that are not associated with it in the natural state. The nucleotides are operably linked, or (3) do not occur in nature as part of a longer sequence.
如本文所用，术语“CDR”或“互补决定区”意指重链和轻链多肽的可变结构域内发现的非连续抗原结合位点。在文献Kabat et al.,J.Biol.Chem.252:6609-6616(1977)；Kabat et al.,U.S.Dept.of Health and Human Services,“Sequences of proteins of immunological interest”(1991)；Chothia et al.,J.Mol.Biol.196:901-917(1987)；Al-Lazikani B.et al.,J.Mol.Biol.,273:927-948(1997)；MacCallum et al.,J.Mol.Biol.262:732-745(1996)；Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008)；Lefranc M.P.et al.,Dev.Comp.Immunol.,27:55-77(2003)；和Honegger and Plückthun,J.Mol.Biol.,309:657-670(2001)中已经描述这些特殊的区域，其中当彼此之间互相比较时，这些定义包括氨基酸残基的重合或子集。然而，采用任何一种定义方式来指示抗体或移植抗体或其变体的CDR，均包括在本文所定义和使用的术语范围之内。表1中列了由上述引用的各篇参考文献所定义的CDR所包括的氨基酸残基的位置，以示比较。CDR预测的算法和结合界面在本领域是已知的，包括，例如Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008)；Ehrenmann F.et al.,Nucleic Acids Res.,38:D301-D307(2010)；和Adolf-Bryfogle J.et al.,Nucleic Acids Res.,43:D432-D438(2015)中均有描述。本段中所引用的参考文献的内容以其整体引用并入本文中，以用于本申请和可能包含在本文中的一个或多个权利要求中。As used herein, the term "CDR" or "complementarity determining region" means the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides. In the literature Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat et al., U.S. Dept. of Health and Human Services, "Sequences of proteins of immunological interest" (1991); Chothia et al. al., J. Mol. Biol. 196: 901-917 (1987); Al-Lazikani B. et al., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J. Mol.Biol.262:732-745(1996);Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008);Lefranc M.P.et al.,Dev.Comp.Immunol.,27:55-77( 2003); and Honegger and Plückthun, J. Mol. Biol., 309:657-670 (2001), where these definitions include overlapping or sub-regions of amino acid residues when compared to each other. set. However, any definition that refers to the CDRs of an antibody or grafted antibody or a variant thereof is included within the scope of the term as defined and used herein. The positions of the amino acid residues included in the CDRs defined by the above-cited references are listed in Table 1 for comparison. Algorithms and binding interfaces for CDR prediction are known in the art, including, for example, Abhinandan and Martin, Mol. Immunol., 45:3832-3839 (2008); Ehrenmann F. et al., Nucleic Acids Res., 38: D301-D307(2010); and Adolf-Bryfogle J.et al., Nucleic Acids Res., 43:D432-D438(2015). The contents of the references cited in this paragraph are incorporated by reference in their entirety for purposes of this application and one or more claims that may be included herein.
表1:CDR定义

Table 1: CDR definition

1氨基酸残基编号参照上述Kabat et al.中的命名方法 1The numbering of amino acid residues refers to the nomenclature method in Kabat et al. mentioned above.
2氨基酸残基编号参照上述Chothia et al.中的命名方法 2The numbering of amino acid residues refers to the nomenclature method in Chothia et al. mentioned above.
3氨基酸残基编号参照上述MacCallum et al.中的命名方法 3 The numbering of amino acid residues refers to the naming method in MacCallum et al. mentioned above.
4氨基酸残基编号参照上述Lefranc et al.中的命名方法 4 The numbering of amino acid residues refers to the naming method in Lefranc et al. mentioned above.
5氨基酸残基编号参照上述Honegger and Plückthun中的命名方法 5 Amino acid residue numbers refer to the naming method in Honegger and Plückthun above.
术语“嵌合抗体”是指，重链和/或轻链的一部分与来自特定种属或属于特定抗体种类或亚类的抗体中的相应序列一致或具有同源性，而这个(些)链的剩余部分与来自另一种属或属于其它抗体种类或亚类的抗体中的相应序列一致或具有同源性的抗体，以及此类抗体的片段，只要其具有本申请中的生物学活性(见U.S.Patent No.4,816,567；and Morrison et al.,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984))。The term "chimeric antibody" means that a portion of the heavy chain and/or light chain is identical or homologous to the corresponding sequence in an antibody from a specific species or belonging to a specific antibody class or subclass, and this chain(s) Antibodies whose remainder are identical to or homologous to corresponding sequences in antibodies from another genus or belonging to other antibody classes or subclasses, as well as fragments of such antibodies, as long as they have the biological activity in this application ( See U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
“Fv”是包含完整抗原识别及结合位点的最小抗体片段。该片段是由一个重链可变结构域和一个轻链可变结构域紧密非共价连接形成的二聚体。通过这两个域的折叠衍生出6个高变环(轻链和重链中各3个环)，所述高变环为抗体提供了用于结合抗原的氨基酸残基，并且赋予抗体与抗原结合的特异性。然而，即使单个可变结构域(或Fv片段的一半，其仅包含对抗原具有特异性的3个CDRs)也具有识别和结合抗原的能力，尽管其亲和力低于完整的结合位点。"Fv" is the smallest antibody fragment that contains complete antigen recognition and binding sites. This fragment is a dimer formed by a heavy chain variable domain and a light chain variable domain tightly non-covalently linked. The folding of these two domains results in 6 hypervariable loops (3 loops each in the light chain and heavy chain), which provide the antibody with the amino acid residues for binding to the antigen and confer a binding relationship between the antibody and the antigen. Binding specificity. However, even a single variable domain (or half of an Fv fragment, which contains only the 3 CDRs specific for the antigen) has the ability to recognize and bind the antigen, albeit with lower affinity than the complete binding site.
“单链Fv”，也可简写成“sFv”或“scFv”，是包含被连接成单一多肽链的VH和VL抗体域的抗体片段。在一些实施例中，scFv多肽进一步包括VH和VL域之间的连接多肽，该连接多肽使得scFv形成抗原结合的理想结构。关于scFv的概述，见Pluckthun in The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,Springer-Verlag,New York,pp.269-315(1994)。A "single chain Fv", which may also be abbreviated as "sFv" or "scFv", is an antibody fragment that contains the V H and V L antibody domains linked into a single polypeptide chain. In some embodiments, the scFv polypeptide further includes a linker polypeptide between the VH and VL domains that allows the scFv to form an ideal structure for antigen binding. For an overview of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).
术语“双链抗体(diabody)”是在VH和VL域之间采用短接头(例如5～10个残基)，构建scFv片段(见上段内容)制备而成的一种小抗体片段，这样就使得可变结构域在链间而不是链内进行配对，产生一个双价片段，即具有两个抗原结合位点的片段。双特异性的双链抗体是两个“交叉”scFv片段的异二聚体，其中两个抗体的VH和VL域位于不同的多肽链上。在EP 404,097；WO 93/11161；Hollinger et al.,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993)中全面描述了双链抗体。The term "diabody" is a small antibody fragment prepared by using a short linker (for example, 5 to 10 residues) between the V H and V L domains to construct an scFv fragment (see the previous paragraph). This allows the variable domains to pair inter-chain rather than intra-chain, resulting in a bivalent fragment, that is, a fragment with two antigen-binding sites. Bispecific diabodies are heterodimers of two "cross-over" scFv fragments, in which the VH and VL domains of the two antibodies are located on different polypeptide chains. Diabodies are fully described in EP 404,097; WO 93/11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).
非人源(如啮齿类)抗体的“人源化”形式是嵌合抗体，其包括最少的来自非人源抗体的序列。大多数情况下，人源化抗体是人源免疫球蛋白(受体抗体)，其中受体抗体的高变区(HVR)残基被来自非人源种属例如小鼠、大鼠、兔或非人类哺乳动物的且具有理想的抗体特异性，亲和力和性能的高变区残基所取代(供体抗体)。在某些情况下，人源免疫球蛋白框架区中的残基被相应的非人源残基所取代。另外，人源化抗体可以包括在受体抗体或供体抗体中均不存在的残基。这些修饰能够进一步改善抗体的性能。通常，人源化抗体会包含基本上所有，至少一个，通常两个可变结构域，其中所有或基本上所有的高变环均与非人免疫球蛋白的高变环相对应，以及所有或基本上所有的框架区均是人免疫球蛋白序列。人源抗体任选地也还包括免疫球蛋白恒定区 (Fc)的至少一部分，通常是人免疫球蛋白的恒定区。具体细节可以参考Jones et al.,Nature 321:522-525(1986)；Riechmann et al.,Nature 332:323-329(1988)；和Presta,Curr.Op.Struct.Biol.2:593-596(1992)。"Humanized" forms of non-human (eg, rodent) antibodies are chimeric antibodies, which include minimal sequence from the non-human antibody. In most cases, humanized antibodies are human immunoglobulins (recipient antibodies) in which the hypervariable region (HVR) residues of the receptor antibody are modified from a non-human species such as mouse, rat, rabbit or Replacement of hypervariable region residues that are non-human mammalian and possess the desired antibody specificity, affinity and performance (donor antibody). In some cases, residues in the human immunoglobulin framework region are replaced with corresponding non-human residues. Additionally, humanized antibodies may include residues that are not present in either the recipient antibody or the donor antibody. These modifications can further improve antibody performance. Typically, a humanized antibody will contain substantially all, at least one, and usually two variable domains in which all or substantially all of the hypervariable loops correspond to hypervariable loops of a non-human immunoglobulin, and all or Essentially all framework regions are human immunoglobulin sequences. The human antibody optionally also includes an immunoglobulin constant region At least a portion of (Fc), usually the constant region of a human immunoglobulin. For specific details, please refer to Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992).
本文所鉴定的多肽和抗体序列的“氨基酸序列同一性百分比(％)”或“同源性”被定义：在认为保守性取代属于序列同一性的一部分的情况下进行序列对比，候选序列与待比较多肽序列中相同氨基酸残基所占的百分比。可以通过本领域技术范围内的多种比对方式来确定氨基酸序列同一性百分比，例如，使用如BLAST、BLAST-2、ALIGN、Megalign(DNASTAR)、或MUSCLE软件等可公开获得的计算机软件。本领域技术人员可以确定用于测量比对的合适的参数，包括在所比较序列的全长上实现最大化比对所需的任何算法。然而，为了本文的目的，氨基酸序列同一性百分比数值是使用序列比对电脑程序MUSCLE(Edgar,R.C.,Nucleic Acids Research 32(5):1792-1797,2004；Edgar,R.C.,BMC Bioinformatics 5(1):113,2004)生成的。The "percent amino acid sequence identity (%)" or "homology" of the polypeptide and antibody sequences identified herein is defined as follows: Sequence comparisons are made where conservative substitutions are considered part of the sequence identity, and the candidate sequence is compared with the candidate sequence to be Compares the percentage of identical amino acid residues in a polypeptide sequence. Percent amino acid sequence identity can be determined by a variety of alignment methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to maximize alignment over the full length of the sequences being compared. However, for the purposes of this article, percent amino acid sequence identity values were determined using the sequence alignment computer program MUSCLE (Edgar, R.C., Nucleic Acids Research 32(5):1792-1797, 2004; Edgar, R.C., BMC Bioinformatics 5(1) :113,2004).
术语“Fc受体”或“FcR”用于描述结合抗体Fc区的受体。在一些实施例中，本申请所述的FcR是结合IgG抗体(一种γ受体)的FcR，包括FcγRI、FcγRII和FcγRIII亚类的受体，包括这些受体的等位基因变体和可变剪接形式。FcγRII受体包括FcγRIIA(“激活受体”)和FcγRIIB(“抑制受体”)，它们具有相似的氨基酸序列，主要在细胞质结构域有所不同。激活受体FcγRIIA的胞质结构域中含有免疫受体酪氨酸活化基序(ITAM)。抑制受体FcγRIIB的胞质结构域中含有免疫受体酪氨酸抑制基序(ITIM)(见M.inAnnu.Rev.Immunol.15:203-234(1997))。所述术语还包括同种异型，例如FcγRIIIA同种异型：FcγRIIIA-Phe158、FcγRIIIA-Val158、FcγRIIA-R131和/或FcγRIIA-H131。在Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991)和Capel et al.,Immunomethods 4:25-34(1994)；以及de Haas et al.,J.Lab.Clin.Med.126:330-41(1995)中对FcRs进行了描述。本申请中术语FcR涵盖其他类型的FcRs，包括将来鉴定的FcRs。术语FcR同时还包括新生儿受体FcRn，其负责向新生儿转移母体IgGs(Guyer et al.,J.Immunol.117:587(1976)以及Kim et al.,J.Immunol.24:249(1994))。The term "Fc receptor" or "FcR" is used to describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR described herein is an FcR that binds an IgG antibody, a gamma receptor, including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and agonist variants of these receptors. Change splicing form. FcγRII receptors include FcγRIIA (“activating receptor”) and FcγRIIB (“inhibitory receptor”), which have similar amino acid sequences and differ mainly in the cytoplasmic domain. The cytoplasmic domain of activating receptor FcγRIIA contains an immunoreceptor tyrosine activation motif (ITAM). The cytoplasmic domain of the inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) (see M.in Annu. Rev. Immunol. 15:203-234 (1997)). The term also includes allotypes, such as FcγRIIIA allotypes: FcγRIIIA-Phel58, FcγRIIIA-Val158, FcγRIIA-R131 and/or FcγRIIA-H131. In Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991) and Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126 FcRs are described in :330-41 (1995). The term FcR in this application covers other types of FcRs, including FcRs identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgGs to the neonate (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994) )).
术语“FcRn”指新生儿Fc受体(FcRn)。FcRn与主要组织相容性复合体(MHC)在结构上相似，由α链非共价结合到β2微球蛋白上组成。新生儿Fc受体FcRn的多种功能在Ghetie and Ward(2000)Annu.Rev.Immunol.18,739-766.中进行了综述。FcRn在免疫球蛋白IgGs从母体向新生儿的被动转运和调控血清IgG水平中起到重要作用。FcRn作为一种救助受体，可以在细胞内和细胞间以完整的形式结合和运输胞吞化的IgG，并使它们免于经受默认的降解途径。The term "FcRn" refers to the neonatal Fc receptor (FcRn). FcRn is structurally similar to the major histocompatibility complex (MHC) and consists of an α chain non-covalently bound to β2 microglobulin. The diverse functions of the neonatal Fc receptor FcRn are reviewed in Ghetie and Ward (2000) Annu. Rev. Immunol. 18, 739-766. FcRn plays an important role in the passive transport of immunoglobulin IgGs from mother to newborn and in regulating serum IgG levels. FcRn serves as a rescue receptor that binds and transports endocytosed IgG in an intact form within and between cells and protects them from default degradation pathways.
人IgG重链恒定区的“CH1结构域”通常从118位氨基酸延伸到215位氨基酸(EU编号系统)。The "CH1 domain" of the human IgG heavy chain constant region generally extends from amino acid 118 to amino acid 215 (EU numbering system).
“铰链区”通常被定义为从人IgG1的216位Glu延伸到230位Pro(Burton,Molec.Immunol.22:161-206(1985))。通过将形成重链间二硫键的第一个和最后一个半胱氨酸残基置于与IgG1相同位置后，可以使得其他IgG同种型的铰链区与IgG1序列比对。 The "hinge region" is generally defined as extending from position Glu 216 to position Pro 230 of human IgG1 (Burton, Molec. Immunol. 22:161-206 (1985)). By placing the first and last cysteine residues that form the inter-heavy chain disulfide bond after the same position as IgG1, the hinge regions of other IgG isotypes can be aligned with the IgG1 sequence.
人IgG Fc区的“CH2结构域”通常从231位氨基酸延伸到340位氨基酸。CH2结构域的独特之处在于，它不会与另一个区域紧密配对，而是在完整的天然IgG分子的两个CH2结构域之间插入了两条N端连接的支链糖链。据推测，糖类可能作为域与域间配对的替代，有助于保持CH2结构域稳定。Burton,Molec.Immunol.22:161-206(1985)。The "CH2 domain" of the human IgG Fc region usually extends from amino acid 231 to amino acid 340. The unique feature of the CH2 domain is that it does not pair closely with another region, but instead has two N-terminal linked branched sugar chains inserted between the two CH2 domains of the intact natural IgG molecule. It is speculated that sugars may serve as a surrogate for domain-to-domain pairing, helping to keep the CH2 domain stable. Burton, Molec. Immunol. 22:161-206 (1985).
“CH3”结构域包括在Fc区内从C末端残基延伸到CH2结构域(从341位氨基酸到抗体序列的C末端，通常为IgG的第446或447位氨基酸残基)。The "CH3" domain includes the region extending from the C-terminal residues within the Fc region to the CH2 domain (from amino acid 341 to the C-terminus of the antibody sequence, usually amino acid residue 446 or 447 of IgG).
“功能性Fc片段”具有天然Fc区序列所具有的“效应功能”。示例性的“效应功能”包括C1q结合；补体依赖的细胞毒作用(CDC)；Fc受体结合；抗体依赖的细胞介导的细胞毒作用(ADCC)；吞噬作用；细胞表面受体的下调(如B细胞受体；BCR)等。这类效应功能通常需要Fc区与结合结构域(如抗体可变区)结合，并且可以使用本领域公知的多种实验方法进行评估。A "functional Fc fragment" has the "effector function" possessed by a native Fc region sequence. Exemplary "effector functions" include Clq binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors ( Such as B cell receptor; BCR), etc. Such effector functions typically require the binding of an Fc region to a binding domain (eg, an antibody variable region) and can be assessed using a variety of experimental methods well known in the art.
具有“改变的”FcR结合亲和力或ADCC活性的IgG Fc变体的抗体，与亲本多肽或包含天然Fc序列的多肽相比，其FcR结合活性和/或ADCC活性增强或减弱。表现出与FcR“结合增强”的Fc变体与亲本多肽或包含天然IgG Fc序列的多肽相比，其与至少一种FcR具有更高的结合亲和力(例如更低的表观Kd或IC50值)。在一些实施例中，与亲本多肽相比，结合能力增强3倍，例如5、10、25、50、60、100、150、200，甚至高达500倍或结合力提高25％到1000％。表现出与FcR“结合降低”的Fc变体，与亲本多肽相比，其与至少一种FcR具有更低的亲和力(例如更高的表观Kd或IC50值)。与亲本多肽相比，其结合能力下降40％或更多。Antibodies with IgG Fc variants that have "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and/or ADCC activity compared to the parent polypeptide or a polypeptide comprising a native Fc sequence. An Fc variant that exhibits "enhanced binding" to an FcR has a higher binding affinity (e.g., a lower apparent Kd or IC50 value) to at least one FcR compared to the parent polypeptide or a polypeptide comprising a native IgG Fc sequence. ). In some embodiments, the binding capacity is enhanced 3-fold, such as 5, 10, 25, 50, 60, 100, 150, 200, even up to 500-fold or a 25% to 1000% increase in binding capacity compared to the parent polypeptide. An Fc variant exhibits "reduced binding" to an FcR, having a lower affinity (eg, a higher apparent Kd or IC50 value) for at least one FcR compared to the parent polypeptide. Its binding capacity is reduced by 40% or more compared to the parent polypeptide.
“抗体依赖的细胞介导的细胞毒作用”或“ADCC”是一种细胞毒性形式，指分泌型的Ig与存在于某些细胞毒性细胞(例如自然杀伤细胞(NK)、中性粒细胞、和巨噬细胞)上的Fc受体(FcRs)结合，使这些细胞毒性效应细胞能够特异性结合携带抗原的靶细胞，随后使用细胞毒素杀死靶细胞。抗体“武装”细胞毒性细胞并且是这种杀伤所必需的。介导ADCC的主要细胞类型中，NK细胞只表达FcγRIII，而单核细胞表达FcγRI、FcγRII和FcγRIII。在Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991)第464页的Table 3中总结了在造血细胞上FcR的表达。评估目标分子的ADCC活性，可以进行体外ADCC实验，在美国专利No.5,500,362或5,821,337中进行了描述。适用于此类实验的效应细胞包括外周血单核细胞(PBMC)和自然杀伤性细胞(NK)。可选地，或者此外，目标分子的ADCC活性也可以在体内进行评估，例如在如Clynes et al.PNAS(USA)95:652-656(1998)中所公开的动物模型中进行了描述。"Antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a form of cytotoxicity that refers to the interaction of secreted Ig cells present on certain cytotoxic cells (e.g., natural killer cells (NK), neutrophils, Binding to Fc receptors (FcRs) on macrophages allows these cytotoxic effector cells to specifically bind to target cells carrying antigens and subsequently kill the target cells using cytotoxins. Antibodies "arm" cytotoxic cells and are required for this killing. Among the main cell types that mediate ADCC, NK cells only express FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess the ADCC activity of a target molecule, an in vitro ADCC assay can be performed, as described in U.S. Patent No. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, or in addition, the ADCC activity of the target molecule can also be assessed in vivo, for example in an animal model as disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).
包含Fc区变体的多肽与包含野生型IgG Fc多肽或亲本多肽相比，在人体效应细胞存在下表现出“增强的ADCC活性”或能够更有效的介导ADCC效应，所述包含Fc区变体的多肽在实验时与包含野生型IgG Fc多肽(或亲本多肽)数量上基本相同时，无论在体外或体内均能更有效的介导ADCC。通常采用本领域已知的任何体外ADCC实验方法来鉴定此类变体，例如用于鉴定ADCC活性的实验或方法，例如在动物模型中等。在一些实施例中，此类变体与野生型Fc(或亲代多肽)相比，介导ADCC的效率提高5到100倍，例如25到50倍。 A polypeptide comprising an Fc region variant that exhibits "enhanced ADCC activity" or is able to mediate ADCC effects more efficiently in the presence of human effector cells than a wild-type IgG Fc polypeptide or a parent polypeptide that contains an Fc region variant When the amount of the antibody polypeptide is substantially the same as that of the wild-type IgG Fc polypeptide (or parent polypeptide) during the experiment, it can more effectively mediate ADCC both in vitro and in vivo. Such variants are generally identified using any in vitro ADCC assay known in the art, such as assays or methods for identifying ADCC activity, such as in animal models and the like. In some embodiments, such variants mediate ADCC 5- to 100-fold, for example, 25- to 50-fold more efficiently than wild-type Fc (or the parent polypeptide).
“补体依赖的细胞毒作用”或“CDC”是指在补体存在的情况下裂解靶细胞。经典的补体途径的激活是由补体系统第一组分(C1q)与结合同源抗原的抗体(具有适宜结构的亚类)相结合而启动的。为了评估补体激活，可以进行CDC实验，如Gazzano-Santoro et al.,J.Immunol.Methods 202:163(1996)中所描述的。在美国专利No.6,194,551B1和WO99/51642中描述了具有改变的Fc区氨基酸序列并增加或降低的C1q结合能力的多肽变体。这些专利出版物的内容通过引用明确地并入本文中。另见Idusogie et al.J.Immunol.164:4178-4184(2000)。"Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (subclasses with appropriate structures) that bind cognate antigens. To assess complement activation, CDC experiments can be performed as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). Polypeptide variants with altered Fc region amino acid sequences and increased or decreased Clq binding capacity are described in US Patent No. 6,194,551 Bl and WO99/51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al. J. Immunol. 164:4178-4184 (2000).
除非另有说明，一种“编码氨基酸序列的核苷酸序列”包括相互之间互为简并形式且编码相同氨基酸序列的所有核苷酸序列。编码蛋白质或RNA的核苷酸序列也可包括内含子，例如编码蛋白质的核苷酸序列在某些形式中包含内含子。Unless otherwise stated, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerates of each other and encode the same amino acid sequence. Nucleotide sequences encoding proteins or RNA may also include introns, for example, nucleotide sequences encoding proteins may include introns in some forms.
术语“可操作性地连接”是指调控序列与异源核苷酸序列之间的功能性连接，从而使后者表达。例如，当第一个核苷酸序列与第二个核苷酸序列处于功能性关系时，第一个核苷酸序列与第二个核苷酸序列为可操作性地连接。例如，如果启动子影响编码序列的转录或表达，该启动子与编码序列为可操作性地连接。通常，可操作性连接的DNA序列是连续的，并且在必要时，可以在同一个阅读框中连接两个蛋白质编码区。The term "operably linked" refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence, thereby allowing expression of the latter. For example, a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence. For example, a promoter is operably linked to a coding sequence if it affects the transcription or expression of the coding sequence. Typically, operably linked DNA sequences are contiguous and, if necessary, two protein-coding regions can be joined in the same reading frame.
“同源”是指两个多肽之间或两个核酸分子之间的序列相似性或序列同一性。如果两个比较序列的同一位置为相同的碱基或氨基酸单体亚基时，例如两个DNA分子的同一位置均为腺嘌呤，则这两个DNA分子在该位置是同源的。两个序列间的同源百分比是指两个序列中共有的匹配或同源位置的数量与位置总数之比再乘以100所得函数。例如，两个序列中如果10个位置中有6个位置是相匹配或同源的，则这两个序列的同源性为60％。举例来说，DNA序列ATTGCC和TATGGC具有50％的同源性。通常来说，在比对两个序列时，以得到最大同源性为目的来进行对比。"Homology" refers to sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position of two compared sequences contains the same base or amino acid monomer subunit, for example, the same position of two DNA molecules both contains adenine, then the two DNA molecules are homologous at that position. The percent homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the total number of positions multiplied by 100. For example, if 6 out of 10 positions in two sequences match or are homologous, the two sequences are 60% homologous. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. Generally speaking, when comparing two sequences, the comparison is performed with the purpose of obtaining maximum homology.
本文所公开的抗Nogo-A抗体或组合物的“有效量”是指足以实现特定目的的量。“有效量”可以凭经验和通过已知的与所述目的相关的方法确定。An "effective amount" of an anti-Nogo-A antibody or composition disclosed herein is an amount sufficient to achieve a specified purpose. An "effective amount" can be determined empirically and by methods known to be relevant to the stated purpose.
术语“治疗有效量”是指本文所公开的抗Nogo-A抗体或其组合物能够有效治疗个体的疾病或者症状的用量。例如在脊髓损伤的情况中，抗Nogo-A抗体或其组合物的治疗有效量是指能够促进(即在一定程度上恢复)损伤皮质脊髓束(CST)的发芽和再生；促进(即在一定程度上恢复)生长锥的生长；促进(即在一定程度上恢复)受损神经突的再生；降低(即在一定程度上解除)神经突生长的抑制；降低(即在一定程度上解除)生长锥生长的抑制；和/或在一定程度上缓解与脊髓损伤相关的基础疾病的一种或多种症状。在一些实施例中，治疗有效量是指能够延长患者生存期的用量。在一些实施例中，治疗有效量是指能够改善患者无进展生存期的用量。The term "therapeutically effective amount" refers to an amount of an anti-Nogo-A antibody or composition thereof disclosed herein that is effective in treating a disease or condition in an individual. For example, in the case of spinal cord injury, a therapeutically effective amount of an anti-Nogo-A antibody or composition thereof is one capable of promoting (i.e., restoring to a certain extent) the sprouting and regeneration of the injured corticospinal tract (CST); promoting (i.e., restoring to a certain extent) To restore (to a certain extent) the growth of growth cones; to promote (i.e. to restore to a certain extent) the regeneration of damaged neurites; to reduce (i.e. to relieve to a certain extent) the inhibition of neurite growth; to reduce (i.e. to relieve to a certain extent) the growth of Inhibition of cone growth; and/or alleviation to a certain extent of one or more symptoms of the underlying disease associated with spinal cord injury. In some embodiments, a therapeutically effective amount refers to an amount capable of prolonging the survival of a patient. In some embodiments, a therapeutically effective amount refers to an amount capable of improving progression-free survival of a patient.
如本文所用的，“药学上可接受的”或“药理学上相容的”是指无生物学活性或者其它不期望性质的材料，例如该材料能够加入到给予患者的药物组合物中，而不会引起显著的不良生物反应，或者，不与组合物中包含的任何其它组分以有害的方式相互作用。药学上可接受的载体或赋形剂优选满足毒理学或制造检测的所需标准和/或包含在美国食品和药品管理局编制的非活性成分指南中。 As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to a material that has no biological activity or other undesirable properties, e.g., the material can be incorporated into a pharmaceutical composition administered to a patient, and Does not cause significant adverse biological reactions or interact in a deleterious manner with any other components contained in the composition. Pharmaceutically acceptable carriers or excipients preferably meet required standards for toxicological or manufacturing testing and/or are included in the Inactive Ingredient Guidelines prepared by the U.S. Food and Drug Administration.
本文中描述的本申请的实施例应理解为包含“由……组成”和/或“基本上由……组成”的实施例。Embodiments of the application described herein should be understood to include embodiments "consisting of" and/or "consisting essentially of."
本文中提及“约”为一个数值或参数，包含(和描述)针对该值或参数本身的变体。例如，涉及“约X”的描述，包括“X”的描述。References herein to "about" a value or parameter include (and describe) variations on the value or parameter itself. For example, descriptions referring to "about X" include descriptions of "X".
如本文所用的，提及“不是(not)”一个数值或参数，通常表示并描述“除了(other than)”某一数值或参数之外。例如，该方法不能用于治疗X型癌症，意味着该方法通常用于治疗除X型癌症之外的其他类型的癌症。As used herein, reference to "not" a value or parameter generally means and describes "other than" a value or parameter. For example, the method cannot be used to treat type X cancer, meaning the method is typically used to treat other types of cancer besides type X cancer.
除非上下文另有明确说明，本文和所述权利要求中所采用的单数形式“一”，“一个”和“该”包括复数对象。As used herein and in the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
抗Nogo-A抗体Anti-Nogo-A antibody
一方面，本申请提供特异性结合Nogo-A的抗人和/或恒河猴Nogo-A抗体。所述抗Nogo-A抗体包括，但不限于，人源化抗体，嵌合抗体，小鼠抗体，人抗体，以及本文所述的包含重链和/或轻链CDRs的抗体分子。一方面，本申请提供与Nogo-A结合的分离的抗体。预期的抗Nogo-A抗体包括，例如，全长抗Nogo-A抗体(如全长IgG1或IgG4)，抗Nogo-A单链抗体，抗Nogo-A Fc融合蛋白，多特异性(如双特异性)抗Nogo-A抗体，抗Nogo-A免疫偶联物，以及诸如此类的。在一些实施例中，抗Nogo-A抗体是全长抗体(如全长IgG1或IgG4)或其抗原结合片段，其特异性结合Nogo-A。在一些实施例中，抗Nogo-A抗体是Fab、Fab’、F(ab)’2、Fab’-SH、单链Fv(scFv)、Fv片段、dAb、Fd、纳米抗体(nanobody)、双链抗体(diabody)或线性抗体。在一些实施例中，特异性结合Nogo-A的抗体是指抗体与Nogo-A结合的亲和力至少是与非靶标结合亲和力的10倍以上(包括例如10、102、103、104、105、106、或107倍)。在一些实施例中，非靶标是指不是Nogo-A的抗原。结合亲和力可通过本领域已知的方法来测定，如ELISA，荧光激活细胞分选(FACS)分析或放射免疫沉淀分析(RIA)。Kd值可以通过本领域已知的方法来测定，如表面等离子共振(SPR)技术或生物层干涉技术(BLI)。In one aspect, the application provides anti-human and/or rhesus Nogo-A antibodies that specifically bind Nogo-A. Such anti-Nogo-A antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy chain and/or light chain CDRs as described herein. In one aspect, the application provides isolated antibodies that bind Nogo-A. Contemplated anti-Nogo-A antibodies include, for example, full-length anti-Nogo-A antibodies (e.g., full-length IgG1 or IgG4), anti-Nogo-A single chain antibodies, anti-Nogo-A Fc fusion proteins, multispecific (e.g., bispecific properties) anti-Nogo-A antibodies, anti-Nogo-A immunoconjugates, and the like. In some embodiments, the anti-Nogo-A antibody is a full-length antibody (eg, full-length IgG1 or IgG4) or an antigen-binding fragment thereof that specifically binds Nogo-A. In some embodiments, the anti-Nogo-A antibody is Fab, Fab', F(ab)' 2 , Fab'-SH, single chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, bis Chain antibody (diabody) or linear antibody. In some embodiments, an antibody that specifically binds Nogo-A means that the affinity of the antibody for binding to Nogo-A is at least 10 times greater than the binding affinity for the non-target (including, for example, 10, 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 times). In some embodiments, non-target refers to an antigen that is not Nogo-A. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence-activated cell sorting (FACS) analysis or radioimmunoprecipitation analysis (RIA). The Kd value can be determined by methods known in the art, such as surface plasmon resonance (SPR) technology or biolayer interference (BLI) technology.
尽管本文广泛地讨论了包含人序列的抗Nogo-A抗体(例如，包含人CDR序列的人重链和轻链可变结构域)，但同时也考虑了非人抗Nogo-A抗体。在一些实施例中，非人抗Nogo-A抗体包括本文所述的抗Nogo-A抗体的人CDR序列和非人框架区序列，在一些实施例中，非人框架区序列包括任何的用于使用如本文所述的一种或多种人CDR序列产生重链和/或轻链可变结构域的序列，包括例如哺乳动物，例如小鼠、大鼠、兔子、猪、牛(例如，牛、公牛、水牛)、鹿、绵羊、山羊、鸡、猫、狗、雪貂、灵长类(例如，小猿，猕猴)等。在一些实施例中，非人抗Nogo-A抗体包括将一种或多种本文所述的人CDR序列移植到非人框架区中(例如，鼠或鸡的框架区序列)所产生的抗Nogo-A抗体。Although anti-Nogo-A antibodies comprising human sequences are discussed broadly herein (eg, human heavy and light chain variable domains comprising human CDR sequences), non-human anti-Nogo-A antibodies are also contemplated. In some embodiments, non-human anti-Nogo-A antibodies include human CDR sequences and non-human framework region sequences of the anti-Nogo-A antibodies described herein. In some embodiments, non-human framework region sequences include any for Sequences for heavy and/or light chain variable domains are generated using one or more human CDR sequences as described herein, including, for example, mammals, such as mouse, rat, rabbit, porcine, bovine (e.g., bovine , bulls, buffalo), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., small apes, macaques), etc. In some embodiments, non-human anti-Nogo-A antibodies include anti-Nogo-A antibodies generated by grafting one or more human CDR sequences described herein into non-human framework regions (e.g., murine or chicken framework sequences). -A antibody.
示例性人Nogo-A的外显子3编码的NiG氨基酸序列包含SEQ ID NO：25所示的氨基酸序列或由SEQ ID NO：25所示的氨基酸序列组成。示例性恒河猴NiG氨基酸序列包含SEQ ID NO：26 所示的氨基酸序列或由SEQ ID NO：26所示的氨基酸序列组成。示例性大鼠NiG氨基酸序列包含SEQ ID NO：27所示的氨基酸序列或由SEQ ID NO：27所示的氨基酸序列组成。The NiG amino acid sequence encoded by exon 3 of an exemplary human Nogo-A includes or consists of the amino acid sequence shown in SEQ ID NO: 25. An exemplary rhesus NiG amino acid sequence contains SEQ ID NO: 26 The amino acid sequence shown may consist of the amino acid sequence shown in SEQ ID NO: 26. An exemplary rat NiG amino acid sequence includes or consists of the amino acid sequence set forth in SEQ ID NO: 27.
在一些实施例中，本文所述抗Nogo-A抗体特异性识别人Nogo-A中的表位。在一些实施例中，所述抗Nogo-A抗体与除人之外其它物种的Nogo-A发生交叉反应。在一些实施例中，所述抗Nogo-A抗体对人Nogo-A是完全特异性的，并且不与其它非人物种发生交叉反应。In some embodiments, the anti-Nogo-A antibodies described herein specifically recognize an epitope in human Nogo-A. In some embodiments, the anti-Nogo-A antibodies cross-react with Nogo-A from species other than human. In some embodiments, the anti-Nogo-A antibody is fully specific for human Nogo-A and does not cross-react with other non-human species.
在一些实施例中，所述抗Nogo-A抗体与Nogo-A蛋白(或其片段)的至少一种等位基因变体交叉反应。在一些实施例中，等位基因变体与天然存在的Nogo-A蛋白(或其片段)相比，具有至多30个(如1、2、3、4、5、6、7、8、9、10、15、20、25或30个)的氨基酸取代(例如保守取代)。在一些实施例中，所述抗Nogo-A抗体不与Nogo-A蛋白(或其片段)的任何等位基因变体发生交叉反应。In some embodiments, the anti-Nogo-A antibody cross-reacts with at least one allelic variant of Nogo-A protein (or fragment thereof). In some embodiments, the allelic variant has up to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) compared to the naturally occurring Nogo-A protein (or fragment thereof). , 10, 15, 20, 25 or 30) amino acid substitutions (eg, conservative substitutions). In some embodiments, the anti-Nogo-A antibody does not cross-react with any allelic variant of the Nogo-A protein (or fragment thereof).
在一些实施例中，所述抗Nogo-A抗体与Nogo-A蛋白的至少一种种间变体发生交叉反应。在一些实施例中，例如，Nogo-A蛋白(或其片段)是人Nogo-A，并且Nogo-A蛋白(或其片段)的种间变体是食蟹猴中的变体。在一些实施例中，所述抗Nogo-A抗体不与Nogo-A蛋白的任何种间变体发生交叉反应。In some embodiments, the anti-Nogo-A antibody cross-reacts with at least one interspecies variant of Nogo-A protein. In some embodiments, for example, the Nogo-A protein (or fragment thereof) is human Nogo-A, and the interspecies variant of the Nogo-A protein (or fragment thereof) is a variant in cynomolgus monkey. In some embodiments, the anti-Nogo-A antibody does not cross-react with any interspecies variant of Nogo-A protein.
在一些实施例中，如本文所述的任一抗Nogo-A抗体，所述抗Nogo-A抗体包含抗体重链恒定区和抗体轻链恒定区。在一些实施例中，所述抗Nogo-A抗体包含IgG1型重链恒定区。在一些实施例中，所述抗Nogo-A抗体包含IgG2型重链恒定区。在一些实施例中，所述抗Nogo-A抗体包含IgG3型重链恒定区。在一些实施例中，所述抗Nogo-A抗体包含IgG4型重链恒定区。在一些实施例中，所述重链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:21。在一些实施例中，所述重链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:22。在一些实施例中，所述抗Nogo-A抗体包含κ轻链恒定区。在一些实施例中，所述轻链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:23。在一些实施例中，所述抗Nogo-A抗体包含λ轻链恒定区。在一些实施例中，所述轻链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:24。在一些实施例中，所述抗Nogo-A抗体包含抗体重链可变结构域和抗体轻链可变结构域。In some embodiments, as any anti-Nogo-A antibody described herein, the anti-Nogo-A antibody comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-Nogo-A antibody comprises an IgG1 heavy chain constant region. In some embodiments, the anti-Nogo-A antibody comprises an IgG2 type heavy chain constant region. In some embodiments, the anti-Nogo-A antibody comprises an IgG3 type heavy chain constant region. In some embodiments, the anti-Nogo-A antibody comprises an IgG4 type heavy chain constant region. In some embodiments, the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 22. In some embodiments, the anti-Nogo-A antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 23. In some embodiments, the anti-Nogo-A antibody comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 24. In some embodiments, the anti-Nogo-A antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
在一些实施例中，所述抗Nogo-A抗体，包含重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYGMH(SEQ ID NO:1)；HC-CDR2，其包含SISHTGKTVFYGESVKG(SEQ ID NO:3)；和HC-CDR3，其包含TELGGDNWFDV(SEQ ID NO:5)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含TGSSSNIGGYDVY(SEQ ID NO:7)；LC-CDR2，其包含DNNKRPS(SEQ ID NO:9)；和LC-CDR3，其包含AAWDDSLYGYI(SEQ ID NO:11)。In some embodiments, the anti-Nogo-A antibody includes a heavy chain variable domain ( VH ), and the VH includes: heavy chain complementarity determining region (HC-CDR) 1, which includes DYGMH (SEQ ID NO: 1); HC-CDR2 comprising SISHTGKTVFYGESVKG (SEQ ID NO: 3); and HC-CDR3 comprising TELGGDNWFDV (SEQ ID NO: 5); and light chain variable domain (V L ), VL contains: light chain complementarity determining region (LC-CDR) 1, which contains TGSSSNIGGYDVY (SEQ ID NO:7); LC-CDR2, which contains DNKRPS (SEQ ID NO:9); and LC-CDR3, which contains AAWDDSLYGYI (SEQ ID NO:11).
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:1所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NO:3所示的氨基酸序列或其变体，所述变体包含至多约3个(例 如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:5所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 3 or a variant thereof, said variant comprising up to about 3 (for example (e.g., 1, 2, or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2, or 3 ) amino acid substitutions.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:1所示的氨基酸序列，HC-CDR2，其包含SEQ ID NO:3所示的氨基酸序列，HC-CDR3，其包含SEQ ID NO:5所示的氨基酸序列。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, HC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 3, HC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 5.
在一些实施例中，所述抗Nogo-A抗体包含VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:7所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NO:9所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NO:11所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises VL , and the VL comprises: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 7 or a variant thereof, the variant comprising up to Substitution of about 3 (for example, 1, 2 or 3) amino acids; LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 9 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 11 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids replacement.
在一些实施例中，所述抗Nogo-A抗体包含VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:7所示的氨基酸序列，LC-CDR2，其包含SEQ ID NO:9所示的氨基酸序列，LC-CDR3，其包含SEQ ID NO:11所示的氨基酸序列。In some embodiments, the anti-Nogo-A antibody comprises a V L comprising: LC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 7, LC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 9, LC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 11.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:1所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NO:3所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:5所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:7所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NO:9所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NO:11所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 3 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 5 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids and VL , the VL comprising: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:7 or a variant thereof, the variant comprising up to about 3 (e.g. 1, 2 or 3 ) amino acid substitutions; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 9 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acid substitutions; and LC-CDR3, which includes the amino acid sequence shown in SEQ ID NO: 11 or a variant thereof, which variant includes substitutions of at most about 3 (eg, 1, 2, or 3) amino acids.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:1所示的氨基酸序列，HC-CDR2，其包含SEQ ID NO:3所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NO:5所示的氨基酸序列；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:7所示的氨基酸序列，LC-CDR2，其包含SEQ ID NO:9所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NO:11所示的氨基酸序列。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, HC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 3, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:5; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence shown in SEQ ID NO:7 Sequences, LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO:9, and LC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:11.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:3，HC-CDR3，其包含氨基酸序列SEQ ID NO:5，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:7，LC-CDR2，其包含氨基酸序列SEQ ID NO:9，LC-CDR3，其包含氨基酸序列SEQ ID NO:11，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。 In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3 , HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 5, or a variant of the V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , the V L comprises: LC- CDR1, which comprises the amino acid sequence SEQ ID NO: 7, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 9, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 11, or a variant of said V L , which LC-CDRs contain substitutions of up to about 5 amino acids.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:3，和HC-CDR3，其包含氨基酸序列SEQ ID NO:5；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:7，LC-CDR2，其包含氨基酸序列SEQ ID NO:9，和LC-CDR3，其包含氨基酸序列SEQ ID NO:11。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:5; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:7, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:9, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:11.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含如SEQ ID NOs:13-16中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，所述VL包含如SEQ ID NOs:18-19中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2 and a VH as set forth in any of the amino acid sequences of SEQ ID NOs: 13-16. HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in any one of the amino acid sequences of SEQ ID NOs: 18-19.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:13所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:18所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising HC- CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 13; and V L , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 18.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:14所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:19所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 14; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 19.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:15所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:19所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 15; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 19.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:16所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:19所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 16; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 19.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含SEQ ID NOs:13-16中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:13-16中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含SEQ ID NOs:18-19中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:18-19中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含SEQ ID NOs:13-16中任一所示的氨基酸序列，以及VL，所述VL包含SEQ ID NOs:18-19中任一所示的氨基酸序列。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprises the amino acid sequence shown in any one of SEQ ID NOs: 13-16 or a variant thereof, the variant is identical to SEQ ID NOs: 13-16. The amino acid sequence shown in any one of NOs: 13-16 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and V L , the V L includes the amino acid sequence shown in any one of SEQ ID NOs: 18-19 or a variant thereof, and the variant has at least the same amino acid sequence as the amino acid sequence shown in any one of SEQ ID NOs: 18-19 About 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity. In some embodiments, the anti-Nogo-A antibody comprises a V H comprising the amino acid sequence set forth in any one of SEQ ID NOs: 13-16, and a V L comprising SEQ ID NOs : The amino acid sequence shown in any one of 18-19.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:13或其变体，所述变体与氨基酸序列SEQ ID NO:13具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:18或其变体，所述变体与氨基酸序列SEQ ID NO:18具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:13，以及VL，所述VL包含氨基酸序列SEQ ID NO:18。 In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 13 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 18 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 18 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:13, and a VL comprising the amino acid sequence SEQ ID NO:18.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:14或其变体，所述变体与氨基酸序列SEQ ID NO:14具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:14，以及VL，所述VL包含氨基酸序列SEQ ID NO:19。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 14 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 19 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 19 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:14, and a VL comprising the amino acid sequence SEQ ID NO:19.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:15或其变体，所述变体与氨基酸序列SEQ ID NO:15具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:15，以及VL，所述VL包含氨基酸序列SEQ ID NO:19。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 15 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 19 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 19 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:15, and a VL comprising the amino acid sequence SEQ ID NO:19.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:16或其变体，所述变体与氨基酸序列SEQ ID NO:16具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:16，以及VL，所述VL包含氨基酸序列SEQ ID NO:19。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 16 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 19 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 19 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:16, and a VL comprising the amino acid sequence SEQ ID NO:19.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:4，HC-CDR3，其包含氨基酸序列SEQ ID NO:6，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:8，LC-CDR2，其包含氨基酸序列SEQ ID NO:10，LC-CDR3，其包含氨基酸序列SEQ ID NO:12，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4 , HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 6, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC- CDR1, which comprises the amino acid sequence SEQ ID NO: 8, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 10, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 12, or a variant of said V L , which LC-CDRs contain substitutions of up to about 5 amino acids.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:4，和HC-CDR3，其包含氨基酸序列SEQ ID NO:6；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:8，LC-CDR2，其包含氨基酸序列SEQ ID NO:10，和LC-CDR3，其包含氨基酸序列SEQ ID NO:12。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 6; and VL , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 8, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 10, and LC-CDR3, which contains the amino acid sequence SEQ ID NO: 12.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:17所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:20所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 17; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO:20.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:17或其变体，所述变体与氨基酸序列SEQ ID NO:17具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:20 或其变体，所述变体与氨基酸序列SEQ ID NO:20具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:17，以及VL，所述VL包含氨基酸序列SEQ ID NO:20。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 17 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence SEQ ID NO:20 Identity. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:17, and a VL comprising the amino acid sequence SEQ ID NO:20.
在一些实施例中，所述抗Nogo-A抗体，包含重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYGMH(SEQ ID NO:28)；HC-CDR2，其包含VIWYHGSKKYYADSVKD(SEQ ID NO:48)；和HC-CDR3，其包含SIAETTDYGLDS(SEQ ID NO:65)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLLYRGGKTFLY(SEQ ID NO:85)；LC-CDR2，其包含ELSNRAS(SEQ ID NO:100)；和LC-CDR3，其包含MQGIQLPWT(SEQ ID NO:111)。In some embodiments, the anti-Nogo-A antibody comprises a heavy chain variable domain (V H ), and the V H comprises: heavy chain complementarity determining region (HC-CDR) 1, which comprises SYGMH (SEQ ID NO:28); HC-CDR2 comprising VIWYHGSKKYYADSVKD (SEQ ID NO:48); and HC-CDR3 comprising SIAETTDYGLDS (SEQ ID NO:65); and light chain variable domain (V L ), VL contains: light chain complementarity determining region (LC-CDR) 1, which contains RSSQSLLYRGGKTFLY (SEQ ID NO:85); LC-CDR2, which contains ELSNRAS (SEQ ID NO:100); and LC-CDR3, which contains MQGIQLPWT (SEQ ID NO:111).
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:28所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NO:48所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:65所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 65 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids replacement.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:28所示的氨基酸序列，HC-CDR2，其包含SEQ ID NO:48所示的氨基酸序列，HC-CDR3，其包含SEQ ID NO:65所示的氨基酸序列。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, HC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 48, HC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 65.
在一些实施例中，所述抗Nogo-A抗体包含VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:85所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NO:100所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NO:111所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises VL , the VL comprises: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:85 or a variant thereof, the variant comprising up to Substitution of about 3 (for example, 1, 2 or 3) amino acids; LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 111 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids replacement.
在一些实施例中，所述抗Nogo-A抗体包含VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:85所示的氨基酸序列，LC-CDR2，其包含SEQ ID NO:100所示的氨基酸序列，LC-CDR3，其包含SEQ ID NO:111所示的氨基酸序列。In some embodiments, the anti-Nogo-A antibody comprises a VL comprising: LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:85, LC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 100, LC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 111.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:28所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NO:48所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:65所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:85所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NO:100所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NO:111所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。 In some embodiments, the anti-Nogo-A antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof, the variant comprising at most Substitution of about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof, said variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 65 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids and VL , the VL comprising: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:85 or a variant thereof, the variant comprising up to about 3 (e.g. 1, 2 or 3 ) amino acid substitutions; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and LC-CDR3, which includes the amino acid sequence shown in SEQ ID NO: 111 or a variant thereof, which variant includes substitutions of up to about 3 (eg, 1, 2, or 3) amino acids.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:28所示的氨基酸序列，HC-CDR2，其包含SEQ ID NO:48所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NO:65所示的氨基酸序列；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:85所示的氨基酸序列，LC-CDR2，其包含SEQ ID NO:100所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NO:111所示的氨基酸序列。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, HC-CDR2 comprising SEQ ID NO: The amino acid sequence shown in 48, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:65; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence shown in SEQ ID NO:85 Sequences, LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO: 100, and LC-CDR3, which includes the amino acid sequence shown in SEQ ID NO: 111.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:28，HC-CDR2，其包含氨基酸序列SEQ ID NO:48，HC-CDR3，其包含氨基酸序列SEQ ID NO:65，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:85，LC-CDR2，其包含氨基酸序列SEQ ID NO:100，LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 28, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 48 , HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 65, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC- CDR1, which comprises the amino acid sequence SEQ ID NO: 85, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 100, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 111, or a variant of said V L , which LC-CDRs contain substitutions of up to about 5 amino acids.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:28，HC-CDR2，其包含氨基酸序列SEQ ID NO:48，和HC-CDR3，其包含氨基酸序列SEQ ID NO:65；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:85，LC-CDR2，其包含氨基酸序列SEQ ID NO:100，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 28, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 48 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:65; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:85, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 100, and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 111.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含如SEQ ID NOs:127-128中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，所述VL包含如SEQ ID NOs:150-151中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2 and a VH as set forth in any one of the amino acid sequences of SEQ ID NOs: 127-128. HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in any one of the amino acid sequences of SEQ ID NOs: 150-151.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:127所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:150所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 127; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 150.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:128所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:151所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 128; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 151.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:128所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:150所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 128; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 150.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含SEQ ID NOs:127-128中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:127-128中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含SEQ ID NOs:150-151中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:150-151中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含 SEQ ID NOs:127-128中任一所示的氨基酸序列，以及VL，所述VL包含SEQ ID NOs:150-151中任一所示的氨基酸序列。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprises the amino acid sequence shown in any one of SEQ ID NOs: 127-128 or a variant thereof, the variant is identical to SEQ ID NOs: 127-128 or a variant thereof. The amino acid sequence shown in any one of NOs: 127-128 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and V L , the V L includes the amino acid sequence shown in any one of SEQ ID NOs: 150-151 or a variant thereof, and the variant has at least the same amino acid sequence as the amino acid sequence shown in any one of SEQ ID NOs: 150-151. About 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity. In some embodiments, the anti-Nogo-A antibody comprises VH , the VH comprises The amino acid sequence shown in any one of SEQ ID NOs: 127-128, and V L comprising the amino acid sequence shown in any one of SEQ ID NOs: 150-151.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:127或其变体，所述变体与氨基酸序列SEQ ID NO:127具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:127，以及VL，所述VL包含氨基酸序列SEQ ID NO:150。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 127 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 127 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 150 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 150 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:127, and a VL comprising the amino acid sequence SEQ ID NO:150.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:151或其变体，所述变体与氨基酸序列SEQ ID NO:151具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:128，以及VL，所述VL包含氨基酸序列SEQ ID NO:151。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 128 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 151 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 151 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:128, and a VL comprising the amino acid sequence SEQ ID NO:151.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:128，以及VL，所述VL包含氨基酸序列SEQ ID NO:150。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 128 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 150 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 150 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:128, and a VL comprising the amino acid sequence SEQ ID NO:150.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:29，HC-CDR2，其包含氨基酸序列SEQ ID NO:49，和HC-CDR3，其包含氨基酸序列SEQ ID NO:66，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:86，LC-CDR2，其包含氨基酸序列SEQ ID NO:101，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 29, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 49 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 66, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:86, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:101, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:112, or a variant of said VL , whose LC-CDRs contain up to about 5 amino acid substitutions
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:29，HC-CDR2，其包含氨基酸序列SEQ ID NO:49，和HC-CDR3，其包含氨基酸序列SEQ ID NO:66；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:86，LC-CDR2，其包含氨基酸序列SEQ ID NO:101，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112。 In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 29, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 49 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 66; and VL , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 86, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:101, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:112.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:129所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:152所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised of VH as set forth in the amino acid sequence SEQ ID NO: 129; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 152.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:129或其变体，所述变体与氨基酸序列SEQ ID NO:129具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:152或其变体，所述变体与氨基酸序列SEQ ID NO:152具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:129，以及VL，所述VL包含氨基酸序列SEQ ID NO:152。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 129 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 152 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 152 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:129, and a VL comprising the amino acid sequence SEQ ID NO:152.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:30，HC-CDR2，其包含氨基酸序列SEQ ID NO:50，和HC-CDR3，其包含氨基酸序列SEQ ID NO:67，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:87，LC-CDR2，其包含氨基酸序列SEQ ID NO:102，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 30, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 50 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 67, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 87, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 102, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 113, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:30，HC-CDR2，其包含氨基酸序列SEQ ID NO:50，和HC-CDR3，其包含氨基酸序列SEQ ID NO:67；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:87，LC-CDR2，其包含氨基酸序列SEQ ID NO:102，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 30, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 50 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:67; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:87, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 102, and LC-CDR3, which contains the amino acid sequence SEQ ID NO: 113.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:130所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:153所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 130; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 153.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:153具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:130，以及VL，所述VL包含氨基酸序列SEQ ID NO:153。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 130 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 153 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 153 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:130, and a VL comprising the amino acid sequence SEQ ID NO:153.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:68，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及 VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 68, or a variant of said V H , whose HC-CDRs comprise substitutions of up to about 5 amino acids; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 88, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114, or a variant of the V L containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:68；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:68; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:114.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:131所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:154所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 131; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 154.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:131或其变体，所述变体与氨基酸序列SEQ ID NO:131具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:154或其变体，所述变体与氨基酸序列SEQ ID NO:154具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:131，以及VL，所述VL包含氨基酸序列SEQ ID NO:154。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 154 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 154 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:131, and a VL comprising the amino acid sequence SEQ ID NO:154.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:32，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:69，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 32, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 69, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:114, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:32，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:69；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 32, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:69; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:114.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:132所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:155所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO: 132; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 155.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:132或其变体，所述变体与氨基酸序列SEQ ID NO:132具有至少约80％(例如至少80％、85％、90％、 95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:155或其变体，所述变体与氨基酸序列SEQ ID NO:155具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:132，以及VL，所述VL包含氨基酸序列SEQ ID NO:155。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 132 80% (e.g. at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 155 or a variant thereof that is identical to the amino acid sequence SEQ ID NO. :155 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:132, and a VL comprising the amino acid sequence SEQ ID NO:155.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:33，HC-CDR2，其包含氨基酸序列SEQ ID NO:52，和HC-CDR3，其包含氨基酸序列SEQ ID NO:70，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:89，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:115，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 33, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 52 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 70, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:89, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:104, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:115, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:33，HC-CDR2，其包含氨基酸序列SEQ ID NO:52，和HC-CDR3，其包含氨基酸序列SEQ ID NO:70；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:89，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:115。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 33, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 52 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:70; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:89, LC-CDR2, which includes the amino acid sequence SEQ ID NO:104, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:115.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:133所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:156所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 133; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 156.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:133或其变体，所述变体与氨基酸序列SEQ ID NO:133具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:156或其变体，所述变体与氨基酸序列SEQ ID NO:156具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:133，以及VL，所述VL包含氨基酸序列SEQ ID NO:156。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 156 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 156 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:133, and a VL comprising the amino acid sequence SEQ ID NO:156.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:34，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:71，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 34, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 71, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:114, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:34，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸 序列SEQ ID NO:71；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 34, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53 , and HC-CDR3, which contains the amino acid Sequence SEQ ID NO:71; and VL comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:88, LC-CDR2 comprising the amino acid sequence SEQ ID NO:103, and LC-CDR3, It contains the amino acid sequence SEQ ID NO:114.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:134所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:157所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 134; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 157.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:134或其变体，所述变体与氨基酸序列SEQ ID NO:134具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:157或其变体，所述变体与氨基酸序列SEQ ID NO:157具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:134，以及VL，所述VL包含氨基酸序列SEQ ID NO:157。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 157 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 157 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:134, and a VL comprising the amino acid sequence SEQ ID NO:157.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:35，HC-CDR2，其包含氨基酸序列SEQ ID NO:54，和HC-CDR3，其包含氨基酸序列SEQ ID NO:72，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:90，LC-CDR2，其包含氨基酸序列SEQ ID NO:105，和LC-CDR3，其包含氨基酸序列SEQ ID NO:116，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 35, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 72, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 90, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 105, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 116, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:35，HC-CDR2，其包含氨基酸序列SEQ ID NO:54，和HC-CDR3，其包含氨基酸序列SEQ ID NO:72；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:90，LC-CDR2，其包含氨基酸序列SEQ ID NO:105，和LC-CDR3，其包含氨基酸序列SEQ ID NO:116。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 35, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:72; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:90, LC-CDR2, which includes the amino acid sequence SEQ ID NO:105, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:116.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:135所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:158所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 135; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 158.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:135或其变体，所述变体与氨基酸序列SEQ ID NO:135具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:158或其变体，所述变体与氨基酸序列SEQ ID NO:158具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:135，以及VL，所述VL包含氨基酸序列SEQ ID NO:158。 In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 135 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 158 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 158 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:135, and a VL comprising the amino acid sequence SEQ ID NO:158.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:36，HC-CDR2，其包含氨基酸序列SEQ ID NO:55，和HC-CDR3，其包含氨基酸序列SEQ ID NO:73，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 36, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 55 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 73, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 91, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 117, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:36，HC-CDR2，其包含氨基酸序列SEQ ID NO:55，和HC-CDR3，其包含氨基酸序列SEQ ID NO:73；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 36, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 55 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:73; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:91, LC-CDR2, which includes the amino acid sequence SEQ ID NO:106, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:117.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:136所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:159所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 136; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 159.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:136，以及VL，所述VL包含氨基酸序列SEQ ID NO:159。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 159 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 159 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:136, and a VL comprising the amino acid sequence SEQ ID NO:159.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:37，HC-CDR2，其包含氨基酸序列SEQ ID NO:56，和HC-CDR3，其包含氨基酸序列SEQ ID NO:74，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 37, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 56 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 74, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 91, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 117, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:37，HC-CDR2，其包含氨基酸序列SEQ ID NO:56，和HC-CDR3，其包含氨基酸序列SEQ ID NO:74；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117。 In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 37, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 56 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:74; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:91, LC-CDR2, which includes the amino acid sequence SEQ ID NO:106, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:117.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:137所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:159所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 137; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 159.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:137，以及VL，所述VL包含氨基酸序列SEQ ID NO:159。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 159 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 159 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:137, and a VL comprising the amino acid sequence SEQ ID NO:159.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:57，和HC-CDR3，其包含氨基酸序列SEQ ID NO:75，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:92，LC-CDR2，其包含氨基酸序列SEQ ID NO:107，和LC-CDR3，其包含氨基酸序列SEQ ID NO:118，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 57 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 75, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 92, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 107, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 118, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:57，和HC-CDR3，其包含氨基酸序列SEQ ID NO:75；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:92，LC-CDR2，其包含氨基酸序列SEQ ID NO:107，和LC-CDR3，其包含氨基酸序列SEQ ID NO:118。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 31, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 57 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:75; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:92, LC-CDR2, which includes the amino acid sequence SEQ ID NO:107, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:118.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:138所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:160所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 138; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 160.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:138或其变体，所述变体与氨基酸序列SEQ ID NO:138具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:160或其变体，所述变体与氨基酸序列SEQ ID NO:160具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:138，以及VL，所述VL包含氨基酸序列SEQ ID NO:160。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 160 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 160 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:138, and a VL comprising the amino acid sequence SEQ ID NO:160.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:38，HC-CDR2，其包含氨基酸序列SEQ ID NO:58，和HC-CDR3，其包含氨基酸序列SEQ ID NO:76，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及 VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:93，LC-CDR2，其包含氨基酸序列SEQ ID NO:108，和LC-CDR3，其包含氨基酸序列SEQ ID NO:119，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 38, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 58 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 76, or a variant of the V H whose HC-CDRs comprise substitutions of up to about 5 amino acids; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 93, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 108, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 119, or a variant of the V L containing at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:38，HC-CDR2，其包含氨基酸序列SEQ ID NO:58，和HC-CDR3，其包含氨基酸序列SEQ ID NO:76；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:93，LC-CDR2，其包含氨基酸序列SEQ ID NO:108，和LC-CDR3，其包含氨基酸序列SEQ ID NO:119。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 38, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 58 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:76; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:93, LC-CDR2, which includes the amino acid sequence SEQ ID NO:108, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:119.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:139所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:161所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 139; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 161.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:139或其变体，所述变体与氨基酸序列SEQ ID NO:139具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:161或其变体，所述变体与氨基酸序列SEQ ID NO:161具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:139，以及VL，所述VL包含氨基酸序列SEQ ID NO:161。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 139 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 161 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 161 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:139, and a VL comprising the amino acid sequence SEQ ID NO:161.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:39，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:77，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 39, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 77, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:120, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:39，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:77；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 39, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:77; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:120.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:140所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:162所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising HC- CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 140; and V L , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 162.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:140或其变体，所述变体与氨基酸序列SEQ ID NO:140具有至少约80％(例如至少80％、85％、90％、 95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:162或其变体，所述变体与氨基酸序列SEQ ID NO:162具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:140，以及VL，所述VL包含氨基酸序列SEQ ID NO:162。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO: 140 80% (e.g. at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 162 or a variant thereof that is identical to the amino acid sequence SEQ ID NO. :162 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:140, and a VL comprising the amino acid sequence SEQ ID NO:162.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:40，HC-CDR2，其包含氨基酸序列SEQ ID NO:59，和HC-CDR3，其包含氨基酸序列SEQ ID NO:78，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:94，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:121，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 40, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 59 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 78, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 94, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 121, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:40，HC-CDR2，其包含氨基酸序列SEQ ID NO:59，和HC-CDR3，其包含氨基酸序列SEQ ID NO:78；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:94，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:121。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 40, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 59 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:78; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:94, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:121.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:141所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:163所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 141; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 163.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:141或其变体，所述变体与氨基酸序列SEQ ID NO:141具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:163或其变体，所述变体与氨基酸序列SEQ ID NO:163具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:141，以及VL，所述VL包含氨基酸序列SEQ ID NO:163。In some embodiments, the anti-Nogo-A antibody comprises: VH , the VH comprising the amino acid sequence SEQ ID NO:141 or a variant thereof, the variant having an amino acid sequence of at least about SEQ ID NO:141 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 163 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 163 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:141, and a VL comprising the amino acid sequence SEQ ID NO:163.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:41，HC-CDR2，其包含氨基酸序列SEQ ID NO:60，和HC-CDR3，其包含氨基酸序列SEQ ID NO:79，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 41, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 60 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 79, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:114, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:41，HC-CDR2，其包含氨基酸序列SEQ ID NO:60，和HC-CDR3，其包含氨基酸 序列SEQ ID NO:79；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 41, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 60 , and HC-CDR3, which contains the amino acid Sequence SEQ ID NO:79; and VL comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:88, LC-CDR2 comprising the amino acid sequence SEQ ID NO:103, and LC-CDR3, It contains the amino acid sequence SEQ ID NO:114.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:142所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:164所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 142; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 164.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:142或其变体，所述变体与氨基酸序列SEQ ID NO:142具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:164或其变体，所述变体与氨基酸序列SEQ ID NO:164具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:142，以及VL，所述VL包含氨基酸序列SEQ ID NO:164。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 164 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 164 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:142, and a VL comprising the amino acid sequence SEQ ID NO:164.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:42，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 42, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO:88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO:120, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:42，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 42, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 51 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:80; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:120.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:143所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:165所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 143; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 165.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:143或其变体，所述变体与氨基酸序列SEQ ID NO:143具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:165或其变体，所述变体与氨基酸序列SEQ ID NO:165具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:143，以及VL，所述VL包含氨基酸序列SEQ ID NO:165。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 165 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 165 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:143, and a VL comprising the amino acid sequence SEQ ID NO:165.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:122，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 61 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 81, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 122, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:122。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 61 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:81; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:109, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:122.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:144所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:166所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 144; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 166.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:144或其变体，所述变体与氨基酸序列SEQ ID NO:144具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:166或其变体，所述变体与氨基酸序列SEQ ID NO:166具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:144，以及VL，所述VL包含氨基酸序列SEQ ID NO:166。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 166 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 166 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:144, and a VL comprising the amino acid sequence SEQ ID NO:166.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:44，HC-CDR2，其包含氨基酸序列SEQ ID NO:62，和HC-CDR3，其包含氨基酸序列SEQ ID NO:82，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:96，LC-CDR2，其包含氨基酸序列SEQ ID NO:110，和LC-CDR3，其包含氨基酸序列SEQ ID NO:123，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 44, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 62 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 82, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 96, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 110, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 123, or a variant of said V L , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:44，HC-CDR2，其包含氨基酸序列SEQ ID NO:62，和HC-CDR3，其包含氨基酸序列SEQ ID NO:82；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:96，LC-CDR2，其包含氨基酸序列SEQ ID NO:110，和LC-CDR3，其包含氨基酸序列SEQ ID NO:123。 In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 44, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 62 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:82; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:96, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 110, and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 123.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:145所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:167所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 145; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 167.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:145或其变体，所述变体与氨基酸序列SEQ ID NO:145具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:167或其变体，所述变体与氨基酸序列SEQ ID NO:167具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:145，以及VL，所述VL包含氨基酸序列SEQ ID NO:167。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 167 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 167 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:145, and a VL comprising the amino acid sequence SEQ ID NO:167.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:45，HC-CDR2，其包含氨基酸序列SEQ ID NO:63，和HC-CDR3，其包含氨基酸序列SEQ ID NO:83，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:97，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:124，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 45, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 63 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 83, or a variant of the V H , which contains up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 97, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 124, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:45，HC-CDR2，其包含氨基酸序列SEQ ID NO:63，和HC-CDR3，其包含氨基酸序列SEQ ID NO:83；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:97，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:124。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 45, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 63 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:83; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:97, LC-CDR2, which includes the amino acid sequence SEQ ID NO:104, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:124.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:146所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:168所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 146; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 168.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:168或其变体，所述变体与氨基酸序列SEQ ID NO:168具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:146，以及VL，所述VL包含氨基酸序列SEQ ID NO:168。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 168 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 168 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:146, and a VL comprising the amino acid sequence SEQ ID NO:168.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:46，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及 VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:98，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 46, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V H , whose HC-CDRs comprise substitutions of up to about 5 amino acids; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 98, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 114, or a variant of the V L containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:46，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:98，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 46, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:80; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:98, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:114.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:147所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:169所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 147; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 169.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:169或其变体，所述变体与氨基酸序列SEQ ID NO:169具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:147，以及VL，所述VL包含氨基酸序列SEQ ID NO:169。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 169 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 169 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:147, and a VL comprising the amino acid sequence SEQ ID NO:169.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:47，HC-CDR2，其包含氨基酸序列SEQ ID NO:64，和HC-CDR3，其包含氨基酸序列SEQ ID NO:84，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:99，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:125，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 47, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 64 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 84, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 99, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 125, or a variant of said VL , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:47，HC-CDR2，其包含氨基酸序列SEQ ID NO:64，和HC-CDR3，其包含氨基酸序列SEQ ID NO:84；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:99，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:125。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 47, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 64 , and HC-CDR3, which includes the amino acid sequence SEQ ID NO:84; and VL , which VL includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:99, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:125.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:148所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:170所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 148; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 170.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％(例如至少80％、85％、90％、 95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:170或其变体，所述变体与氨基酸序列SEQ ID NO:170具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:148，以及VL，所述VL包含氨基酸序列SEQ ID NO:170。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof that is at least about 80% (e.g. at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 170 or a variant thereof that is identical to the amino acid sequence SEQ ID NO. :170 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:148, and a VL comprising the amino acid sequence SEQ ID NO:170.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:126，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 61 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 81, or a variant of said V H , whose HC-CDRs comprise up to about 5 amino acid substitutions; and V L , said V L comprises: LC -CDR1, which comprises the amino acid sequence SEQ ID NO: 95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 126, or a variant of said V L , containing up to about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:126。In some embodiments, the anti-Nogo-A antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 43, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 61 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:81; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO:109, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:126.
在一些实施例中，所述抗Nogo-A抗体包含VH，其包含如氨基酸序列SEQ ID NO:149所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:171所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。In some embodiments, the anti-Nogo-A antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 149; and VL , It contains LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in the amino acid sequence SEQ ID NO: 171.
在一些实施例中，所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:171或其变体，所述变体与氨基酸序列SEQ ID NO:171具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗Nogo-A抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:149，以及VL，所述VL包含氨基酸序列SEQ ID NO:171。 In some embodiments, the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof that is at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 171 or Variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO: 171 sex. In some embodiments, the anti-Nogo-A antibody comprises a VH comprising the amino acid sequence SEQ ID NO:149, and a VL comprising the amino acid sequence SEQ ID NO:171.
在一些实施例中，上述氨基酸取代限于本文表4中所示的“示例性取代”。在一些实施例中，氨基酸取代限于本文表4中所示的“优选取代”。In some embodiments, the above-described amino acid substitutions are limited to the "exemplary substitutions" set forth in Table 4 herein. In some embodiments, amino acid substitutions are limited to the "preferred substitutions" set forth in Table 4 herein.
在一些实施例中，功能性表位可通过组合丙氨酸扫描法来解析。在此过程中，组合丙氨酸扫描技术可用于鉴定Nogo-A蛋白中与抗Nogo-A抗体相互作用所必需的氨基酸。在一些实施例中，该表位是构象的，同时可以采用与Nogo-A蛋白结合的抗Nogo-A抗体的晶体结构来鉴定表位。In some embodiments, functional epitopes can be resolved by combined alanine scanning methods. In this process, combinatorial alanine scanning technology can be used to identify amino acids in the Nogo-A protein that are necessary for interaction with anti-Nogo-A antibodies. In some embodiments, the epitope is conformational and the crystal structure of an anti-Nogo-A antibody bound to Nogo-A protein can be used to identify the epitope.
在一些实施例中，本申请提供与本文所述的任一种抗Nogo-A抗体竞争性结合Nogo-A的抗体。在一些实施例中，提供能够与本文所述的任一种抗Nogo-A抗体竞争性地结合Nogo-A上的表位的抗体。在一些实施例中，提供抗Nogo-A抗体，其与包含VH和VL的抗Nogo-A抗体分子结合 相同的表位，其中所述VH包含SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列，以及所述VL包含SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列。在一些实施例中，提供抗Nogo-A抗体，其与包含VH和VL的抗Nogo-A抗体竞争性地结合Nogo-A，其中所述VH包含SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列，以及所述VL包含SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列。In some embodiments, the application provides antibodies that compete for binding to Nogo-A with any of the anti-Nogo-A antibodies described herein. In some embodiments, antibodies are provided that are capable of binding to an epitope on Nogo-A competitively with any of the anti-Nogo-A antibodies described herein. In some embodiments, anti-Nogo-A antibodies are provided that bind to anti-Nogo-A antibody molecules comprising VH and VL The same epitope, wherein the V H includes the amino acid sequence shown in any one of SEQ ID NOs: 13-17 and 127-149, and the V L includes any of SEQ ID NOs: 18-20 and 150-171. The amino acid sequence shown in 1. In some embodiments, anti-Nogo-A antibodies are provided that compete for binding to Nogo-A with anti-Nogo-A antibodies comprising V H and V L , wherein the V H comprises SEQ ID NOs: 13-17, 127 The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171, and the V L includes the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171.
在一些实施例中，可以利用竞争实验来鉴定与本文所述的抗Nogo-A抗体竞争性结合Nogo-A的单克隆抗体。竞争实验可以通过识别相同的或空间上重叠的表位或者通过一个抗体竞争性抑制另一抗体与抗原结合来确定两个抗体是否结合相同的表位。在某些实施例中，这种竞争性抗体与本文所述的抗体结合相同的表位。一些示例性的竞争实验包括，但不限于如Harlow and Lane(1988)Antibodies:A Laboratory Manual ch.14(Cold Spring Harbor Laboratory，Cold Spring Harbor,N.Y.)中所提到的常规实验。用于解析抗体结合的表位的详细示例性方法如Morris(1996)"Epitope Mapping Protocols,"in Methods in Molecular Biology vol.66(Humana Press,Totowa,N.J.)中所述。在一些实施例中，如果每种抗体阻断另一种抗体结合的50％或更多，则称其结合相同的表位。在一些实施例中，与本文所述的抗Nogo-A抗体竞争的抗体是嵌合抗体、人源化抗体或全人抗体。In some embodiments, competition experiments can be used to identify monoclonal antibodies that compete with the anti-Nogo-A antibodies described herein for binding to Nogo-A. Competition experiments can determine whether two antibodies bind the same epitope by identifying the same or spatially overlapping epitope or by one antibody competitively inhibiting the binding of another antibody to the antigen. In certain embodiments, such competing antibodies bind the same epitope as the antibodies described herein. Some exemplary competition experiments include, but are not limited to, conventional experiments as mentioned in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.). Detailed exemplary methods for resolving epitopes bound by antibodies are described in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, N.J.). In some embodiments, each antibody is said to bind the same epitope if it blocks 50% or more of the binding of the other antibody. In some embodiments, the antibody that competes with an anti-Nogo-A antibody described herein is a chimeric antibody, a humanized antibody, or a fully human antibody.
示例性抗Nogo-A抗体序列如表2、表3所示，其中根据Kabat定义方式进行CDR编号。本领域技术人员将认识到有多种已知算法来预测CDR的位置以及界定抗体轻、重链可变区。包含如本文所述抗体的CDRs、VH和/或VL序列，但基于预测算法而非下表中所示例的抗体也在本申请的范围内。Exemplary anti-Nogo-A antibody sequences are shown in Table 2 and Table 3, where CDR numbering is performed according to Kabat definition. Those skilled in the art will recognize that there are a variety of known algorithms for predicting the location of CDRs and defining antibody light and heavy chain variable regions. Antibodies containing the CDRs, VH and/or VL sequences of antibodies as described herein, but based on prediction algorithms other than those exemplified in the table below are also within the scope of the present application.
表2示例性抗Nogo-A抗体CDR序列
Table 2 Exemplary anti-Nogo-A antibody CDR sequences
表2A示例性抗Nogo-A抗体CDR序列



Table 2A Exemplary anti-Nogo-A antibody CDR sequences



表3示例性序列


Table 3 Exemplary sequences


表3A示例性序列


Table 3A Exemplary Sequences


Nogo-ANogo-A
Nogo-A蛋白是浆膜蛋白质家族成员。Nogo-A、Nogo-B和Nogo-C是浆膜蛋白4(RTN4，也称为NOGO)基因编码的3种蛋白产物。这三种异构体共有相同的羧基端网状同源结构域(RTN)。该RTN结构域与其他三个网状结构基因RTN1、RTN2和RTN3编码的蛋白具有高度的相似性(GrandPre等，Nature,2000；Oertle等，Trends Cell Biol.2003)，它们在神经系统和其他器官中的功能大多未知。Nogo蛋白的RTN结构域包含两个长疏水段，每个疏水段的长度足以跨越细胞膜两次。它们由66个氨基酸片段连接在一起，该片段被称为Nogo-66(GrandPre等，Nature,2000)。Nogo-A、Nogo-B和Nogo-C的N端结构差异较大，其中仅Nogo-A被证明在中枢神经系统中发挥强烈的抑制作用(GrandPre等，Nature,2000；Huber等，J Neurosci,2002年)，这表明有一个重要的功能域位于Nogo-A氨基末端的特定部分。通过筛选Nogo-A缺失构建体文库，发现了一个具有神经突生长和成纤维细胞扩散抑制活性的区域，该区域被命名为Nogo-A-Δ20(Oertle等，J Neurosci,2003；Kempf A等，PLoS Biol.2014.)。然而，Nogo-A的羧基末端Nogo-66结构域也被认为具有强烈的神经突生长抑制活性(Fournier等，Nature,2001)。虽然足以发挥它们的抑制 功能，但是Nogo-A-Δ20和Nogo-66作为一个更大的Nogo-A衍生片段的一部分时被证明具有更强的活性，如Nogo-A-ext(也被称为NiR-G，鼠aa 1-979)或Nogo-22(鼠aa 966-1163)(Huebner等，J Biol Chem,2011；Oertle等，J Neurosci,2003)。Nogo-A protein is a member of the plasma membrane protein family. Nogo-A, Nogo-B and Nogo-C are three protein products encoded by the plasma membrane protein 4 (RTN4, also known as NOGO) gene. These three isoforms share the same carboxy-terminal reticular homology domain (RTN). This RTN domain is highly similar to the proteins encoded by the other three reticular structure genes RTN1, RTN2 and RTN3 (GrandPre et al., Nature, 2000; Oertle et al., Trends Cell Biol. 2003), which are involved in the nervous system and other organs. The functions in are mostly unknown. The RTN domain of Nogo protein contains two long hydrophobic segments, each of which is long enough to span the cell membrane twice. They are linked together by a 66-amino acid segment called Nogo-66 (Grand Pre et al., Nature, 2000). The N-terminal structures of Nogo-A, Nogo-B and Nogo-C are quite different, among which only Nogo-A has been shown to exert a strong inhibitory effect in the central nervous system (GrandPre et al., Nature, 2000; Huber et al., J Neurosci, 2002), suggesting that there is an important functional domain located in a specific portion of the amino terminus of Nogo-A. By screening a Nogo-A deletion construct library, a region with neurite growth and fibroblast spreading inhibitory activity was discovered, which was named Nogo-A-Δ20 (Oertle et al., J Neurosci, 2003; Kempf A et al., PLoS Biol. 2014.). However, the carboxy-terminal Nogo-66 domain of Nogo-A is also considered to have strong neurite growth inhibitory activity (Fournier et al., Nature, 2001). Although sufficient to exert their inhibitory functional, but Nogo-A-Δ20 and Nogo-66 were shown to be more active when part of a larger Nogo-A-derived fragment, such as Nogo-A-ext (also known as NiR-G, mouse aa 1-979) or Nogo-22 (mouse aa 966-1163) (Huebner et al., J Biol Chem, 2011; Oertle et al., J Neurosci, 2003).
Nogo-A受体Nogo-A receptor
Nogo-A通过两个不同的胞外结构域Nogo-A-Δ20(鼠aa544-725)和Nogo-66(鼠aa1026-1091)发挥其抑制活性(Schwab ME等，Nat Rev Neurosci.2010；Oertle T等，J Neurosci.2003)。第一个被鉴定的Nogo受体是糖基磷脂酰肌醇(GPI)连接的富有亮氨酸重复序列(LRR)的蛋白Nogo受体1(NgR1，也被称为Nogo-66受体和浆膜蛋白4受体)(Fournier AE等，Nature,2001)。NgR1由473个氨基酸组成，包含N末端信号序列、8个富含亮氨酸的重复序列(LRR)LRR1-LRR8、富含亮氨酸的重复序列C端结构域(LRRCT)(这3个区域共同形成胞外结构域)和GPI锚定结构域。通过GPI锚定结构，NgR1与外部神经元质膜连接。NgR1在啮齿类动物或小鸡的发育早期不表达，但在成年动物中显示高表达水平；NgR1在大部分CNS区域包括脊髓中表达(Hunt等，J Neurocytol.2002a,b)。Nogo-A通过其抑制性Nogo-66结构域与NgR1结合起始胞内信号级联反应。因为NgR不包含跨膜结构域，信号转导需要将NgR/配体相互作用的信号转导至共受体p75或TROY与LINGO1，形成功能性的三元复合物，从而抑制神经突的生长。这种结合通过未知的中间体导致细胞内Ca2+的增加，和Rho-Rho相关的含有卷曲的蛋白激酶(ROCK)途径的激活。通过RHOA信号传递，肌动蛋白细胞骨架失稳，从而导致生长锥塌陷。除了NgR1，Nogo-66还通过辅助蛋白和配对的免疫球蛋白样受体B(PIRB)(Atwal JK等，Science.2008)相互作用，诱导生长抑制。NgR1也与抑制生长的髓鞘质相关糖蛋白(MAG)和髓鞘质少突胶质细胞糖蛋白(OMGP)结合(Domeniconi,M等，Neuron,2002；Wang,K.C.等，Nature,2002)。Nogo-A exerts its inhibitory activity through two different extracellular domains, Nogo-A-Δ20 (mouse aa544-725) and Nogo-66 (mouse aa1026-1091) (Schwab ME et al., Nat Rev Neurosci. 2010; Oertle T et al., J Neurosci. 2003). The first Nogo receptor to be identified was the glycosylphosphatidylinositol (GPI)-linked leucine-rich repeat (LRR) protein Nogo receptor 1 (NgR1, also known as the Nogo-66 receptor and plasma membrane protein 4 receptor) (Fournier AE et al., Nature, 2001). NgR1 consists of 473 amino acids, including an N-terminal signal sequence, eight leucine-rich repeats (LRR) LRR1-LRR8, and a leucine-rich repeat C-terminal domain (LRRCT) (these three regions Together they form the extracellular domain) and the GPI anchoring domain. Through a GPI-anchored structure, NgR1 is connected to the outer neuronal plasma membrane. NgR1 is not expressed in early development of rodents or chicks, but shows high expression levels in adult animals; NgR1 is expressed in most CNS regions including the spinal cord (Hunt et al., J Neurocytol. 2002a,b). Nogo-A binds to NgR1 through its inhibitory Nogo-66 domain to initiate intracellular signaling cascades. Because NgR does not contain a transmembrane domain, signal transduction requires transducing the NgR/ligand interaction signal to the co-receptor p75 or TROY and LINGO1 to form a functional ternary complex, thereby inhibiting neurite growth. This binding leads to an increase in intracellular Ca 2+ and activation of the Rho-Rho-related Frizzled-containing kinase (ROCK) pathway through unknown intermediates. Through RHOA signaling, the actin cytoskeleton is destabilized, resulting in growth cone collapse. In addition to NgR1, Nogo-66 also induces growth inhibition through interaction with accessory proteins and paired immunoglobulin-like receptor B (PIRB) (Atwal JK et al., Science. 2008). NgR1 also binds to the growth-inhibitory myelin-associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (OMGP) (Domeniconi, M et al., Neuron, 2002; Wang, KC et al., Nature, 2002).
Anissa Kempf等人发现G蛋白偶联受体(GPCR)鞘氨醇1-磷酸受体2(S1PR2)是Nogo-A的Δ20结构域的功能性受体(Kempf A等，PLoS Biol.2014.)。通过药理或基因途径干扰S1PR2的活性，都可以阻断Nogo-A-Δ20介导的抑制作用。该研究还证明了Nogo-A-Δ20通过胞外受体环2和3结合S1PR2，这与之前描述的S1P结合部位不同(Hanson MA等，Scince.2012.)。Nogo-A-Δ20通过G蛋白G13、白血病相关的Rho鸟嘌呤交换因子(RhoGEF)LARG和RhoA发出信号。敲除或阻断S1PR2能抵消Nogo-A-Δ20和髓鞘介导的对神经元外生长和细胞扩散的抑制。急性S1PR2阻断可增加海马和皮质的长期突触可塑性，与Nogo-A中和作用类似。这些结果加强了最近提出的Nogo-A在限制突触可塑性以稳定神经元回路的生理作用(Mironova YA等，Trends Neurosci.2013.)。Anissa Kempf et al. discovered that the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) is a functional receptor for the Δ20 domain of Nogo-A (Kempf A et al., PLoS Biol. 2014.) . Interfering with the activity of S1PR2 through pharmacological or genetic pathways can block the inhibitory effect mediated by Nogo-A-Δ20. This study also demonstrated that Nogo-A-Δ20 binds S1PR2 via extracellular receptor loops 2 and 3, which is distinct from the previously described S1P binding site (Hanson MA et al., Scince. 2012.). Nogo-A-Δ20 signals through the G protein G13, leukemia-associated Rho guanine exchange factor (RhoGEF) LARG, and RhoA. Knocking down or blocking S1PR2 counteracts Nogo-A-Δ20 and myelin-mediated inhibition of neuronal outgrowth and cell spreading. Acute S1PR2 blockade increases long-term synaptic plasticity in the hippocampus and cortex, similar to Nogo-A neutralization. These results strengthen the recently proposed physiological role of Nogo-A in limiting synaptic plasticity to stabilize neuronal circuits (Mironova YA et al., Trends Neurosci. 2013.).
全长抗Nogo-A抗体Full length anti-Nogo-A antibody
在一些实施例中，所述抗Nogo-A抗体是全长抗Nogo-A抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgA、IgD、IgE、IgG或IgM。在一些实施例中，所述全长抗Nogo-A抗体包含IgG恒定区域，例如IgG1、IgG2、IgG3、IgG4或其变体的恒定区域。在一些实施例中，所述全长抗 Nogo-A抗体包含λ轻链恒定区。在一些实施例中，所述全长抗Nogo-A抗体包含κ轻链恒定区。在一些实施例中，所述全长抗Nogo-A抗体是全长的人抗Nogo-A抗体。在一些实施例中，所述全长抗Nogo-A抗体包含小鼠免疫球蛋白Fc序列。在一些实施例中，所述全长抗Nogo-A抗体包含已经改变的或以其他方式改变的Fc序列，使得其具有增强的抗体依赖的细胞介导的细胞毒作用(ADCC)和补体依赖的细胞毒作用(CDC)的效应功能。In some embodiments, the anti-Nogo-A antibody is a full-length anti-Nogo-A antibody. In some embodiments, the full-length anti-Nogo-A antibody is IgA, IgD, IgE, IgG, or IgM. In some embodiments, the full-length anti-Nogo-A antibody comprises an IgG constant region, such as that of IgG1, IgG2, IgG3, IgG4, or a variant thereof. In some embodiments, the full-length anti- The Nogo-A antibody contains the lambda light chain constant region. In some embodiments, the full-length anti-Nogo-A antibody comprises a kappa light chain constant region. In some embodiments, the full-length anti-Nogo-A antibody is a full-length human anti-Nogo-A antibody. In some embodiments, the full-length anti-Nogo-A antibody comprises mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-Nogo-A antibody comprises an Fc sequence that has been altered or otherwise altered such that it has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent Cytotoxicity (CDC) effector function.
因此，例如，在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，所述抗Nogo-A抗体与Nogo-A特异性结合。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。Thus, for example, in some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, the anti-Nogo-A antibody specifically binding to Nogo-A. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG2恒定区的全长抗Nogo-A抗体，所述抗Nogo-A抗体与Nogo-A特异性结合。在一些实施例中，所述IgG2是人IgG2。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG2 constant region is provided, the anti-Nogo-A antibody specifically binding to Nogo-A. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
在一些实施例中，提供一种包含IgG3恒定区的全长抗Nogo-A抗体，所述抗Nogo-A抗体与Nogo-A特异性结合。在一些实施例中，所述IgG3是人IgG3。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG3 constant region is provided, the anti-Nogo-A antibody specifically binding to Nogo-A. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，所述抗Nogo-A抗体与Nogo-A特异性结合。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, the anti-Nogo-A antibody specifically binding to Nogo-A. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-2、28-47中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:3-4、48-64中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:5-6、65-84中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:7-8、85- 99中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，LC-CDR2，其包含SEQ ID NOs:9-10、100-110中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:11-12、111-126中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3) amino acids Substitution; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3 ) amino acid substitution; and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ ID NOs: 7-8, 85- The amino acid sequence shown in any one of 99 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions, LC-CDR2, which includes SEQ ID NOs: 9-10, The amino acid sequence shown in any one of 100-110, or a variant thereof, the variant comprising a substitution of up to about 3 (eg, 1, 2 or 3) amino acids; and LC-CDR3, comprising SEQ ID NOs: 11 -The amino acid sequence shown in any one of 12, 111-126, or a variant thereof, the variant comprising a substitution of up to about 3 (eg, 1, 2 or 3) amino acids. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG2恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-2、28-47中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:3-4、48-64中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:5-6、65-84中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:7-8、85-99中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:9-10、100-110中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:11-12、111-126中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG2是人IgG2。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG2 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3) amino acids Substitution; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3 ) amino acid substitution; and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) substitution of amino acids; and b) light chain variable domain, said light chain variable domain comprising: LC-CDR1, which comprises any one of SEQ ID NOs: 7-8, 85-99 The amino acid sequence or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acid substitutions; LC-CDR2 comprising any one of SEQ ID NOs: 9-10, 100-110 The amino acid sequence shown, or a variant thereof, comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and LC-CDR3, comprising SEQ ID NOs: 11-12, 111-126 The amino acid sequence shown in any one or a variant thereof, the variant comprising a substitution of up to about 3 (eg, 1, 2 or 3) amino acids. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
在一些实施例中，提供一种包含IgG3恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-2、28-47中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，HC-CDR2，其包含SEQ ID NOs:3-4、48-64中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:5-6、65-84中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:7-8、85-99中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:9-10、100-110中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:11-12、111-126中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸 的取代。在一些实施例中，所述IgG3是人IgG3。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG3 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3) amino acids Substitution, HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3 ) amino acid substitution; and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) substitution of amino acids; and b) light chain variable domain, said light chain variable domain comprising: LC-CDR1, which comprises any one of SEQ ID NOs: 7-8, 85-99 The amino acid sequence or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; LC-CDR2, which comprises any one of SEQ ID NOs: 9-10, 100-110 The amino acid sequences shown, or variants thereof, comprising substitutions of up to about 3 (eg, 1, 2, or 3) amino acids; and LC-CDR3, comprising SEQ ID NOs: 11-12, 111-126 The amino acid sequence shown in any one or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2 or 3) amino acids replacement. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-2、28-47中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:3-4、48-64中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:5-6、65-84中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:7-8、85-99中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，LC-CDR2，其包含SEQ ID NOs:9-10、100-110中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，和LC-CDR3，其包含SEQ ID NOs:11-12、111-126中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47 or a variant thereof, the variant comprising at most about 3 (for example, 1, 2 or 3) amino acids Substitution; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3 ) amino acid substitution; and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) substitution of amino acids; and b) light chain variable domain, said light chain variable domain comprising: LC-CDR1, which comprises any one of SEQ ID NOs: 7-8, 85-99 The amino acid sequence or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids, LC-CDR2, comprising any one of SEQ ID NOs: 9-10, 100-110 The amino acid sequence shown, or a variant thereof, comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids, and an LC-CDR3 comprising SEQ ID NOs: 11-12, 111-126 The amino acid sequence shown in any one or a variant thereof, the variant comprising a substitution of up to about 3 (eg, 1, 2 or 3) amino acids. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-2、28-47中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:3-4、48-64中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:5-6、65-84中任一所示的氨基酸序列，或者所述重链可变结构域的变体，其HC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:7-8、85-99中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:9-10、100-110中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:11-12、111-126中任一所示的氨基酸序列，或者所述轻链可变结构域的变体，其LC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。 In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 Amino acid sequence, and HC-CDR3, which includes the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84, or a variant of the heavy chain variable domain, whose HC-CDR sequence includes Substitutions of up to about 5 (eg, 1, 2, 3, 4, or 5) amino acids; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ ID NOs : The amino acid sequence shown in any one of 7-8 and 85-99, LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 9-10, 100-110, and LC-CDR3, which includes The amino acid sequence shown in any one of SEQ ID NOs: 11-12 and 111-126, or a variant of the light chain variable domain, whose LC-CDR sequence contains at most about 5 (for example, 1, 2, 3, 4 or 5) amino acid substitutions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-2、28-47中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:3-4、48-64中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:5-6、65-84中任一所示的氨基酸序列，或者所述重链可变结构域的变体，其HC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:7-8、85-99中任一所示的氨基酸序列，LC-CDR2，包含SEQ ID NOs:9-10、100-110中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:11-12、111-126中任一所示的氨基酸序列，或者所述轻链可变结构域的变体，其LC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 sequence, and HC-CDR3, which contains the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84, or a variant of the heavy chain variable domain, whose HC-CDR sequence contains up to A substitution of about 5 (e.g., 1, 2, 3, 4, or 5) amino acids; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ ID NOs: The amino acid sequence shown in any one of 7-8 and 85-99, LC-CDR2, including the amino acid sequence shown in any one of SEQ ID NOs: 9-10, 100-110, and LC-CDR3, which includes SEQ ID NOs: The amino acid sequence shown in any one of NOs: 11-12 and 111-126, or a variant of the light chain variable domain, whose LC-CDR sequence contains at most about 5 (for example, 1, 2, 3, 4 or 5) amino acid substitutions. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-2、28-47中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:3-4、48-64中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:5-6、65-84中任一所示的氨基酸序列；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:7-8、85-99中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:9-10、100-110中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:11-12、111-126中任一所示的氨基酸序列。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 Amino acid sequence, and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84; and b) light chain variable domain, the light chain variable domain comprising: LC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 7-8, 85-99, LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 9-10, 100-110 sequence, and LC-CDR3, which includes the amino acid sequence shown in any one of SEQ ID NOs: 11-12, 111-126. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-2、28-47中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:3-4、48-64中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:5-6、65-84中任一所示的氨基酸序列；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:7-8、85-99中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:9-10、100-110中任一所示的氨基酸序列，和LC- CDR3，其包含SEQ ID NOs:11-12、111-126中任一所示的氨基酸序列。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 28-47, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 48-64 Amino acid sequence, and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 65-84; and b) light chain variable domain, said light chain variable domain comprising: LC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 7-8, 85-99, LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 9-10, 100-110 sequence, and LC- CDR3, which includes the amino acid sequence shown in any one of SEQ ID NOs: 11-12 and 111-126. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:3，和HC-CDR3，其包含氨基酸序列SEQ ID NO:5；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:7，LC-CDR2，其包含氨基酸序列SEQ ID NO:9，和LC-CDR3，其包含氨基酸序列SEQ ID NO:11。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 5; and b) the light chain may Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence SEQ ID NO:9, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:11. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:4，和HC-CDR3，其包含氨基酸序列SEQ ID NO:6；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:8，LC-CDR2，其包含氨基酸序列SEQ ID NO:10，和LC-CDR3，其包含氨基酸序列SEQ ID NO:12。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 2, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 6; and b) the light chain may Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 8, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 10, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:12. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:28，HC-CDR2，其包含氨基酸序列SEQ ID NO:48，和HC-CDR3，其包含氨基酸序列SEQ ID NO:65；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:85，LC-CDR2，其包含氨基酸序列SEQ ID NO:100，和LC-CDR3，其包含氨基酸序列SEQ  ID NO:111。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 28, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 48, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 65; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 85, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 100, and LC-CDR3, which comprises the amino acid sequence sequenceSEQ ID NO:111. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:29，HC-CDR2，其包含氨基酸序列SEQ ID NO:49，和HC-CDR3，其包含氨基酸序列SEQ ID NO:66；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:86，LC-CDR2，其包含氨基酸序列SEQ ID NO:101，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 29, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 49, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 66; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:86, LC-CDR2, which includes the amino acid sequence SEQ ID NO:101, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:112. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:30，HC-CDR2，其包含氨基酸序列SEQ ID NO:50，和HC-CDR3，其包含氨基酸序列SEQ ID NO:67；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:87，LC-CDR2，其包含氨基酸序列SEQ ID NO:102，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 30, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 50, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 67; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:87, LC-CDR2, which includes the amino acid sequence SEQ ID NO:102, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:113. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:68；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基 酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 31, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 68; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of an amino group The acid sequence consists of SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:32，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:69；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 32, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 69; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:33，HC-CDR2，其包含氨基酸序列SEQ ID NO:52，和HC-CDR3，其包含氨基酸序列SEQ ID NO:70；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:89，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:115。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 33, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 52, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 70; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:89, LC-CDR2, which includes the amino acid sequence SEQ ID NO:104, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:115. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:34，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:71；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组 成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 34, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 71; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23 become. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:35，HC-CDR2，其包含氨基酸序列SEQ ID NO:54，和HC-CDR3，其包含氨基酸序列SEQ ID NO:72；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:90，LC-CDR2，其包含氨基酸序列SEQ ID NO:105，和LC-CDR3，其包含氨基酸序列SEQ ID NO:116。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 35, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 54, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 72; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 90, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 105, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:116. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:36，HC-CDR2，其包含氨基酸序列SEQ ID NO:55，和HC-CDR3，其包含氨基酸序列SEQ ID NO:73；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 36, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 55, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 73; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 91, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:117. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:37，HC-CDR2，其包含氨基酸序列SEQ ID NO:56，和HC-CDR3，其包含氨基酸序列SEQ ID NO:74；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重 链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 37, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 56, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 74; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 91, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:117. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, heavy The chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:57，和HC-CDR3，其包含氨基酸序列SEQ ID NO:75；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:92，LC-CDR2，其包含氨基酸序列SEQ ID NO:107，和LC-CDR3，其包含氨基酸序列SEQ ID NO:118。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 31, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 57, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 75; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 92, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 107, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:118. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:38，HC-CDR2，其包含氨基酸序列SEQ ID NO:58，和HC-CDR3，其包含氨基酸序列SEQ ID NO:76；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:93，LC-CDR2，其包含氨基酸序列SEQ ID NO:108，和LC-CDR3，其包含氨基酸序列SEQ ID NO:119。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 38, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 58, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 76; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 93, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 108, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:119. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:39，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:77；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 39, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 77; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:120. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:40，HC-CDR2，其包含氨基酸序列SEQ ID NO:59，和HC-CDR3，其包含氨基酸序列SEQ ID NO:78；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:94，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:121。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 40, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 59, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 78; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 94, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:121. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:41，HC-CDR2，其包含氨基酸序列SEQ ID NO:60，和HC-CDR3，其包含氨基酸序列SEQ ID NO:79；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 41, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 60, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 79; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:42，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 42, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:120. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:42，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 42, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:120. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:122。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 95, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:44，HC-CDR2，其包含氨基酸序列SEQ ID NO:62，和HC-CDR3，其包含氨基酸序列SEQ ID NO:82；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:96，LC-CDR2，其包含氨基酸序列SEQ ID NO:110，和LC-CDR3，其包含氨基酸序列SEQ ID NO:123。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 44, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 62, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 82; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 96, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 110, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:123. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:45，HC-CDR2，其包含氨基酸序列SEQ ID NO:63，和HC-CDR3，其包含氨基酸序列SEQ ID NO:83；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:97，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:124。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 45, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 63, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 83; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 97, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:124. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:46，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:98，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 46, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 98, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:47，HC-CDR2，其包含氨基酸序列SEQ ID NO:64，和HC-CDR3，其包含氨基酸序列SEQ ID NO:84；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:99，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:125。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 47, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 64, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 84; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 99, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:125. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:126。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:126. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:3，和HC-CDR3，其包含氨基酸序列SEQ ID NO:5；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:7，LC-CDR2，其包含氨基酸序列SEQ ID NO:9，和LC-CDR3，其包含氨基酸序列SEQ ID NO:11。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 5; and b) the light chain may Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence SEQ ID NO:9, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:11. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:4，和HC-CDR3，其包含氨基酸序列SEQ ID NO:6；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:8，LC-CDR2，其包含氨基酸序列SEQ ID NO:10，和LC-CDR3，其包含氨基酸序列SEQ ID NO:12。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23 组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 2, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 6; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 8, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 10, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:12. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:28，HC-CDR2，其包含氨基酸序列SEQ ID NO:48，和HC-CDR3，其包含氨基酸序列SEQ ID NO:65；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:85，LC-CDR2，其包含氨基酸序列SEQ ID NO:100，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 28, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 48, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 65; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:85, LC-CDR2, which includes the amino acid sequence SEQ ID NO:100, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:111. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:29，HC-CDR2，其包含氨基酸序列SEQ ID NO:49，和HC-CDR3，其包含氨基酸序列SEQ ID NO:66；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:86，LC-CDR2，其包含氨基酸序列SEQ ID NO:101，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 29, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 49, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 66; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:86, LC-CDR2, which includes the amino acid sequence SEQ ID NO:101, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:112. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:30，HC-CDR2，其包含氨基酸序列SEQ ID NO:50，和HC-CDR3，其包含氨基酸序列SEQ ID NO:67；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:87，LC-CDR2，其包含氨基酸序列SEQ ID NO:102，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 30, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 50, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 67; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 87, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 102, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:113. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:68；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 31, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 68; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:32，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:69；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 32, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 69; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:33，HC-CDR2，其包含氨基酸序列SEQ ID NO:52，和HC-CDR3，其包含氨基酸序列SEQ ID NO:70；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:89，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:115。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 33, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 52, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 70; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 89, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:115. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:34，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:71；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 34, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 71; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:35，HC-CDR2，其包含氨基酸序列SEQ ID NO:54，和HC-CDR3，其包含氨基酸序列SEQ ID NO:72；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:90，LC-CDR2，其包含氨基酸序列SEQ ID NO:105，和LC-CDR3，其包含氨基酸序列SEQ ID NO:116。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 35, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 54, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 72; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 90, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 105, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:116. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:36，HC-CDR2，其包含氨基酸序列SEQ ID NO:55，和HC-CDR3，其包含氨基酸序列SEQ ID NO:73；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 36, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 55, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 73; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 91, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:117. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:37，HC-CDR2，其包含氨基酸序列SEQ ID NO:56，和HC-CDR3，其包含氨基酸序列SEQ ID NO:74；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 37, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 56, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 74; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 91, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:117. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:57，和HC-CDR3，其包含氨基酸序列SEQ ID NO:75；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:92，LC-CDR2，其包含氨基酸序列SEQ ID NO:107，和LC-CDR3，其包含氨基酸序列SEQ ID NO:118。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 31, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 57, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 75; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 92, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 107, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:118. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:38，HC-CDR2，其包含氨基酸序列SEQ ID NO:58，和HC-CDR3，其包含氨基酸序列SEQ ID NO:76；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:93，LC-CDR2，其包含氨基酸序列SEQ ID NO:108，和LC-CDR3，其包含氨基酸序列SEQ ID NO:119。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 38, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 58, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 76; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 93, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 108, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:119. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:39，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:77；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 39, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 77; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:120. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:40，HC-CDR2，其包含氨基酸序列SEQ ID NO:59，和HC-CDR3，其包含氨基酸序列SEQ ID NO:78；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:94，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:121。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 40, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 59, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 78; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 94, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:121. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:41，HC-CDR2，其包含氨基酸序列SEQ ID NO:60，和HC-CDR3，其包含氨基酸序列SEQ ID NO:79；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 41, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 60, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 79; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 88, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:42，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 42, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:120. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:42，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 42, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:88, LC-CDR2, which includes the amino acid sequence SEQ ID NO:103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:120. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:122。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 43, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 81; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 95, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:44，HC-CDR2，其包含氨基酸序列SEQ ID NO:62，和HC-CDR3，其包含氨基酸序列SEQ ID NO:82；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:96，LC-CDR2，其包含氨基酸序列SEQ ID NO:110，和LC-CDR3，其包含氨基酸序列SEQ ID NO:123。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 44, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 62, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 82; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 96, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 110, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:123. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:45，HC-CDR2，其包含氨基酸序列SEQ ID NO:63，和HC-CDR3，其包含氨基酸序列SEQ ID NO:83；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:97，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:124。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 45, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 63, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 83; and b) the light chain can variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 97, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:124. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:46，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:98，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID  NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 46, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80; and b) the light chain can Variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 98, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence Sequence SEQ ID NO:114. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 NO:23 composition. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:47，HC-CDR2，其包含氨基酸序列SEQ ID NO:64，和HC-CDR3，其包含氨基酸序列SEQ ID NO:84；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:99，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:125。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 47, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 64, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 84; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 99, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:125. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:126。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising : HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81; and b) the light chain can Variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 95, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which includes the amino acid sequence Sequence SEQ ID NO:126. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组 成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 or a variant thereof, which has at least about 80% ( For example, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising SEQ ID NOs : The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21 The component and the light chain constant region comprise or consist of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG2恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG2是人IgG2。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG2 constant region is provided, wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 or a variant thereof, which has at least about 80% ( For example, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising SEQ ID NOs : The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG3恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG3是人IgG3。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG3 constant region is provided, wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 or a variant thereof, which has at least about 80% ( For example, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising SEQ ID NOs : The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 or a variant thereof, which has at least about 80% ( For example, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising SEQ ID NOs : The amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in any one of SEQ ID NOs: 18-20 and 150-171 (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:13-17、127-149中任一所示的氨基酸序 列，以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgGl constant region is provided, wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149 column, and a light chain variable domain ( VL ), the VL comprising the amino acid sequence shown in any one of SEQ ID NOs: 18-20, 150-171. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:13-17、127-149中任一所示的氨基酸序列，以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:18-20、150-171中任一所示的氨基酸序列。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: The amino acid sequence shown in any one of 13-17 and 127-149, and the light chain variable domain ( VL ), the VL comprising the amino acid sequence shown in any one of SEQ ID NOs: 18-20, 150-171 Amino acid sequence. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:13或其变体，所述变体与氨基酸序列SEQ ID NO:13具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:18或其变体，所述变体与氨基酸序列SEQ ID NO:18具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:13; and VL comprising the amino acid sequence SEQ ID NO:18 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:18 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:14或其变体，所述变体与氨基酸序列SEQ ID NO:14具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。 In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14; and VL , which comprises the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:15或其变体，所述变体与氨基酸序列SEQ ID NO:15具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:15; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:16或其变体，所述变体与氨基酸序列SEQ ID NO:16具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:17或其变体，所述变体与氨基酸序列SEQ ID NO:17具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:20或其变体，所述变体与氨基酸序列SEQ ID NO:20具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof, the variant V L has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 17; and VL comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 20 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含SEQ ID NO:127所示的氨基酸序列或其变体，所述变体与SEQ ID NO:127所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:150所示的氨基酸序列或其变体，所述变体与SEQ ID NO:150所示的氨基酸序列具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸 序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 127 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 127; and V L comprising the amino acid sequence set forth in SEQ ID NO: 150 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 150 has at least about 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of amino acids The sequence SEQ ID NO:21 consists of and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含SEQ ID NO:128所示的氨基酸序列或其变体，所述变体与SEQ ID NO:128所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:151所示的氨基酸序列或其变体，所述变体与SEQ ID NO:151所示的氨基酸序列具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 128; and V L comprising the amino acid sequence set forth in SEQ ID NO: 151 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 151 has at least about 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含SEQ ID NO:128所示的氨基酸序列或其变体，所述变体与SEQ ID NO:128所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:150所示的氨基酸序列或其变体，所述变体与SEQ ID NO:150所示的氨基酸序列具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 128; and V L comprising the amino acid sequence set forth in SEQ ID NO: 150 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 150 has at least about 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含SEQ ID NO:129所示的氨基酸序列或其变体，所述变体与SEQ ID NO:129所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:152所示的氨基酸序列或其变体，所述变体与SEQ ID NO:152所示的氨基酸序列具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。 In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 129 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 129; and V L comprising the amino acid sequence set forth in SEQ ID NO: 152 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 152 has at least about 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:153具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:130; and VL comprising the amino acid sequence SEQ ID NO:153 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:153. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:131或其变体，所述变体与氨基酸序列SEQ ID NO:131具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:154或其变体，所述变体与氨基酸序列SEQ ID NO:154具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:131; and VL comprising the amino acid sequence SEQ ID NO:154 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:154. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:132或其变体，所述变体与氨基酸序列SEQ ID NO:132具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:155或其变体，所述变体与氨基酸序列SEQ ID NO:155具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:132; and VL comprising the amino acid sequence SEQ ID NO:155 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:155. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:133或其变体，所述变体与氨基酸序列SEQ ID NO:133具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:156或其变体，所述变体与氨基酸序列SEQ ID NO:156具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及 轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:133; and VL comprising the amino acid sequence SEQ ID NO:156 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:156. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21 and The light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:134或其变体，所述变体与氨基酸序列SEQ ID NO:134具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:157或其变体，所述变体与氨基酸序列SEQ ID NO:157具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:134; and VL comprising the amino acid sequence SEQ ID NO:157 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:157. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:135或其变体，所述变体与氨基酸序列SEQ ID NO:135具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:158或其变体，所述变体与氨基酸序列SEQ ID NO:158具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:135; and VL comprising the amino acid sequence SEQ ID NO:158 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:158. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:136; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒 定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:137; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant The defined region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:138或其变体，所述变体与氨基酸序列SEQ ID NO:138具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:160或其变体，所述变体与氨基酸序列SEQ ID NO:160具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:138; and VL comprising the amino acid sequence SEQ ID NO:160 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:160. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:139或其变体，所述变体与氨基酸序列SEQ ID NO:139具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:161或其变体，所述变体与氨基酸序列SEQ ID NO:161具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:139; and VL comprising the amino acid sequence SEQ ID NO:161 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:161 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:140或其变体，所述变体与氨基酸序列SEQ ID NO:140具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:162或其变体，所述变体与氨基酸序列SEQ ID NO:162具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:140; and VL comprising the amino acid sequence SEQ ID NO:162 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:162 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:141或其变体，所述变体与氨基酸序列SEQ ID NO:141具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:163或其变体，所述变体与氨 基酸序列SEQ ID NO:163具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 141 or a variant thereof, the variant V L has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 141; and VL comprising the amino acid sequence SEQ ID NO: 163 or a variant thereof, which variant is identical to the amino acid sequence SEQ ID NO: 141. The amino acid sequence SEQ ID NO: 163 has at least about 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:142或其变体，所述变体与氨基酸序列SEQ ID NO:142具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:164或其变体，所述变体与氨基酸序列SEQ ID NO:164具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:142; and VL comprising the amino acid sequence SEQ ID NO:164 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:164. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:143或其变体，所述变体与氨基酸序列SEQ ID NO:143具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:165或其变体，所述变体与氨基酸序列SEQ ID NO:165具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:143; and VL comprising the amino acid sequence SEQ ID NO:165 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:165. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:144或其变体，所述变体与氨基酸序列SEQ ID NO:144具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:166或其变体，所述变体与氨基酸序列SEQ ID NO:166具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。 In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:144; and VL comprising the amino acid sequence SEQ ID NO:166 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:166 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:145或其变体，所述变体与氨基酸序列SEQ ID NO:145具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:167或其变体，所述变体与氨基酸序列SEQ ID NO:167具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:145; and VL comprising the amino acid sequence SEQ ID NO:167 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:167. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:168或其变体，所述变体与氨基酸序列SEQ ID NO:168具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:146; and VL comprising the amino acid sequence SEQ ID NO:168 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:168 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:169或其变体，所述变体与氨基酸序列SEQ ID NO:169具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:147; and VL comprising the amino acid sequence SEQ ID NO:169 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:169 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:170或其变体，所述变体与氨基酸序列SEQ ID NO:170具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及 轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:148; and VL comprising the amino acid sequence SEQ ID NO:170 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:170. Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21 and The light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG1恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:171或其变体，所述变体与氨基酸序列SEQ ID NO:171具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG1 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:149; and VL comprising the amino acid sequence SEQ ID NO:171 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:171 Approximately 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:13或其变体，所述变体与氨基酸序列SEQ ID NO:13具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:18或其变体，所述变体与氨基酸序列SEQ ID NO:18具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:13; and VL comprising the amino acid sequence SEQ ID NO:18 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:18 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:14或其变体，所述变体与氨基酸序列SEQ ID NO:14具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:15或其变体，所述变体与氨基酸序列SEQ ID NO:15具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区 包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:15; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region Comprising or consisting of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:16或其变体，所述变体与氨基酸序列SEQ ID NO:16具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16; and VL comprising the amino acid sequence SEQ ID NO:19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:17或其变体，所述变体与氨基酸序列SEQ ID NO:17具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:20或其变体，所述变体与氨基酸序列SEQ ID NO:20具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof, the variant V L has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 17; and VL comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 20 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含SEQ ID NO:127所示的氨基酸序列或其变体，所述变体与SEQ ID NO:127所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:150所示的氨基酸序列或其变体，所述变体与SEQ ID NO:150所示的氨基酸序列具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 127 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 127; and V L comprising the amino acid sequence set forth in SEQ ID NO: 150 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 150 has at least about 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含SEQ ID NO:128所示的氨基酸序列或其变体，所述变体与SEQ ID NO:128所示的 氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:151所示的氨基酸序列或其变体，所述变体与SEQ ID NO:151所示的氨基酸序列具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, Said variant is identical to that shown in SEQ ID NO:128 The amino acid sequence has at least about 80% sequence identity; and V L includes the amino acid sequence set forth in SEQ ID NO: 151 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 151 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含SEQ ID NO:128所示的氨基酸序列或其变体，所述变体与SEQ ID NO:128所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:150所示的氨基酸序列或其变体，所述变体与SEQ ID NO:150所示的氨基酸序列具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 128; and V L comprising the amino acid sequence set forth in SEQ ID NO: 150 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 150 has at least about 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含SEQ ID NO:129所示的氨基酸序列或其变体，所述变体与SEQ ID NO:129所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:152所示的氨基酸序列或其变体，所述变体与SEQ ID NO:152所示的氨基酸序列具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 129 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 129; and V L comprising the amino acid sequence set forth in SEQ ID NO: 152 or a variant thereof, the variant having The amino acid sequence shown in SEQ ID NO: 152 has at least about 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:153具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列 SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:130; and VL comprising the amino acid sequence SEQ ID NO:153 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:153. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence Composed of SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:131或其变体，所述变体与氨基酸序列SEQ ID NO:131具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:154或其变体，所述变体与氨基酸序列SEQ ID NO:154具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:131; and VL comprising the amino acid sequence SEQ ID NO:154 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:154. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:132或其变体，所述变体与氨基酸序列SEQ ID NO:132具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:155或其变体，所述变体与氨基酸序列SEQ ID NO:155具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:132; and VL comprising the amino acid sequence SEQ ID NO:155 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:155. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:133或其变体，所述变体与氨基酸序列SEQ ID NO:133具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:156或其变体，所述变体与氨基酸序列SEQ ID NO:156具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:133; and VL comprising the amino acid sequence SEQ ID NO:156 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:156. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:134或其变体，所述变体与氨基酸序列SEQ ID NO:134具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:157或其变体，所述变体与氨基酸序列SEQ ID NO:157具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。 在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:134; and VL comprising the amino acid sequence SEQ ID NO:157 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:157. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:135或其变体，所述变体与氨基酸序列SEQ ID NO:135具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:158或其变体，所述变体与氨基酸序列SEQ ID NO:158具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:135; and VL comprising the amino acid sequence SEQ ID NO:158 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:158. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:136; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:137; and VL comprising the amino acid sequence SEQ ID NO:159 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:138或其变体，所述变体与氨基酸序列SEQ ID NO:138具 有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:160或其变体，所述变体与氨基酸序列SEQ ID NO:160具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof, the variant Body and amino acid sequence SEQ ID NO: 138 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 160 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 160. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:139或其变体，所述变体与氨基酸序列SEQ ID NO:139具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:161或其变体，所述变体与氨基酸序列SEQ ID NO:161具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:139; and VL comprising the amino acid sequence SEQ ID NO:161 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:161 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:140或其变体，所述变体与氨基酸序列SEQ ID NO:140具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:162或其变体，所述变体与氨基酸序列SEQ ID NO:162具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:140; and VL comprising the amino acid sequence SEQ ID NO:162 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:162 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:141或其变体，所述变体与氨基酸序列SEQ ID NO:141具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:163或其变体，所述变体与氨基酸序列SEQ ID NO:163具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。 In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 141 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:141; and VL comprising the amino acid sequence SEQ ID NO:163 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:163. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:142或其变体，所述变体与氨基酸序列SEQ ID NO:142具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:164或其变体，所述变体与氨基酸序列SEQ ID NO:164具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:142; and VL comprising the amino acid sequence SEQ ID NO:164 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:164. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:143或其变体，所述变体与氨基酸序列SEQ ID NO:143具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:165或其变体，所述变体与氨基酸序列SEQ ID NO:165具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:143; and VL comprising the amino acid sequence SEQ ID NO:165 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:165. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:144或其变体，所述变体与氨基酸序列SEQ ID NO:144具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:166或其变体，所述变体与氨基酸序列SEQ ID NO:166具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:144; and VL comprising the amino acid sequence SEQ ID NO:166 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:166 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:145或其变体，所述变体与氨基酸序列SEQ ID NO:145具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:167或其变体，所述变体与氨基酸序列SEQ ID NO:167具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及 轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:145; and VL comprising the amino acid sequence SEQ ID NO:167 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:167. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22 and The light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:168或其变体，所述变体与氨基酸序列SEQ ID NO:168具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:146; and VL comprising the amino acid sequence SEQ ID NO:168 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:168. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:169或其变体，所述变体与氨基酸序列SEQ ID NO:169具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:147; and VL comprising the amino acid sequence SEQ ID NO:169 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:169 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:170或其变体，所述变体与氨基酸序列SEQ ID NO:170具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:148; and VL comprising the amino acid sequence SEQ ID NO:170 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:170. Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，提供一种包含IgG4恒定区的全长抗Nogo-A抗体，其中抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:171或其变体，所述变体与氨基酸序列SEQ ID NO:171具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒 定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, a full-length anti-Nogo-A antibody comprising an IgG4 constant region is provided, wherein the anti-Nogo-A antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof, the variant VL has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:149; and VL comprising the amino acid sequence SEQ ID NO:171 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:171 Approximately 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant The defined region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
结合亲和力binding affinity
结合亲和力采用Kd、Koff、Kon或Ka表示。如本文所用，术语Koff是指抗体从抗原/抗体复合物中解离的速率常数，通过动力学选择装置测定。术语Kon是指抗体与抗原结合形成抗原/抗体复合物的结合速率常数。本文所用的平衡解离常数Kd是指特定抗体抗原相互作用时的解离常数，是指在抗体分子溶液中，抗原占据所有抗体结合位点的一半并且达到平衡时所需的抗原浓度，等于Koff/Kon。Kd的测定假设所有的结合分子均在溶液中。抗体与细胞壁连接的情况，例如在酵母表达系统中，相应的平衡解离速率常数采用EC50来表示，其是Kd的一个良好的近似值。亲和结合常数Ka是解离常数Kd的倒数。Binding affinity is expressed as Kd, Koff, Kon or Ka. As used herein, the term Koff refers to the rate constant for the dissociation of an antibody from an antigen/antibody complex, as measured by a kinetic selection device. The term Kon refers to the binding rate constant at which an antibody binds to an antigen to form an antigen/antibody complex. The equilibrium dissociation constant Kd used in this article refers to the dissociation constant when a specific antibody-antigen interacts. It refers to the antigen concentration required when the antigen occupies half of all antibody binding sites in the antibody molecule solution and reaches equilibrium, which is equal to Koff /Kon. The determination of Kd assumes that all bound molecules are in solution. In the case of antibodies bound to the cell wall, such as in yeast expression systems, the corresponding equilibrium dissociation rate constant is expressed as EC 50 , which is a good approximation of Kd. The affinity binding constant Ka is the reciprocal of the dissociation constant Kd.
解离常数(Kd)可以作为反应抗体部分与抗原亲和力的指标。例如，可以通过Scatchard方法使用标记有各种标记物的抗体，和Biacore仪器(由Amersham Biosciences制造)进行简单分析，根据用户手册或附带试剂盒，通过表面等离子体共振来分析生物分子间的相互作用。使用这些方法得到的Kd值，用单位M来表示。与靶标特异性结合的抗体可能具有，例如≤10-7M、≤10-8M、≤10-9M、≤10-10M、≤10-11M、≤10-12M或≤10-13M的Kd值。The dissociation constant (Kd) can be used as an indicator of the affinity of the reactive antibody moiety to the antigen. For example, a simple analysis can be performed by the Scatchard method using antibodies labeled with various markers and a Biacore instrument (manufactured by Amersham Biosciences) to analyze interactions between biomolecules by surface plasmon resonance according to the user manual or the included kit. . The Kd value obtained using these methods is expressed in the unit M. Antibodies that specifically bind a target may have, for example, ≤10 -7 M, ≤10 -8 M, ≤10 -9 M, ≤10 -10 M, ≤10 -11 M , ≤10 -12 M, or ≤10 - Kd value of 13 M.
抗体的结合特异性可以通过本领域已知的方法进行实验测定。这些方法包括，但不限于Western blots、ELISA-、RIA-、ECL-、IRMA-、EIA-、BIAcore测试和肽扫描等。The binding specificity of an antibody can be determined experimentally by methods known in the art. These methods include, but are not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore testing, and peptide scanning.
在一些实施例中，所述抗Nogo-A抗体特异性结合Nogo-A靶标，其Kd值为10-7M至10-13M(例如10-7M至10-13M、10-8M至10-13M、10-9M至10-13M或10-10M至10-12M)。因此，在一些实施例中，抗Nogo-A抗体与Nogo-A之间结合的Kd值为10-7M至10-13M、1×10-7M至5×10- 13M、10-7M至10-12M、10-7M至10-11M、10-7M至10-10M、10-7M至10-9M、10-8M至10- 13M、1×10-8M至5×10-13M、10-8M至10-12M、10-8M至10-11M、10-8M至10-10M、10-8M至10-9M、5×10-9M至1×10-13M、5×10-9M至1×10-12M、5×10-9M至1×10-11M、5×10-9M至1×10- 10M、10-9M至10-13M、10-9M至10-12M、10-9M至10-11M、10-9M至10-10M、5×10-10M至1×10-13M、5×10-10M至1×10-12M、5×10-10M至1×10-11M、10-10M至10-13M、1×10-10M至5×10- 13M、1×10-10M至1×10-12M、1×10-10M至5×10-12M、1×10-10M至1×10-11M、10-11M至10- 13M、1×10-11M至5×10-13M、10-11M至10-12M、10-12M至10-13M。在一些实施例中，抗Nogo-A抗体与Nogo-A之间结合的Kd值为10-7M至10-13M。In some embodiments, the anti-Nogo-A antibody specifically binds to the Nogo-A target with a Kd value of 10 -7 M to 10 -13 M (e.g., 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M). Therefore, in some embodiments, the Kd value of the binding between the anti-Nogo-A antibody and Nogo-A is 10 -7 M to 10 -13 M, 1×10 -7 M to 5×10 - 13 M, 10 - 7 M to 10 -12 M, 10 -7 M to 10 -11 M, 10 -7 M to 10 -10 M, 10 -7 M to 10 -9 M, 10 -8 M to 10 - 13 M, 1× 10 -8 M to 5×10 -13 M, 10 -8 M to 10 -12 M, 10 -8 M to 10 -11 M, 10 -8 M to 10 -10 M, 10 -8 M to 10 -9 M, 5×10 -9 M to 1×10 -13 M, 5×10 -9 M to 1×10 -12 M, 5×10 -9 M to 1×10 -11 M, 5×10 -9 M to 1×10 - 10 M, 10 -9 M to 10 -13 M, 10 -9 M to 10 -12 M, 10 -9 M to 10 -11 M, 10 -9 M to 10 -10 M, 5× 10 -10 M to 1×10 -13 M, 5×10 -10 M to 1×10 -12 M, 5×10 -10 M to 1×10 -11 M, 10 -10 M to 10 -13 M, 1×10 -10 M to 5×10 - 13 M, 1×10 -10 M to 1×10 -12 M, 1×10 -10 M to 5×10 -12 M, 1×10 -10 M to 1 ×10 -11 M, 10 -11 M to 10 - 13 M, 1×10 -11 M to 5×10 -13 M, 10 -11 M to 10 -12 M, 10 -12 M to 10 -13 M. In some embodiments, the Kd value for binding between the anti-Nogo-A antibody and Nogo-A is 10 -7 M to 10 -13 M.
在一些实施例中，抗Nogo-A抗体与非靶标之间结合的Kd值高于抗Nogo-A抗体与靶标的Kd值，并且本文中引用的一些实施例中，抗Nogo-A抗体与靶标(例如，Nogo-A)的结合亲和力高于抗Nogo-A抗体与非靶标的结合亲和力。一些实施例中，非靶标是指非Nogo-A的抗原。在一些 实施例中，抗Nogo-A抗体(针对Nogo-A)与非Nogo-A靶标结合的Kd值间至少相差10倍，例如10-100倍、100-1000倍、103-104倍、104-105倍、105-106倍、106-107倍、107-108倍、108-109倍、109-1010倍、1010-1011倍、1011-1012倍。In some embodiments, the Kd value for binding between the anti-Nogo-A antibody and the non-target is higher than the Kd value for the anti-Nogo-A antibody and the target, and in some embodiments cited herein, the Kd value for the anti-Nogo-A antibody binding to the target (e.g., Nogo-A) has a higher binding affinity than the anti-Nogo-A antibody to the non-target. In some embodiments, non-target refers to an antigen other than Nogo-A. in some In embodiments, the Kd value of the anti-Nogo-A antibody (for Nogo-A) binding to the non-Nogo-A target is at least 10 times different, such as 10-100 times, 100-1000 times, 10 3 -10 4 times, 10 4 -10 5 times, 10 5 -10 6 times, 10 6 -10 7 times, 10 7 -10 8 times, 10 8 -10 9 times, 10 9 -10 10 times, 10 10 -10 11 times, 10 11 -10 12 times.
在一些实施例中，所述抗Nogo-A抗体与非靶标结合的Kd值为10-1M至10-6M(例如10-1M至10-6M、10-1M至10-5M、10-2M至10-4M)。在一些实施例中，所述非靶标是指非Nogo-A的抗原。因此，在一些实施例中，抗Nogo-A抗体与非Nogo-A靶标之间结合的Kd值为10-1M至10- 6M、1×10-1M至5×10-6M、10-1M至10-5M、1×10-1M至5×10-5M、10-1M至10-4M、1×10-1M至5×10-4M、10-1M至10-3M、1×10-1M至5×10-3M、10-1M至10-2M、10-2M至10-6M、1×10-2M至5×10-6M、10-2M至10-5M、1×10-2M至5×10-5M、10-2M至10-4M、1×10-2M至5×10-4M、10-2M至10-3M、10-3M至10-6M、1×10-3M至5×10-6M、10-3M至10-5M、1×10-3M至5×10-5M、10-3M至10-4M、10-4M至10-6M、1×10-4M至5×10-6M、10-4M至10-5M、10-5M至10-6M。In some embodiments, the anti-Nogo-A antibody binds to a non-target with a Kd value of 10 -1 M to 10 -6 M (e.g., 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M). In some embodiments, the non-target refers to an antigen other than Nogo-A. Therefore, in some embodiments, the Kd value for binding between the anti-Nogo-A antibody and the non-Nogo-A target is 10 -1 M to 10 -6 M , 1×10 -1 M to 5×10 -6 M, 10 -1 M to 10 -5 M, 1×10 -1 M to 5×10 -5 M, 10 -1 M to 10 -4 M, 1×10 -1 M to 5×10 -4 M, 10 - 1 M to 10 -3 M, 1×10 -1 M to 5×10 -3 M, 10 -1 M to 10 -2 M, 10 -2 M to 10 -6 M, 1× 10 -2 M to 5 ×10 -6 M, 10 -2 M to 10 -5 M, 1×10 -2 M to 5×10 -5 M, 10 -2 M to 10 -4 M, 1×10 -2 M to 5×10 -4 M, 10 -2 M to 10 -3 M, 10 -3 M to 10 -6 M, 1×10 -3 M to 5×10 -6 M, 10 -3 M to 10 -5 M, 1× 10 -3 M to 5×10 -5 M, 10 -3 M to 10 -4 M, 10 -4 M to 10 -6 M, 1×10 -4 M to 5× 10 -6 M , 10 -4 M to 10 -5 M, 10 -5 M to 10 -6 M.
在一些实施例中，当提及抗Nogo-A抗体以高结合亲和力特异性地识别Nogo-A靶标，并以低结合亲和力结合非靶标时，所述抗Nogo-A抗体与Nogo-A靶标结合的Kd值为10-7M至10-13M(例如10-7M至10-13M、10-8M至10-13M、10-9M至10-13M、10-10M至10-12M)，并且与非靶标结合的Kd值为10-1M至10-6M(例如10-1M至10-6M、10-1M至10-5M、10-2M至10-4M)。In some embodiments, an anti-Nogo-A antibody binds to a Nogo-A target when it is referred to that an anti-Nogo-A antibody specifically recognizes a Nogo-A target with high binding affinity and binds to a non-target with low binding affinity. The Kd value is 10 -7 M to 10 -13 M (such as 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M, 10 -10 M to 10 -12 M), and the Kd value for binding to non-target is 10 -1 M to 10 -6 M (for example, 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).
在一些实施例中，当提及抗Nogo-A抗体特异性地识别Nogo-A时，将所述抗Nogo-A抗体的结合亲和力与对照抗Nogo-A抗体(例如ATI-355)的结合亲和力进行比较。在一些实施例中，对照抗Nogo-A抗体与Nogo-A之间结合的Kd值可以是本申请所述的抗Nogo-A抗体与Nogo-A之间结合的Kd值的至少2倍，例如2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、10-100倍、100-1000倍、103-104倍。In some embodiments, when an anti-Nogo-A antibody is referred to as specifically recognizing Nogo-A, the binding affinity of the anti-Nogo-A antibody is compared to the binding affinity of a control anti-Nogo-A antibody (e.g., ATI-355). Compare. In some embodiments, the Kd value for the binding between the control anti-Nogo-A antibody and Nogo-A can be at least 2 times the Kd value for the binding between the anti-Nogo-A antibody and Nogo-A described herein, for example 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 10-100 times, 100-1000 times, 10 3 -10 4 times.
核酸nucleic acid
编码抗Nogo-A抗体的核酸分子也被考虑在内。在一些实施例中，提供一种(或一组)编码全长抗Nogo-A抗体的核酸，包括本文所述的任一种全长抗Nogo-A抗体。在一些实施例中，本文所述的抗Nogo-A抗体的核酸(或一组核酸)还可以包括编码多肽标签的核酸序列(例如蛋白纯化标签，His标签、HA标签)。Nucleic acid molecules encoding anti-Nogo-A antibodies are also considered. In some embodiments, a nucleic acid (or set of) nucleic acids encoding a full-length anti-Nogo-A antibody is provided, including any of the full-length anti-Nogo-A antibodies described herein. In some embodiments, the nucleic acid (or set of nucleic acids) of the anti-Nogo-A antibody described herein may also include a nucleic acid sequence encoding a polypeptide tag (eg, protein purification tag, His tag, HA tag).
同时本文还考虑了包含抗Nogo-A抗体的分离的宿主细胞，编码抗Nogo-A抗体多肽组分的分离的核酸，或者包含编码本文所述的抗Nogo-A抗体多肽组分的核酸的载体。Also contemplated herein are isolated host cells comprising an anti-Nogo-A antibody, an isolated nucleic acid encoding an anti-Nogo-A antibody polypeptide component, or a vector comprising a nucleic acid encoding an anti-Nogo-A antibody polypeptide component described herein. .
本申请还包括这些核酸序列的变体。例如，变体包括至少在中等严格杂交条件下与编码本申请的抗Nogo-A抗体的核酸序列杂交的核苷酸序列。Variants of these nucleic acid sequences are also encompassed by the present application. For example, variants include nucleotide sequences that hybridize under at least moderately stringent hybridization conditions to a nucleic acid sequence encoding an anti-Nogo-A antibody of the present application.
本申请同时还提供可将本申请中核酸序列插入到其中的载体。The present application also provides a vector into which the nucleic acid sequence of the present application can be inserted.
简言之，将编码抗Nogo-A抗体的天然或合成的核酸插入到合适的表达载体中，使得核酸可操作性的连接到5’和3’端调控元件，例如包括启动子(例如淋巴细胞特异性启动子)和3’非翻译区(UTR)，可表达抗Nogo-A抗体(例如全长的抗Nogo-A抗体)。所述载体可适用于在真核宿主 细胞中复制和整合。典型的克隆与表达载体包含调控目标核酸序列的表达的转录和翻译终止子、起始序列和启动子。Briefly, the natural or synthetic nucleic acid encoding the anti-Nogo-A antibody is inserted into a suitable expression vector such that the nucleic acid is operably linked to the 5' and 3' end regulatory elements, such as a promoter (e.g., lymphocyte Specific promoter) and 3' untranslated region (UTR), can express anti-Nogo-A antibodies (such as full-length anti-Nogo-A antibodies). The vector is suitable for use in eukaryotic hosts Replication and integration in cells. Typical cloning and expression vectors contain transcriptional and translational terminators, initiation sequences, and promoters that regulate expression of the nucleic acid sequence of interest.
本申请所述的核酸也可以通过使用标准的基因递送方案，用于核酸免疫和基因治疗。核酸递送方法是本领域已知的。例如参见U.S.Pat.Nos.5,399,346、5,580,859、5,589,466，通过引用其全部内容并入本文。在一些实施例中，本申请还提供基因治疗载体。The nucleic acids described herein can also be used for nucleic acid immunization and gene therapy using standard gene delivery protocols. Nucleic acid delivery methods are known in the art. See, for example, U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, the entire contents of which are incorporated herein by reference. In some embodiments, the application also provides gene therapy vectors.
可以将核酸克隆到许多类型的载体中。例如，可以将核酸克隆到载体中，所述载体包括，但不限于，质粒、噬菌粒、噬菌体衍生物、动物病毒和柯斯质粒。特别感兴趣的载体包括表达载体、复制载体、探针生成载体和测序载体。Nucleic acids can be cloned into many types of vectors. For example, nucleic acids can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors and sequencing vectors.
此外，表达载体可以以病毒载体的形式提供给细胞。病毒载体技术是本领域熟知的，并且描述于例如Green and Sambrook(2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York)，以及其它病毒学或分子生物学手册中。可用作载体的病毒包括，但不限于，逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。通常，合适的载体包括一个在至少一种生物体中起作用的复制起点、启动子序列、方便的限制性内切酶位点以及一个或多个选择标记物(参见例如，WO 01/96584；WO 01/29058；和U.S.Pat.No.6,326,193)。Additionally, expression vectors can be provided to cells in the form of viral vectors. Viral vector technology is well known in the art and is described, for example, in Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and other virology or molecular biology manuals. Viruses that can be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses. Typically, suitable vectors include an origin of replication functional in at least one organism, promoter sequences, convenient restriction enzyme sites, and one or more selectable markers (see, e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193).
已经开发了许多基于病毒的系统，用于将基因转移到哺乳动物细胞中。例如，逆转录病毒为基因递送系统提供了便利的平台。可以应用本领域已知的技术，将选择的基因插入载体中并包装在逆转录病毒颗粒中。然后分离重组病毒，在体内或体外递送至受试者的细胞中。许多逆转录病毒系统在本领域中是已知的。在一些实施例中，使用腺病毒载体。许多腺病毒载体在本领域中是已知的。在一些实施例中，使用慢病毒载体。衍生自逆转录病毒的载体，例如慢病毒，是实现长期基因转移的合适工具，因为它们使得转基因长期稳定的整合以及在子代细胞中繁殖。慢病毒载体相对于衍生自肿瘤的逆转录病毒例如小鼠白血病病毒具有额外的优势，因为它们可以转导非分裂细胞，例如肝细胞。同时，其还具有低免疫原性的额外优势。A number of virus-based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. The selected genes can be inserted into vectors and packaged in retroviral particles using techniques known in the art. The recombinant virus is then isolated and delivered to the subject's cells in vivo or in vitro. Many retroviral systems are known in the art. In some embodiments, adenoviral vectors are used. Many adenoviral vectors are known in the art. In some embodiments, lentiviral vectors are used. Vectors derived from retroviruses, such as lentiviruses, are suitable tools for long-term gene transfer because they enable long-term stable integration of the transgene and propagation in progeny cells. Lentiviral vectors have an additional advantage over tumor-derived retroviruses such as murine leukemia virus in that they can transduce non-dividing cells such as hepatocytes. At the same time, it has the additional advantage of low immunogenicity.
其它的启动子元件，例如，增强子，调控转录起始频率。通常它们位于起始位点上游30-110bp处，虽然最近发现很多启动子也包含起始位点下游的功能元件。启动子元件之间的间隔通常是灵活的，所以当元件彼此之间位置互换或移动时仍保持启动子的功能。在胸苷激酶(tk)启动子中，启动子元件之间的间隔增加到50bp活性才会开始下降。Other promoter elements, such as enhancers, regulate the frequency of transcription initiation. Typically they are located 30-110 bp upstream of the start site, although recently many promoters have been found to also contain functional elements downstream of the start site. The spacing between promoter elements is usually flexible, so that promoter function is maintained when elements are interchanged or moved with each other. In the thymidine kinase (tk) promoter, activity does not begin to decrease until the spacing between promoter elements increases to 50 bp.
合适启动子的一个示例是即时早期巨细胞病毒(CMV)启动子序列。该启动子序列是一个很强的组成型启动子序列，可以驱动任何与其可操作性连接的多核苷酸序列高水平表达。合适启动子的另一个示例是延伸因子1α(EF-1α)启动子。然而，也可以使用其它组成型启动子，包括但不限于猿猴病毒40(SV40)早期启动子、小鼠乳腺肿瘤病毒(MMTV)、人免病缺陷病毒长末端重复序列(HIV-LTR)启动子、MoMuLV启动子、禽类白血病病毒启动子、Epstein-Barr病毒即刻早期启动子、劳斯氏肉瘤病毒启动子以及人类基因启动子，例如包括但不限于肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子。此外，不应将本申请局限在仅使用组成型启动子，诱导型启动子也是本申请考虑的部分。诱导型启动子的使用提供了一种分子开关，当需要 这种表达时，能启动其与之可操作性连接的多核苷酸序列表达，当不需要时，则关闭表达。诱导型启动子包含，但不局限于，金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。An example of a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence that can drive high-level expression of any polynucleotide sequence operably linked to it. Another example of a suitable promoter is the elongation factor 1α (EF-1α) promoter. However, other constitutive promoters may also be used, including, but not limited to, simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter , MoMuLV promoter, avian leukemia virus promoter, Epstein-Barr virus immediate early promoter, Rous sarcoma virus promoter and human gene promoters, such as but not limited to actin promoter, myosin promoter, Hemoglobin promoter and creatine kinase promoter. Furthermore, this application should not be limited to the use of only constitutive promoters, inducible promoters are also considered as part of this application. The use of inducible promoters provides a molecular switch when needed This expression enables the expression of the polynucleotide sequence to which it is operably linked, and turns off the expression when it is not needed. Inducible promoters include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.
在一些实施例中，抗Nogo-A抗体的表达是可诱导的。在一些实施例中，编码抗Nogo-A抗体的核酸序列可操作的连接到诱导型启动子上，包括本文所述的任一诱导型启动子。In some embodiments, expression of anti-Nogo-A antibodies is inducible. In some embodiments, a nucleic acid sequence encoding an anti-Nogo-A antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.
诱导型启动子inducible promoter
诱导型启动子的使用提供了一种分子开关，当需要表达时，可启动与之可操作性连接的多核苷酸序列表达，而在不需要表达时，则关闭表达。真核细胞中适用的示例性诱导型启动子包括，但不限于，激素调节元件(例如，参见Mader,S.and White,J.H.(1993)Proc.Natl.Acad.Sci.USA 90:5603-5607)、合成配体调节元件(参见Spencer,D.M.et al(1993)Science 262:1019-1024)以及电离辐射调控元件(参见Manome,Y.et al.(1993)Biochemistry 32:10607-10613；Datta,R.et al.(1992)Proc.Natl.Acad.Sci.USA 89:1014-10153)。其它适用于体内或体外哺乳动物系统的示例性诱导型启动子参见Gingrich et al.(1998)Annual Rev.Neurosci 21:377-405。在一些实施例中，用于表达抗Nogo-A抗体的诱导型启动子系统为Tet系统。在一些实施例中，用于表达抗Nogo-A抗体的诱导型启动子系统为大肠杆菌lac抑制系统。The use of an inducible promoter provides a molecular switch that turns on the expression of a polynucleotide sequence operably linked to it when expression is desired, and turns off expression when expression is not needed. Exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone regulatory elements (see, e.g., Mader, S. and White, J.H. (1993) Proc. Natl. Acad. Sci. USA 90:5603-5607 ), synthetic ligand regulatory elements (see Spencer, D.M. et al (1993) Science 262:1019-1024) and ionizing radiation regulatory elements (see Manome, Y. et al. (1993) Biochemistry 32:10607-10613; Datta, R. et al. (1992) Proc. Natl. Acad. Sci. USA 89:1014-10153). Other exemplary inducible promoters suitable for use in mammalian systems in vivo or in vitro are described in Gingrich et al. (1998) Annual Rev. Neurosci 21:377-405. In some embodiments, the inducible promoter system used to express anti-Nogo-A antibodies is the Tet system. In some embodiments, the inducible promoter system used to express anti-Nogo-A antibodies is an E. coli lac repressor system.
本申请所采用的一个示例性诱导型启动子系统为Tet系统。该系统是基于Gossen等(1993)描述的Tet系统。在一个示例性实施例中，目标多核苷酸由包含一个或多个Tet操纵子(TetO)位点的启动子控制。在非激活状态，Tet阻遏物(TetR)与TetO位点结合并抑制启动子的转录。在激活状态，例如，在存在诱导剂如四环素(Tc)、无水四环素、多西环素(Dox)或其活性类似物的情况下，诱导剂会使TetR从TetO上释放，从而导致转录发生。多西环素是四环素抗生素家族中的一员，其化学名为1-二甲氨基-2,4a,5,7-五羟基-11-甲基-4,6-二氧基-1,4a,11,11a,12,12a-六氢四烯-3-甲酰胺。An exemplary inducible promoter system used in this application is the Tet system. This system is based on the Tet system described by Gossen et al. (1993). In an exemplary embodiment, the target polynucleotide is controlled by a promoter containing one or more Tet operator (TetO) sites. In the inactive state, Tet repressor (TetR) binds to the TetO site and inhibits transcription from the promoter. In the activated state, for example, in the presence of inducers such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox) or their active analogs, the inducer causes TetR to be released from TetO, resulting in transcription. . Doxycycline is a member of the tetracycline antibiotic family, its chemical name is 1-dimethylamino-2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxy-1,4a ,11,11a,12,12a-hexahydrotetraene-3-carboxamide.
在一个实施例中，TetR经密码子优化适用于在哺乳动物细胞中表达，例如小鼠或人类细胞。由于遗传密码的简并性，大多数氨基酸由不止一个密码子编码，从而使得给定核酸的序列具有大量的变体，而其编码的氨基酸序列没有任何改变。然而，许多生物体在密码子使用方面存在差异，也称为“密码子偏好”(即，给定氨基酸使用特定密码子的偏好)。密码子偏好通常与特定密码子的优势tRNA种类的存在有关，反过来又提高了mRNA翻译的效率。因此可以通过密码子优化来定制源自特定物种的编码序列(例如，原核生物)，以提高其在不同物种(例如，真核生物)中的表达。In one embodiment, TetR is codon-optimized for expression in mammalian cells, such as mouse or human cells. Due to the degeneracy of the genetic code, most amino acids are encoded by more than one codon, resulting in a large number of variants in the sequence of a given nucleic acid without any change in the sequence of its encoded amino acid. However, many organisms have differences in codon usage, also known as "codon preference" (i.e., the preference for a given amino acid to use a specific codon). Codon preference is often associated with the presence of dominant tRNA species for specific codons, which in turn increases the efficiency of mRNA translation. Coding sequences derived from a specific species (e.g., prokaryotes) can thus be tailored through codon optimization to enhance their expression in different species (e.g., eukaryotes).
Tet系统的其它具体变体，包括以下的“Tet-Off”和“Tet-On”系统。在Tet-off系统中，转录在Tc或Dox存在下是失活的。在该系统中，由TetR与单纯疱疹病毒VP16强转录激活结构域融合组成的四环素调控的转录激活蛋白(tTA)，在四环素反应启动子元件(TRE)转录控制下调控靶核酸的表达。TRE元件由TetO序列串联与启动子(通常是来源于人巨细胞病毒即刻早期启动子的最小 启动子序列)融合组成。在不存在Tc或Dox的情况下，tTA结合TRE并激活靶基因的转录。在存在Tc或Dox的情况下，tTA不能结合TRE，靶基因不能表达。Other specific variations of the Tet system include the "Tet-Off" and "Tet-On" systems below. In the Tet-off system, transcription is inactive in the presence of Tc or Dox. In this system, the tetracycline-regulated transcriptional activator (tTA), which is composed of the fusion of TetR and the strong transcriptional activation domain of herpes simplex virus VP16, regulates the expression of target nucleic acids under the transcriptional control of the tetracycline-responsive promoter element (TRE). The TRE element consists of a TetO sequence in tandem with a promoter (usually a minimal promoter derived from the human cytomegalovirus immediate early promoter). promoter sequence) fusion composition. In the absence of Tc or Dox, tTA binds TREs and activates transcription of target genes. In the presence of Tc or Dox, tTA cannot bind to TRE and target genes cannot be expressed.
相反，在Tet-On系统中，转录在Tc或Dox存在下是激活的。Tet-On系统是基于反向四环素调控的转录激活因子rtTA。与tTA一样，rtTA是由TetR阻遏物与VP16转录激活结构域组成的融合蛋白。然而，TetR的DNA结合区中4个氨基酸的变化改变了rtTA的结合特性，使其在存在Dox的情况下只能识别靶转基因TRE上的tetO序列。所以在Tet-On系统中，只有在存在Dox的情况下，rtTA才能激活TRE调控的靶基因的转录。In contrast, in the Tet-On system, transcription is activated in the presence of Tc or Dox. The Tet-On system is based on the reverse tetracycline-regulated transcriptional activator rtTA. Like tTA, rtTA is a fusion protein composed of the TetR repressor and the VP16 transcriptional activation domain. However, a 4-amino acid change in the DNA-binding region of TetR changes the binding properties of rtTA, causing it to only recognize the tetO sequence on the target transgene TRE in the presence of Dox. Therefore, in the Tet-On system, rtTA can activate the transcription of TRE-regulated target genes only in the presence of Dox.
另一种诱导型启动子系统是大肠杆菌的lac阻遏物系统(参见Brown et al.,Cell 49:603-612(1987))。Lac阻遏物系统通过调控与包含lac操纵子(lacO)的启动子可操作性连接的目标多核苷酸的转录发挥功能。Lac阻遏物(lacR)与LacO结合，进而阻止目标多核苷酸的转录。通过合适的诱导剂来诱导目标多核苷酸的表达，例如，异丙基-β-D硫代半乳糖吡喃苷(IPTG)。Another inducible promoter system is the lac repressor system of E. coli (see Brown et al., Cell 49:603-612 (1987)). The Lac repressor system functions by regulating the transcription of a target polynucleotide operably linked to a promoter containing the lac operator (lacO). Lac repressor (lacR) binds to LacO, thereby preventing the transcription of the target polynucleotide. Expression of the polynucleotide of interest is induced by a suitable inducer, for example, isopropyl-β-D thiogalactopyranoside (IPTG).
为了评估多肽或其部分的表达，待导入细胞的表达载体还可包含选择标记基因或报告基因或二者都有，以便于从病毒载体转染或感染的细胞群体中识别和选择表达细胞。在其他方面，选择标记可以携带在单独的DNA片段上并在共转染实验中使用。选择标记基因或报告基因都可侧接于合适的调控序列，使其在宿主细胞中能够表达。有用的选择标记包括，例如，抗生素耐药基因，如neo以及类似基因。To assess the expression of a polypeptide or portion thereof, the expression vector to be introduced into the cell may also contain a selectable marker gene or a reporter gene or both to facilitate the identification and selection of expressing cells from a population of cells transfected or infected with the viral vector. In other aspects, the selectable marker can be carried on separate DNA fragments and used in co-transfection experiments. Either the selectable marker gene or the reporter gene can be flanked by appropriate regulatory sequences to enable expression in the host cell. Useful selectable markers include, for example, antibiotic resistance genes such as neo and similar genes.
报告基因可用于鉴定潜在的转染细胞和评价调控序列的功能。通常，报告基因是不存在于受体生物体或组织中或不由受体生物体或组织表达的基因，其编码一种多肽，其表达表现为一些易于检测的特性，例如酶活性。当DNA导入受体细胞后，在合适的时间检测报告基因的表达。合适的报告基因可包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌碱性磷酸酶或绿色荧光蛋白的基因(参见,Ui-Tel et al.,2000 FEBS Letters 479:79-82)。合适的表达系统是公知的，可以通过已知的技术制备或通过商业途径获得。通常，把可显示报告基因最高表达水平的最小5’侧翼区的构建体认定为启动子。此类启动子区可以与报告基因连接，并用于评估某些物质在调节启动子驱动的转录中能力。Reporter genes can be used to identify potentially transfected cells and evaluate the function of regulatory sequences. Typically, a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and encodes a polypeptide whose expression is manifested by some readily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cells, the expression of the reporter gene is detected at the appropriate time. Suitable reporter genes may include genes encoding luciferase, β-galactosidase, chloramphenicol acetyltransferase, secreted alkaline phosphatase, or green fluorescent protein (see, Ui-Tel et al., 2000 FEBS Letters 479 :79-82). Suitable expression systems are well known and can be prepared by known techniques or commercially available. Typically, the construct with the smallest 5' flanking region that shows the highest expression level of the reporter gene is considered the promoter. Such promoter regions can be linked to reporter genes and used to assess the ability of certain substances to regulate promoter-driven transcription.
在一些实施例中，提供编码本文所述的任一种全长抗Nogo-A抗体的核酸。在一些实施例中，所述核酸包括编码全长抗Nogo-A抗体重链和轻链的一个或多个核酸序列。在一些实施例中，所述一个或多个核酸序列中的每一个包含在单独的载体中。在一些实施例中，至少有一些核酸序列包含在同一载体中。在一些实施例中，所有核酸序列包含在同一载体中。载体可以选自，例如，哺乳动物表达载体和病毒载体(如源自逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒的载体)。In some embodiments, nucleic acids encoding any of the full-length anti-Nogo-A antibodies described herein are provided. In some embodiments, the nucleic acid includes one or more nucleic acid sequences encoding full-length anti-Nogo-A antibody heavy and light chains. In some embodiments, each of the one or more nucleic acid sequences is contained in a separate vector. In some embodiments, at least some of the nucleic acid sequences are included in the same vector. In some embodiments, all nucleic acid sequences are contained in the same vector. Vectors may be selected, for example, from mammalian expression vectors and viral vectors (eg, vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses).
将基因导入细胞并表达的方法在本领域是已知的。在涉及表达载体的上下文中，通过本领域的任何方法载体可以很容易地导入宿主细胞中，如哺乳动物细胞、细菌、酵母或昆虫细胞。例如表达载体可以通过物理、化学或生物方法导入宿主细胞。 Methods of introducing genes into cells and expressing them are known in the art. In the context of expression vectors, the vector can be readily introduced into host cells, such as mammalian cells, bacteria, yeast or insect cells, by any method in the art. For example, expression vectors can be introduced into host cells by physical, chemical or biological methods.
将多核苷酸导入宿主细胞的物理方法包括磷酸钙沉淀、脂质体转染、基因枪法、显微注射、电穿孔法以及诸如此类。制备包含载体和/或外源核酸的细胞的方法在本领域是熟知的。参见例如Green and Sambrook(2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York)。在一些实施例中，通过磷酸钙转染法将多核苷酸导入宿主细胞。Physical methods of introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, biolistic methods, microinjection, electroporation, and the like. Methods of preparing cells containing vectors and/or exogenous nucleic acids are well known in the art. See, for example, Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). In some embodiments, the polynucleotide is introduced into the host cell by calcium phosphate transfection.
将目标多核苷酸导入宿主细胞的生物学方法包括使用DNA和RNA载体。病毒载体，特别是逆转录病毒载体，已成为将基因插入哺乳动物细胞，例如人类细胞中的最广泛使用的方法。其它病毒载体可以源自慢病毒、痘病毒、单纯疱疹病毒1型、腺病毒和腺相关病毒等。参见如U.S.Pat.Nos.5,350,674和5,585,362。Biological methods for introducing polynucleotides of interest into host cells include the use of DNA and RNA vectors. Viral vectors, especially retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells. Other viral vectors can be derived from lentivirus, poxvirus, herpes simplex virus type 1, adenovirus, adeno-associated virus, etc. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362.
将多核苷酸导入宿主细胞的化学方法包括胶体分散系统，例如高分子复合物、纳米胶囊、微球、磁珠和以脂质为基础的系统，其包括水包油乳剂、胶团、混合胶团和脂质体。一种在体内和体外被用作递送载体的示例性胶体系统是脂质体(例如，人工膜囊)。Chemical methods for introducing polynucleotides into host cells include colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems including oil-in-water emulsions, micelles, and mixed gels pellets and liposomes. One exemplary colloidal system used as a delivery vehicle both in vivo and in vitro is liposomes (eg, artificial membrane vesicles).
在使用非病毒递送系统的情况下，示例性的递送载体是脂质体。考虑使用脂质制剂将核酸导入宿主细胞(体外、离体或体内)。在另一方面，所述核酸可以与脂质结合。与脂质结合的核酸可被包裹进脂质体的水性内部，散布在脂质体的脂质双层内，通过与脂质体和寡核苷酸结合的连接分子连接在脂质体，包埋在脂质体中，与脂质体形成复合物，分散在含有脂质的溶液中，与脂质混合，与脂质结合，悬浮在脂质中，包含在胶束中或与胶束混合，或以其它方式与脂质结合。脂质、脂质/DNA或脂质/表达载体相关的组合物在溶液中不限于任何特定结构。例如，它们可能以双分子层结构、以胶束或以“塌陷”结构存在。它们也可以简单的分散在溶液中，可能形成大小或形状不均匀的聚集体。脂质是脂肪物质，可以是天然存在的或是合成的脂质。例如，脂质包括天然存在于细胞质中的脂肪滴，以及含有长链脂肪烃及其衍生物的一类化合物，例如脂肪酸、醇、胺、氨基醇和醛。Where non-viral delivery systems are used, an exemplary delivery vehicle is liposomes. Consider using lipid formulations to introduce nucleic acids into host cells (in vitro, ex vivo, or in vivo). In another aspect, the nucleic acid can be associated with lipids. The nucleic acid bound to the lipid can be packaged into the aqueous interior of the liposome, spread within the lipid bilayer of the liposome, and connected to the liposome through a linker molecule that binds to the liposome and the oligonucleotide. Buried in liposomes, forming complexes with liposomes, dispersed in solutions containing lipids, mixed with lipids, bound to lipids, suspended in lipids, contained in micelles or mixed with micelles , or otherwise combined with lipids. Lipid, lipid/DNA or lipid/expression vector related compositions are not limited to any particular structure in solution. For example, they may exist in bilayer structures, in micelles or in "collapsed" structures. They can also simply disperse in solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances that can be naturally occurring or synthetic lipids. For example, lipids include lipid droplets that occur naturally in the cytoplasm, as well as a class of compounds containing long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, aminoalcohols, and aldehydes.
无论采用何种方法将外源核酸导入宿主细胞中或以其他方式将细胞暴露于本申请的抑制剂中，为了确认重组DNA序列存在于宿主细胞中，可以进行多种实验。这类实验包括例如本领域技术人员熟知的“分子生物学”实验。例如Southern和Northern blotting，RT-PCR和PCR；“生物化学”实验，例如检测某一特定多肽存在或不存在，例如通过免疫学方法(ELISAs和Western blots)或者通过本文所述的实验来进行鉴定均落入本申请范围内。Regardless of which method is used to introduce exogenous nucleic acid into a host cell or otherwise expose the cell to the inhibitor of the present application, a variety of experiments can be performed in order to confirm that the recombinant DNA sequence is present in the host cell. Such experiments include, for example, "molecular biology" experiments well known to those skilled in the art. For example, Southern and Northern blotting, RT-PCR and PCR; "biochemical" experiments, such as detecting the presence or absence of a specific polypeptide, such as by immunological methods (ELISAs and Western blots) or by experiments described in this article All fall within the scope of this application.
抗Nogo-A抗体的制备Preparation of anti-Nogo-A antibodies
在一些实施例中，所述抗Nogo-A抗体是单克隆抗体或源于单克隆抗体。在一些实施例中，所述抗Nogo-A抗体包含来自单克隆抗体的VH和VL，或者其变体。在一些实施例中，所述抗Nogo-A抗体进一步包括来自单克隆抗体的CH1和CL区域，或者其变体。单克隆抗体可以应用例如本领域已知的方法制备，包括杂交瘤细胞法、噬菌体展示方法或应用重组DNA法。此外，示例性的噬菌体展示法在本文及以下的实施例中进行了描述。In some embodiments, the anti-Nogo-A antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-Nogo-A antibody comprises VH and VL from a monoclonal antibody, or a variant thereof. In some embodiments, the anti-Nogo-A antibody further includes CH1 and CL regions from a monoclonal antibody, or variants thereof. Monoclonal antibodies can be prepared using, for example, methods known in the art, including hybridoma cell methods, phage display methods, or using recombinant DNA methods. Additionally, exemplary phage display methods are described herein and in the Examples below.
在杂交瘤细胞法中，通常采用免疫剂免疫仓鼠、小鼠或其他适合的宿主动物，以引发产生或能够产生与免疫剂特异性结合的抗体的淋巴细胞。或者，可以在体外免疫淋巴细胞。免疫剂可包 括目标蛋白的多肽或融合蛋白。通常，如果需要人源细胞，采用外周血淋巴细胞(PBLs)，而如果需要非人哺乳动物来源细胞，则会使用脾细胞或淋巴结细胞。使用适当的融合剂将淋巴细胞与永生细胞系进行融合，例如聚乙二醇，以形成杂交瘤细胞。永生细胞系通常是转化的哺乳动物细胞，尤其是啮齿类、牛科和人源的骨髓瘤细胞。通常采用大鼠或小鼠骨髓瘤细胞系。杂交瘤细胞可以在合适的培养基中进行培养，所述培养基优选含有一种或多种抑制未融合永生细胞生长或存活的物质。例如，如果亲本细胞缺乏次黄嘌呤-鸟嘌呤磷酸核糖转移酶(HGPRT或HPRT)，则杂交瘤细胞培养基通常包括次黄嘌呤、氨蝶呤和胸苷(HAT培养基)，该培养基能阻止HGPRT缺陷细胞生长。In the hybridoma cell method, an immune agent is usually used to immunize hamsters, mice or other suitable host animals to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the immune agent. Alternatively, lymphocytes can be immunized in vitro. Immunizers can be included A polypeptide or fusion protein including the target protein. Typically, if cells of human origin are desired, peripheral blood lymphocytes (PBLs) are used, whereas if cells of non-human mammalian origin are desired, spleen cells or lymph node cells are used. Lymphocytes are fused to immortalized cell lines using an appropriate fusion agent, such as polyethylene glycol, to form hybridoma cells. Immortal cell lines are typically transformed mammalian cells, particularly myeloma cells of rodent, bovine, and human origin. Typically, rat or mouse myeloma cell lines are used. Hybridoma cells can be cultured in a suitable medium, which preferably contains one or more substances that inhibit the growth or survival of unfused immortal cells. For example, if the parent cells lack the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), hybridoma cell culture medium typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), which can Prevents the growth of HGPRT-deficient cells.
在一些实施例中，永生化细胞系有效融合，通过所选择的抗体生产细胞保证抗体高水平稳定表达，并且对某些培养基敏感，例如HAT培养基。在一些实施例中，永生细胞系是小鼠骨髓瘤细胞系，可以从例如，加利福尼亚圣地亚哥的索尔克细胞保藏中心和弗吉尼亚马纳萨斯的美国典型培养物保藏中心获得。同时还描述了人骨髓瘤和鼠-人杂交骨髓瘤细胞系用于制备人源单克隆抗体。In some embodiments, the immortalized cell lines fuse efficiently, ensure high-level and stable expression of the antibody by the selected antibody-producing cells, and are sensitive to certain media, such as HAT media. In some embodiments, the immortal cell line is a mouse myeloma cell line, available from, for example, the Salk Cell Collection in San Diego, California, and the American Type Culture Collection in Manassas, Virginia. Also described are human myeloma and mouse-human hybrid myeloma cell lines for the preparation of human monoclonal antibodies.
然后可以测定培养杂交瘤细胞的培养基中是否存在针对多肽的单克隆抗体。由杂交瘤细胞产生的单克隆抗体的结合特异性可以通过免疫沉淀法或体外结合实验确定，如放射性免疫测定法(RIA)或酶联免疫吸附法(ELISA)。此类技术或分析方法在本领域是已知的。单克隆抗体的结合亲和力可以通过例如Munson and Pollard,Anal.Biochem.,107:220(1980)中所述的斯卡查德(Scatchard)分析确定。The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide. The binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by immunoprecipitation or in vitro binding experiments, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art. The binding affinity of a monoclonal antibody can be determined by Scatchard analysis as described, for example, in Munson and Pollard, Anal. Biochem., 107:220 (1980).
在鉴定出所需的杂交瘤细胞后，可以通过有限稀释法对目标克隆进行亚克隆，并通过标准方法进行培养。基于此目的适合的培养基包括，例如改良Eagle培养基(DMEM)和RPMI-1640培养基。或者，杂交瘤细胞可以在哺乳动物体内以腹水的形式生长。After the desired hybridoma cells are identified, the clones of interest can be subcloned by limiting dilution and cultured by standard methods. Suitable media for this purpose include, for example, modified Eagle's medium (DMEM) and RPMI-1640 medium. Alternatively, hybridoma cells can be grown in mammals in the form of ascites fluid.
亚克隆分泌的单克隆抗体可以通过常规免疫球蛋白纯化方法从培养基或腹水中分离或纯化，例如蛋白A-琼脂糖凝胶、羟基磷灰石色谱层析、凝胶电泳、透析或亲和层析。Monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascitic fluid by conventional immunoglobulin purification methods, such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity Chromatography.
在一些实施例中，根据本文所述的任一抗Nogo-A抗体，所述抗Nogo-A抗体包含选自抗体文库(例如展示scFv或Fab片段的噬菌体文库)的克隆的序列。所述克隆可以通过筛选具有所需活性的抗体片段组合文库的方法进行鉴定。例如，本领域已知多种方法用于产生噬菌体展示文库以及筛选这些文库来获得所需结合特性的抗体。这些方法在例如Hoogenboom et al.,Methods in Molecular Biology 178:1-37(O'Brien et al.,ed.,Human Press,Totowa,N.J.,2001)中进行了综述，并且在例如McCafferty et al.,Nature 348:552-554；Clackson et al.,Nature 352:624-628(1991)；Marks et al.,J.Mol.Biol.222:581-597(1992)；Marks and Bradbury,Methods in Molecular Biology 248:161-175(Lo,ed.,Human Press,Totowa,N.J.,2003)；Sidhu et al.,J.Mol.Biol.338(2):299-310(2004)；Lee et al.,J.Mol.Biol.340(5):1073-1093(2004)；Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004)；and Lee et al.,J.Immunol.Methods 284(1-2):119-132(2004)中进行了进一步描述。 In some embodiments, according to any anti-Nogo-A antibody described herein, the anti-Nogo-A antibody comprises sequences selected from clones of an antibody library (eg, a phage library displaying scFv or Fab fragments). The clones can be identified by screening a combinatorial library of antibody fragments with the desired activity. For example, various methods are known in the art for generating phage display libraries and screening these libraries for antibodies with desired binding properties. These methods are reviewed, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and in, for example, McCafferty et al. ,Nature 348:552-554;Clackson et al.,Nature 352:624-628(1991);Marks et al.,J.Mol.Biol.222:581-597(1992);Marks and Bradbury,Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J.Mol.Biol.340(5):1073-1093(2004); Fellouse, Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004); and Lee et al., J.Immunol .Methods 284(1-2):119-132(2004) is further described.
在某些噬菌体展示方法中，通过聚合酶链式反应(PCR)分别克隆VH和VL基因的所有组成成分，并在噬菌体文库中随机重组，然后筛选能够结合抗原的噬菌体，如Winter et al.,Ann.Rev.Immunol.,12:433-455(1994)中所述。噬菌体通常以scFv片段或以Fab片段形式展示抗体片段。免疫来源的文库噬菌体提供针对免疫原的高亲和力抗体而不需要构建杂交瘤细胞。或者，可以克隆天然库(例如来自人)，来提供针对多种非自身抗原和自身抗原的单一抗体来源，而不需任何免疫，如Griffiths et al.,EMBO J,12:725-734(1993)中所述。最后，天然文库也可以通过克隆来自干细胞的非重排V-gene片段，并使用包含随机序列的PCR引物编码CDR3高变区并且在体外完成重排的方法进行制备，如Hoogenboom and Winter,J.Mol.Biol.,227:381-388(1992)中所述。描述人抗体噬菌体文库的专利出版物包括，例如U.S.Pat.No.5,750,373和US Patent Publication Nos.2005/0079574、2005/0119455、2005/0266000、2007/0117126、2007/0160598、2007/0237764、2007/0292936和2009/0002360。In some phage display methods, all components of the V H and V L genes are cloned separately through polymerase chain reaction (PCR), randomly recombined in a phage library, and then screened for phages that can bind the antigen, such as Winter et al. ., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments as scFv fragments or as Fab fragments. Immunogenically derived library phages provide high-affinity antibodies against immunogens without the need to construct hybridoma cells. Alternatively, natural libraries (eg from humans) can be cloned to provide a single source of antibodies against multiple non-self and self-antigens without the need for any immunization, as in Griffiths et al., EMBO J, 12:725-734 (1993 ) as stated in. Finally, natural libraries can also be prepared by cloning non-rearranged V-gene fragments from stem cells and using PCR primers containing random sequences to encode the CDR3 hypervariable region and completing the rearrangement in vitro, such as Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, US Pat. No. 5,750,373 and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/029 2936 and 2009/0002360.
通过噬菌体展示筛选文库中能够特异性结合靶标Nogo-A的抗Nogo-A抗体部分的方法来制备所述的抗Nogo-A抗体。该文库可以是人scFv噬菌体展示文库，具有至少1×109(例如至少1×109、2.5×109、5×109、7.5×109、1×1010、2.5×1010、5×1010、7.5×1010或1×1011)种多样性的独特的人抗体片段。在一些实施例中，所述文库是人天然文库，通过从健康受试者的PMBCs和脾脏中提取的DNA构建，包含所有人重链和轻链亚家族。在一些实施例中，所述文库是人天然文库，通过从各种疾病患者体内分离的PMBCs中提取的DNA构建，例如自身免疫病的患者、癌症患者和感染性疾病的患者。在一些实施例中，所述文库是半合成的人文库，其中重链CDR3完全是随机的，所有氨基酸(除了半胱氨酸)以相同的概率存在于任何给定的位置。(参见例如,Hoet,R.M.et al.,Nat.Biotechnol.23(3):344-348,2005)。在一些实施例中，半合成的人文库的重链CDR3长度在5到24个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24个)氨基酸之间。在一些实施例中，所述文库是全合成的噬菌体展示文库。在一些实施例中，所述文库是非人噬菌体展示文库。The anti-Nogo-A antibody is prepared by phage display screening the anti-Nogo-A antibody part in the library that can specifically bind to the target Nogo-A. The library may be a human scFv phage display library with at least 1×10 9 (e.g., at least 1×10 9 , 2.5×10 9 , 5×10 9 , 7.5×10 9 , 1×10 10 , 2.5× 10 10 , 5 ×10 10 , 7.5×10 10 or 1×10 11 ) diversity of unique human antibody fragments. In some embodiments, the library is a human natural library, constructed from DNA extracted from PMBCs and spleens of healthy subjects, containing all human heavy and light chain subfamilies. In some embodiments, the library is a human natural library constructed from DNA extracted from PMBCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases. In some embodiments, the library is a semi-synthetic human library in which the heavy chain CDR3s are completely random and all amino acids (except cysteine) are present with equal probability at any given position. (See, eg, Hoet, RM et al., Nat. Biotechnol. 23(3):344-348, 2005). In some embodiments, the heavy chain CDR3 length of the semi-synthetic human library ranges from 5 to 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23 or 24) between amino acids. In some embodiments, the library is a fully synthetic phage display library. In some embodiments, the library is a non-human phage display library.
与靶标Nogo-A具有高亲和力的噬菌体克隆可以通过噬菌体与靶标Nogo-A的迭代结合进行筛选，所述靶标Nogo-A与固相支持物结合(例如用于溶液淘选的珠子或用于细胞淘选的哺乳动物细胞)，接下来去除未结合的噬菌体，并洗脱特异性结合噬菌体。随后，洗脱结合的噬菌体克隆并用于感染合适的宿主细胞，例如E.coli XL1-Blue，进行表达和纯化。可以通过多轮淘选(例如，2、3、4、5、6或更多轮)，例如溶液淘选、细胞淘选或两者结合以富集特异性结合Nogo-A的噬菌体克隆。富集的噬菌体克隆与靶标Nogo-A的特异性结合可以通过本领域已知的任何方法进行检测，包括例如ELISA和FACS。Phage clones with high affinity to target Nogo-A can be screened by iterative binding of phage to target Nogo-A bound to a solid support (e.g. beads for solution panning or cells for cell panned mammalian cells), followed by removal of unbound phage and elution of specifically bound phage. Subsequently, bound phage clones are eluted and used to infect suitable host cells, such as E. coli XL1-Blue, for expression and purification. Phage clones that specifically bind Nogo-A can be enriched by multiple rounds of panning (eg, 2, 3, 4, 5, 6, or more rounds), such as solution panning, cell panning, or a combination of both. Specific binding of the enriched phage clones to the target Nogo-A can be detected by any method known in the art, including, for example, ELISA and FACS.
筛选抗体文库的另一种方法是在酵母细胞表面展示蛋白质。Wittrup等(美国专利6,699,658和6,696,251)开发了一种酵母细胞展示文库的方法。在此酵母展示系统中，一个组分包括锚定在酵母细胞壁上的酵母凝集素蛋白(Aga1)，另一个组分包括凝集素蛋白Aga2的第二个亚基，该亚基可以通过二硫键与Aga1蛋白结合进而展示在酵母细胞表面上。通过将Aga1基因整合到酵母染色 体中来表达Aga1蛋白。将单链可变片段(scFv)文库与酵母展示质粒中的Aga2基因融合，将其转化后，该文库由于附加的营养标记的存在可保留在酵母中。Aga1和Aga2蛋白均在半乳糖诱导型启动子的控制下表达。Another way to screen antibody libraries is to display proteins on the surface of yeast cells. Wittrup et al. (US Patents 6,699,658 and 6,696,251) developed a method for displaying libraries in yeast cells. In this yeast display system, one component includes the yeast lectin protein (Aga1), which is anchored to the yeast cell wall, and the other component includes the second subunit of the lectin protein Aga2, which can pass through disulfide bonds. Binds to the Aga1 protein and is displayed on the surface of yeast cells. Staining by integrating the Aga1 gene into yeast to express Aga1 protein in vivo. A single-chain variable fragment (scFv) library is fused to the Aga2 gene in a yeast display plasmid and, after transformation, remains in the yeast due to the presence of an additional nutritional marker. Both Aga1 and Aga2 proteins are expressed under the control of galactose-inducible promoters.
人抗体V基因库(VH和VK片段)是使用一组简并引物通过PCR方法获得(Sblattero，D.and Bradbury,A.Immunotechnology 3,271-278 1998)。PCR模板来自可商购的RNA或cDNA，包括PBMC，脾脏，淋巴结，骨髓和扁桃体。将独立的VH和VK PCR文库合并后，通过重叠延伸PCR将其组装成scFv形式(Sheets，M.D.et al,Proc.Natl.Acad.Sci.USA 95,6157–6162 1998)。为了构建酵母scFv展示文库，通过同源重组将所得的scFv PCR产物克隆到酵母中的酵母展示质粒中。(Chao,G,et al,Nat Protoc.2006；1(2):755-68.Miller KD,et al.Current Protocols in Cytometry 4.7.1-4.7.30,2008)。The human antibody V gene library (V H and V K fragments) was obtained by PCR using a set of degenerate primers (Sblattero, D. and Bradbury, A. Immunotechnology 3, 271-278 1998). PCR templates were derived from commercially available RNA or cDNA, including PBMC, spleen, lymph nodes, bone marrow, and tonsils. Independent V H and V K PCR libraries were combined and assembled into scFv formats by overlap extension PCR (Sheets, MD et al, Proc. Natl. Acad. Sci. USA 95, 6157–6162 1998). To construct a yeast scFv display library, the resulting scFv PCR product was cloned into a yeast display plasmid in yeast by homologous recombination. (Chao, G, et al, Nat Protoc. 2006; 1(2):755-68. Miller KD, et al. Current Protocols in Cytometry 4.7.1-4.7.30, 2008).
可以利用哺乳动物细胞展示系统来筛选抗Nogo-A抗体，其中抗体部分展示在细胞表面上并通过抗原导向的筛选方法分离出特异性靶向Nogo-A的抗体(如U.S.patent No.7,732,195B2中所述)。可以建立展示大量人类IgG抗体基因的中国仓鼠卵巢(CHO)细胞文库，并将其用于发现表达高亲和力抗体基因的克隆。已开发出另一种展示系统，该系统通过可变剪接使同一蛋白同时在细胞表面展示和分泌，其中展示的蛋白表型保持与基因型相关，使得可同时在生物物理和基于细胞功能的分析中表征该分泌的可溶性抗体。该方法克服了先前哺乳动物细胞展示的许多局限性，能够直接筛选和成熟化全长的、糖基化的IgGs形式的抗体(Peter M.Bowers,et al,Methods 2014,65：44-56)。瞬时表达系统适用于在抗体基因恢复之前进行的单轮抗原选择，因此对于从较小文库中选择抗体最有用。稳定的外显体载体提供了一种有吸引力的选择。外显体载体可以高效转染并稳定地维持在低拷贝数，从而允许多轮淘选以及更复杂抗体库的解析。Anti-Nogo-A antibodies can be screened using a mammalian cell display system, in which the antibody moiety is displayed on the cell surface and antibodies specifically targeting Nogo-A are isolated by antigen-directed screening methods (as in U.S. patent No. 7,732,195B2 described). A Chinese hamster ovary (CHO) cell library displaying a large number of human IgG antibody genes can be created and used to discover clones expressing high-affinity antibody genes. An alternative display system has been developed that allows the same protein to be simultaneously displayed and secreted on the cell surface through alternative splicing, in which the phenotype of the displayed protein remains correlated with the genotype, allowing for simultaneous biophysical and cell function-based analyses. Characterize the secreted soluble antibodies. This method overcomes many of the limitations of previous mammalian cell displays and enables direct screening and maturation of antibodies in the form of full-length, glycosylated IgGs (Peter M. Bowers, et al, Methods 2014, 65: 44-56) . Transient expression systems are suitable for a single round of antigen selection prior to antibody gene recovery and are therefore most useful for selecting antibodies from smaller libraries. Stable exosome vectors offer an attractive option. Exosome vectors can be efficiently transfected and stably maintained at low copy numbers, allowing for multiple rounds of panning and elucidation of more complex antibody libraries.
IgG文库是基于分离自一群人类供体的种系序列V基因片段与重排的(D)J区域的连接构建而成。将从2000个人体血液样本中收集的RNA反转录为cDNA，使用VH和VK特异性引物扩增VH和VK片段，并通过凝胶提取纯化。将VH和VK片段分别亚克隆到包含IgG1或K恒定区的展示载体中，然后电穿孔或转导293T到细胞，从而制备IgG文库。为了制备scFv抗体展示文库，连接VH和VK以产生scFv，然后亚克隆到展示载体中，再将其电穿孔或转导293T细胞。众所周知，IgG文库是基于分离自一群供体的种系序列V基因片段与重排的(D)J区域构建而成，供体可以是小鼠，大鼠，兔或猴。The IgG library was constructed based on the ligation of germline sequence V gene fragments isolated from a pool of human donors and rearranged (D)J regions. RNA collected from 2000 human blood samples was reverse transcribed into cDNA, VH and VK fragments were amplified using VH and VK specific primers, and purified by gel extraction. The VH and VK fragments were subcloned into display vectors containing IgG1 or K constant regions respectively, and then electroporated or transduced 293T into cells to prepare IgG libraries. To prepare scFv antibody display libraries, V H and V K are ligated to generate scFv, which is then subcloned into a display vector and electroporated or transduced into 293T cells. As we all know, IgG libraries are constructed based on germline sequence V gene fragments and rearranged (D)J regions isolated from a group of donors, which can be mice, rats, rabbits or monkeys.
单克隆抗体也可以通过重组DNA方法进行制备，例如U.S.Patent No.4,816,567中所述。编码本申请中所述单克隆抗体的DNA可以通过常规方法(例如通过能特异性结合编码鼠源抗体轻链和重链基因的寡聚核苷酸探针)轻易的分离和测序。如上所述的杂交瘤细胞或本申请的Nogo-A特异性噬菌体克隆可以作为这种DNA的来源。分离后，可将DNA置于表达载体中，然后该载体转染入宿主细胞，例如猿猴COS细胞、中华仓鼠卵巢癌(CHO)细胞或不产生免疫球蛋白的骨髓瘤细胞中，获得在重组宿主细胞中合成的单克隆抗体。所述DNA也可以被修饰，例如用编码序列取代人重链和轻链恒定区和/或用框架区替换同源非人序列(U.S.Patent No.4,816,567；Morrison et al., supra)，或通过共价键连接免疫球蛋白的编码序列的全部或部分非免疫球蛋白多肽的编码序列。这种非免疫球蛋白多肽可以取代本申请中抗体的恒定区，或可以取代本申请中抗体可变结构域中的一个抗原结合位点，形成嵌合的二价抗体。Monoclonal antibodies can also be prepared by recombinant DNA methods, such as those described in US Patent No. 4,816,567. DNA encoding the monoclonal antibodies described herein can be readily isolated and sequenced by conventional methods (eg, by oligonucleotide probes that specifically bind to genes encoding the light and heavy chains of murine antibodies). Hybridoma cells as described above or Nogo-A specific phage clones of the present application can be used as a source of such DNA. After isolation, the DNA can be placed into an expression vector, which can then be transfected into host cells, such as simian COS cells, Chinese hamster ovary cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain the expression in the recombinant host. Monoclonal antibodies synthesized in cells. The DNA may also be modified, for example, by replacing human heavy and light chain constant regions with coding sequences and/or by replacing homologous non-human sequences with framework regions (US Patent No. 4,816,567; Morrison et al., supra), or all or part of the coding sequence for a non-immunoglobulin polypeptide linked by a covalent bond to the coding sequence for an immunoglobulin. This non-immunoglobulin polypeptide can replace the constant region of the antibody in this application, or can replace an antigen-binding site in the variable domain of the antibody in this application, forming a chimeric bivalent antibody.
所述抗体可以是单价抗体。制备单价抗体的方法是本领域已知的。例如，一种涉及免疫球蛋白轻链和修饰重链的重组表达方法。通常在Fc区的任意位置截短重链，以阻止重链相互交联。或者，相关的半胱氨酸残基被其它氨基酸残基取代或被缺失以防止交联。The antibody may be a monovalent antibody. Methods of preparing monovalent antibodies are known in the art. For example, one involves a recombinant expression method involving an immunoglobulin light chain and a modified heavy chain. The heavy chain is usually truncated at any position in the Fc region to prevent the heavy chains from cross-linking with each other. Alternatively, the relevant cysteine residues are substituted with other amino acid residues or deleted to prevent cross-linking.
体外方法也适用于制备单价抗体。消化抗体产生抗体片段，特别是Fab片段，可以使用任何本领域已知的方法完成。In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, can be accomplished using any method known in the art.
具有所需结合特异性(抗体-抗原结合位点)的抗体可变结构域可以与免疫球蛋白恒定区融合。优选与免疫球蛋白重链恒定区进行融合，其包括至少部分铰链，CH2和CH3区。在一些实施例中，包含轻链结合必要位点的第一重链恒定区(CH1)至少出现在一种融合体中。编码免疫球蛋白重链融合体的DNA，如果需要，还可以包括编码免疫球蛋白轻链的DNA，被插入进独立的表达载体中，并共转染至合适的宿主生物中。Antibody variable domains with the desired binding specificity (antibody-antigen binding site) can be fused to immunoglobulin constant regions. Fusions to the immunoglobulin heavy chain constant region, including at least part of the hinge, CH2 and CH3 regions, are preferred. In some embodiments, the first heavy chain constant region (CH1), which contains the necessary sites for light chain binding, is present in at least one fusion. DNA encoding the immunoglobulin heavy chain fusion, and if desired, DNA encoding the immunoglobulin light chain, is inserted into a separate expression vector and co-transfected into a suitable host organism.
全人和人源化抗体Fully humanized and humanized antibodies
所述抗Nogo-A抗体(如全长的抗Nogo-A抗体)可以是全人抗体或人源化抗体。非人(如小鼠)抗体部分的人源化形式是嵌合的免疫球蛋白、免疫球蛋白链或其片段(例如Fv、Fab、Fab’、F(ab’)2、scFv或抗体的其他抗原结合子序列)，其通常包括最少的源于非人免疫球蛋白的序列。人源化抗体包括人免疫球蛋白、免疫球蛋白链或其片段(受体抗体)，其中受体CDR的残基被具有所需特异性、亲和力和性能的非人源(供体抗体)CDR残基取代，例如小鼠、大鼠或兔子的CDR。在一些实施例中，人免疫球蛋白Fv框架区残基被相应的非人源残基取代。人源化抗体还可以包含既不属于受体抗体也不在引入的CDR或框架区序列中的氨基酸残基。通常，人源化抗体包含至少一个，通常两个可变结构域，其中全部或基本上全部CDR区对应于非人免疫球蛋白的CDR区，全部或基本上全部框架区是人免疫球蛋白共有序列。The anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) can be a fully human antibody or a humanized antibody. Humanized forms of non-human (e.g., mouse) antibody portions are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., Fv, Fab, Fab', F(ab') 2 , scFv, or other fragments of antibodies Antigen binder sequences), which generally include minimal sequences derived from non-human immunoglobulins. Humanized antibodies include human immunoglobulins, immunoglobulin chains or fragments thereof (recipient antibodies) in which the residues of the acceptor CDRs are replaced by non-human (donor antibody) CDRs with the desired specificity, affinity and properties. Residue substitutions, such as mouse, rat or rabbit CDRs. In some embodiments, human immunoglobulin Fv framework residues are replaced with corresponding non-human residues. Humanized antibodies may also contain amino acid residues that neither belong to the recipient antibody nor are in the introduced CDR or framework sequence. Typically, a humanized antibody contains at least one, and usually two variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are common to human immunoglobulins. sequence.
通常，人源化抗体含有一个或多个从非人源引入的氨基酸残基。那些非人源氨基酸残基通常被称为“移入”残基，通常来自“移入”可变结构域。根据一些实施例，人源化基本上可以按照Winter和其同事的如下方法进行(Jones et al.,Nature,321:522-525(1986)；Riechmann et al.,Nature,332:323-327(1988)；Verhoeyen et al.,Science,239:1534-1536(1988))，通过用啮齿动物CDRs或CDR序列取代人源抗体的相应序列。因此，这种“人源化”抗体部分(U.S.Patent No.4,816,567)，其基本上少于完整的人源抗体，其可变结构域已被来自非人源的相应序列所取代。在实际中，人源化抗体部分是典型的人源抗体部分，其中一些CDR残基和可能的一些框架区残基被来自啮齿类抗体中类似位点的残基所取代。Typically, humanized antibodies contain one or more amino acid residues introduced from a non-human source. Those non-human amino acid residues are often referred to as "implanted" residues, usually from the "imported" variable domain. According to some embodiments, humanization can be performed essentially as described by Winter and colleagues (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 ( 1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by replacing the corresponding sequences of human antibodies with rodent CDRs or CDR sequences. Thus, this "humanized" antibody portion (U.S. Patent No. 4,816,567), which is substantially less than a fully human antibody, has its variable domains replaced by corresponding sequences from non-human sources. In practice, a humanized antibody portion is a typical human antibody portion in which some CDR residues and possibly some framework region residues are replaced by residues from similar positions in rodent antibodies.
全人抗体是人源化的一种替代方式。例如，目前可以制备在免疫后能够产生完整的全人抗体文库而不产生内源性免疫球蛋白的转基因动物(例如，小鼠)。例如，已有报道，嵌合和种系突变小鼠中抗体重链连接区(JH)基因的纯合子缺失，完全抑制了内源性抗体的产生。将人种系免 疫球蛋白基因阵列转移到这种种系突变小鼠体内，可在抗原刺激下产生人源抗体，参见，例如akobovits et al.,PNAS USA,90:2551(1993)；Jakobovits et al.,Nature,362:255-258(1993)；Bruggemann et al.,Year in Immunol.,7:33(1993)；U.S.Patent Nos.5,545,806,5,569,825,5,591,669,5,545,807；和WO 97/17852。或者，可以通过将人类免疫球蛋白基因座引入转基因动物中(例如内源性免疫球蛋白基因已经被部分或全部沉默的小鼠)来制备全人抗体。抗原刺激后，可以发现全人抗体的产生在各个方面都与其在人类中的产生非常相似，包括基因重排、组装和抗体文库。这种方法在例如U.S.Patent Nos.5,545,807；5,545,806；5,569,825；5,625,126；5,633,425；and 5,661,016,and Marks et al.,Bio/Technology,10:779-783(1992)；Lonberg et al.,Nature,368:856-859(1994)；Morrison,Nature,368:812-813(1994)；Fishwild et al.,Nature Biotechnology,14:845-851(1996)；Neuberger,Nature Biotechnology,14:826(1996)；Lonberg and Huszar,Intern.Rev.Immunol.,13:65-93(1995)中进行了描述。Fully human antibodies are an alternative to humanization. For example, it is now possible to generate transgenic animals (eg, mice) that are capable of producing a complete library of fully human antibodies upon immunization without producing endogenous immunoglobulins. For example, it has been reported that homozygous deletion of the antibody heavy chain junction region (JH) gene in chimeric and germline mutant mice completely inhibits endogenous antibody production. immunize people germline Immunoglobulin gene arrays transferred into such germline mutant mice can produce human antibodies under antigen stimulation, see, for example, akobovits et al., PNAS USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggemann et al., Year in Immunol., 7:33 (1993); US Patent Nos. 5,545,806, 5,569,825, 5,591,669, 5,545,807; and WO 97/17852. Alternatively, fully human antibodies can be prepared by introducing human immunoglobulin loci into transgenic animals (eg, mice in which the endogenous immunoglobulin genes have been partially or completely silenced). After antigen stimulation, the production of fully human antibodies can be found to be very similar to their production in humans in all aspects, including gene rearrangement, assembly, and antibody libraries. This method is used in, for example, US Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016, and Marks et al., Bio/Technology, 10:779-783 (1992); Lonberg et al., Nature, 368:856 -859 (1994); Morrison, Nature, 368:812-813 (1994); Fishwild et al., Nature Biotechnology, 14:845-851 (1996); Neuberger, Nature Biotechnology, 14:826 (1996); Lonberg and Described in Huszar, Intern. Rev. Immunol., 13:65-93 (1995).
全人抗体也以通过体外活化B细胞(见U.S.Patents 5,567,610and 5,229,275)或通过使用本领域已知的各种技术来产生，包括噬菌体展示文库。Hoogenboom and Winter,J.Mol.Biol.,227:381(1991)；Marks et al.,J.Mol.Biol.,222:581(1991).Cole et al.和Boerner et al.等人的技术也可以用于制备全人单克隆抗体。见Cole et al.,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,p.77(1985)and Boerner et al.,J.Immunol.,147(1):86-95(1991)。Fully human antibodies can also be produced by activating B cells in vitro (see U.S. Patents 5,567,610 and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227: 381 (1991); Marks et al., J. Mol. Biol., 222: 581 (1991). The technology of Cole et al. and Boerner et al. It can also be used to prepare fully human monoclonal antibodies. See Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991).
抗Nogo-A抗体变体Anti-Nogo-A antibody variants
在一些实施例中，本文提供的抗Nogo-A抗体变体(例如，全长的抗Nogo-A抗体)的氨基酸序列也在考虑中。例如，可能需要改善抗体的结合亲和力和/或其它生物学活性。抗体变体的氨基酸序列可以通过在编码抗体的核苷酸序列中引入适当的修饰或通过肽合成来制备。此类修饰包括例如，抗体氨基酸序列中残基的缺失和/或插入和/或取代。可以通过氨基酸残基缺失、插入和取代的任一组合来完成最终的构建，使其具有所需的特征。例如，抗原结合性。In some embodiments, the amino acid sequences of anti-Nogo-A antibody variants (eg, full-length anti-Nogo-A antibodies) provided herein are also contemplated. For example, it may be desirable to improve the binding affinity and/or other biological activity of the antibody. The amino acid sequences of antibody variants can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the antibody amino acid sequence. The final construct can be accomplished by any combination of deletions, insertions, and substitutions of amino acid residues to give it the desired characteristics. For example, antigen binding.
在一些实施例中，提供具有一个或多个氨基酸取代的抗Nogo-A抗体变体。取代突变的目标位点包括高变区(HVRs)和框架区(FRs)。可以在目标抗体中引入氨基酸取代，筛选所需活性的产物，例如，改善的生物活性，保持/改善抗原结合能力，降低的免疫原性，或改善的ADCC或CDC。In some embodiments, anti-Nogo-A antibody variants with one or more amino acid substitutions are provided. Target sites for substitution mutations include hypervariable regions (HVRs) and framework regions (FRs). Amino acid substitutions can be introduced into the antibody of interest and the product screened for the desired activity, for example, improved biological activity, maintained/improved antigen binding capacity, reduced immunogenicity, or improved ADCC or CDC.
保守取代如下表4所示。Conservative substitutions are shown in Table 4 below.
表4保守取代

Table 4 Conservative substitutions

根据侧链性质将氨基酸分为不同类别：Amino acids are divided into different categories based on the nature of their side chains:
a、疏水氨基酸：去甲亮氨酸Norleucine、蛋氨酸Met、丙氨酸Ala、缬氨酸Val、亮氨酸Leu、异亮氨酸Ile；a. Hydrophobic amino acids: Norleucine, Met, Ala, Val, Leu, Ile;
b、中性亲水性氨基酸：半胱氨酸Cys、丝氨酸Ser、苏氨酸Thr、天冬酰胺Asn、谷氨酰胺Gln；b. Neutral hydrophilic amino acids: cysteine Cys, serine Ser, threonine Thr, asparagine Asn, glutamine Gln;
c、酸性氨基酸：天冬氨酸Asp、谷氨酸Glu；c. Acidic amino acids: aspartic acid Asp, glutamic acid Glu;
d、碱性氨基酸：组氨酸His、赖氨酸Lys、精氨酸Arg；d. Basic amino acids: histidine His, lysine Lys, arginine Arg;
e、含有影响链方向的氨基酸：甘氨酸Gly、脯氨酸Pro；e. Contains amino acids that affect chain direction: glycine Gly, proline Pro;
f、芳香族氨基酸：色氨酸Trp、酪氨酸Tyr、苯丙氨酸Phe。f. Aromatic amino acids: tryptophan Trp, tyrosine Tyr, phenylalanine Phe.
非保守氨基酸的取代包含将以上一种类别取代为另一种类别。Substitutions of non-conservative amino acids involve substitution of one category for another category.
一种示例性的取代变体是亲和力成熟的抗体，可采用例如以噬菌体展示为基础的亲和力成熟技术而方便地产生。简言之，将一个或多个CDR残基进行突变，变体抗体部分展示在噬菌体上，并筛选具有特定生物活性(例如，基于hNiG诱导的神经突生长抑制的恢复活性实验或结合亲和力的生物学活性)的变体。可以在HVRs区进行改变(例如，取代)来获得改善的基于hNiG诱导的神经突生长抑制的恢复活性实验或结合亲和力的生物学活性。可以在HVR的“热点区”产生改变，即在体细胞成熟过程中发生高频突变的密码子编码的残基(参见，例如Chowdhury,Methods Mol.Biol.207:179-196(2008))，和/或在特异的决定性残基(SDRs)，检测所得变体VH和VL的结合亲和力。从二级文库中构建和重新选择亲和力成熟的方法已经在一些文献中进行描述，例如，Hoogenboom et al.in Methods in Molecular Biology 178:1-37(O'Brien et al.,ed.,Human Press,Totowa,NJ,(2001))。An exemplary substitution variant is an affinity matured antibody, which can be conveniently produced using, for example, phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, variant antibody moieties are displayed on phage, and organisms screened for specific biological activity (e.g., based on hNiG-induced neurite growth inhibition in a restorative activity assay or binding affinity) chemical activity). Alterations (eg, substitutions) can be made in the HVRs region to obtain improved biological activity based on hNiG-induced neurite growth inhibition restoration assays or binding affinity. Alterations can occur in "hot spots" of HVR, i.e., codon-encoded residues that are highly mutated during somatic cell maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or detect the binding affinity of the resulting variants VH and VL at specific decisive residues (SDRs). Methods for constructing and reselecting affinity matured materials from secondary libraries have been described in the literature, e.g., Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press ,Totowa, NJ, (2001)).
在一些亲和力成熟的实施例中，通过多种方法中的任一种(例如易错PCR，链改组或寡核苷酸定向突变)，将多样性引入选择的用于亲和力成熟的可变基因中。然后创建二级文库。对该文库进行筛选，鉴定出具有所需亲和力的抗体变体。另一种引入多样性的方法包括HVR介导的方式，其中几个HVR残基(例如，一次4-6个残基)被随机化。涉及抗原结合的HVR残基被特异性地识别，例如，采用丙氨酸扫描诱变或建模。通常CDR-H3和CDR-L3区域尤其是重点靶标。 In some affinity maturation embodiments, diversity is introduced into the variable genes selected for affinity maturation by any of a variety of methods, such as error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis. . Secondary libraries are then created. The library is screened to identify antibody variants with the desired affinity. Another way to introduce diversity includes the HVR-mediated manner, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically recognized, for example, using alanine scanning mutagenesis or modeling. Usually the CDR-H3 and CDR-L3 regions are particularly focused targets.
在一些实施例中，取代、插入或缺失可能发生在一个或多个HVRs内，只要这种改变基本上不降低抗体结合抗原的能力。例如，可以在HVRs中产生基本上不降低结合亲和力的保守性改变(例如，本文中提供的保守性取代)。这些改变可能发生在HVR“热点区”或SDRs区域之外。在一些实施例中上文提供的变体VH和VL序列，每一个HVR或者是未发生改变，或者包含不超过1个、2个或3个氨基酸取代。In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, so long as such changes do not substantially reduce the ability of the antibody to bind the antigen. For example, conservative changes (eg, conservative substitutions provided herein) can be made in HVRs that do not substantially reduce binding affinity. These changes may occur outside the HVR "hot zone" or SDRs area. In some embodiments of the variant VH and VL sequences provided above, each HVR is either unchanged or contains no more than 1, 2, or 3 amino acid substitutions.
一种有用的可以鉴定出抗体中能被靶向性突变的氨基酸残基或区域的方法称为“丙氨酸扫描突变”，如Cunningham and Wells(1989)Science,244:1081-1085中所述。在该方法中，一个或一组目标残基(例如，带电残基如精氨酸、天冬氨酸、组氨酸、赖氨酸和谷氨酸)被中性或带负电荷氨基酸(例如，丙氨酸或谷氨酸)取代，以此来确定抗体与抗原相互作用是否受到影响。可以在氨基酸的位置进一步引入取代，来证明该位置对初始取代具有功能敏感性。或者/另外，通过抗原-抗体复合物的晶体结构来鉴定抗体和抗原之间的接触位点。这些接触位点残基和邻近残基可作为取代候选物而被靶向或消除。筛选变体，确定它们是否具有所需要的性质。A useful method for identifying amino acid residues or regions of an antibody that can be targeted mutated is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085 . In this method, one or a group of target residues (e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamic acid) are replaced by neutral or negatively charged amino acids (e.g., , alanine or glutamic acid) substitution to determine whether the interaction between the antibody and the antigen is affected. Further substitutions can be introduced at amino acid positions to demonstrate functional sensitivity of the position to the initial substitution. Alternatively/in addition, the contact sites between the antibody and the antigen are identified through the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues can be targeted or eliminated as substitution candidates. Screen variants to determine if they have the desired properties.
氨基酸序列的插入，包括在氨基端和/或羧基末端的融合，长度范围从1个残基到包含100个或更多个残基的多肽，还包括在序列内插入1个或多个氨基酸残基。末端插入的例子包括N末端具有甲硫氨酰残基的抗体。抗体分子的其它插入变体，包括在抗体分子N-末端或C-末端融合一个酶(例如，ADEPT)或增加抗体血清半衰期的多肽。Insertions of amino acid sequences, including fusions at the amino and/or carboxyl terminus, ranging in length from 1 residue to polypeptides containing 100 or more residues, and including insertion of 1 or more amino acid residues within the sequence base. Examples of terminal insertions include antibodies with a methionyl residue at the N-terminus. Other insertional variants of antibody molecules include fusion of an enzyme (eg, ADEPT) or peptides that increase the serum half-life of the antibody to the N- or C-terminus of the antibody molecule.
Fc区变体Fc region variants
在一些实施例中，将一个或多个氨基酸修饰引入本文所述的抗体(例如，全长抗Nogo-A抗体或抗Nogo-A抗体融合蛋白)的Fc区，从而产生Fc区变体。在一些实施例中，Fc区变体具有增强的ADCC效能，通常与结合Fc的受体(FcRs)有关。在一些实施例中，Fc区变体具有降低的ADCC效能。有很多关于Fc序列的改变或突变影响其效能的例子，例如，WO 00/42072和Shields et al.J Biol.Chem.9(2):6591-6604(2001)描述了与FcRs的结合增强或减弱的抗体变体。这些出版物的内容通过引用并入本文。In some embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody described herein (eg, a full-length anti-Nogo-A antibody or an anti-Nogo-A antibody fusion protein), thereby generating Fc region variants. In some embodiments, Fc region variants have enhanced ADCC potency, typically associated with binding to Fc receptors (FcRs). In some embodiments, Fc region variants have reduced ADCC efficacy. There are many examples of changes or mutations in the Fc sequence affecting its potency. For example, WO 00/42072 and Shields et al. J Biol. Chem. 9(2):6591-6604 (2001) describe enhanced binding to FcRs or Attenuated antibody variants. The contents of these publications are incorporated herein by reference.
抗体依赖的细胞介导的细胞毒作用(ADCC)是治疗性抗体针对肿瘤细胞的作用机制。ADCC是细胞介导的免疫防御，当靶细胞膜表面的抗原被特异性抗体(例如，抗Nogo-A抗体)结合，免疫系统的效应细胞主动裂解靶细胞(例如，癌细胞)。通常ADCC效应涉及由抗体激活的NK细胞。NK细胞表达Fc受体CD16。该受体识别并结合与靶细胞表面相结合的抗体分子的Fc部分。NK细胞表面最常见的Fc受体为CD16或FcγRIII。Fc受体与抗体Fc区的结合导致NK细胞的活化，释放细胞裂解颗粒，随后靶细胞凋亡。ADCC对肿瘤细胞的杀伤作用可以通过转染高亲和力FcR的NK-92细胞的特异性实验来测定。其结果与不表达FcR的野生型NK-92进行比较。Antibody-dependent cell-mediated cytotoxicity (ADCC) is the mechanism of action of therapeutic antibodies against tumor cells. ADCC is a cell-mediated immune defense. When the antigen on the surface of the target cell membrane is bound by a specific antibody (for example, anti-Nogo-A antibody), the effector cells of the immune system actively lyse the target cell (for example, cancer cells). Typically ADCC effects involve NK cells activated by antibodies. NK cells express the Fc receptor CD16. This receptor recognizes and binds to the Fc portion of the antibody molecule bound to the surface of the target cell. The most common Fc receptors on the surface of NK cells are CD16 or FcγRIII. Binding of Fc receptors to the Fc region of antibodies results in activation of NK cells, release of cell lytic granules, and subsequent target cell apoptosis. The killing effect of ADCC on tumor cells can be measured through specific experiments of NK-92 cells transfected with high-affinity FcR. The results were compared with wild-type NK-92, which does not express FcR.
在一些实施例中，本申请还提供抗Nogo-A抗体变体(例如全长抗Nogo-A抗体变体)，其包含具有部分但不是全部的效应功能Fc区，使得其在体内具有延长的半衰期，然而特定的效应功能(例如CDC或ADCC)是非必需的或有害的，这种抗Nogo-A抗体成为本申请理想的候选。通过在体外和/或体内进行细胞毒性检测来确认CDC和/或ADCC活性的减少/消除。例如，通过Fc受 体(FcR)结合试验来确认抗体缺乏FcγR结合能力(因此可能缺乏ADCC活性)但依然保留FcRn的结合能力。介导ADCC的主要细胞中，NK细胞仅表达FcγRIII，而单核细胞表达FcγRI、FcγRII和FcγRIII。Ravetch and Kinet Annu.Rev.Immunol.9:457-492(1991)第464页的表3中总结了FcR在造血细胞上的表达。在体外评估目标分子的ADCC活性的非限制性实例在U.S.Pat.No.5,500,362中进行了描述(参见例如Hellstrom,I.et al.Proc.Nat'l Acad.Sci.USA 83:7059-7063(1986)and Hellstrom,I et al.,Proc.Nat'l Acad.Sci.USA 82:1499-1502(1985)；U.S.Pat.No.5,821,337(see Bruggemann,M.et al.,J.Exp.Med.166:1351-1361(1987))。或者，可以采用非放射性检测方法(参见，例如ACTITM流式细胞术非放射性细胞毒性检测(CellTechnology,Inc.Mountain View,Calif.)和CYTOTOX 96TM非放射性细胞毒性检测(Promega,Madison,Wis.))。此类检测实验采用的效应细胞包括外周血单核细胞(PBMC)和自然杀伤细胞(NK)。或者，另外地，目标分子的ADCC活性在体内进行检测，例如，在动物模型中，如Clynes et al.Proc.Nat'l Acad.Sci.USA 95:652-656(1998)中所述。同时还可以进行C1q结合试验来确认抗体不能与C1q结合，从而缺乏CDC活性。参见，例如WO 2006/029879和WO 2005/100402中C1q和C3c结合ELISA。为了评估补体激活情况，可进行CDC检测(参见，例如Gazzano-Santoro et al.,J.Immunol.Methods 202:163(1996)；Cragg,M.S.et al.,Blood 101:1045-1052(2003)；和Cragg,M.S.and M.J.Glennie,Blood 103:2738-2743(2004))。使用本领域已知的方法来测定FcRn结合和体内清除/半衰期(参见，例如，Petkova,S.B.et al.,Int'l.Immunol.18(12):1759-1769(2006))。In some embodiments, the application also provides anti-Nogo-A antibody variants (e.g., full-length anti-Nogo-A antibody variants) that comprise an Fc region having some, but not all, of the effector functions such that they have extended in vivo half-life, however specific effector functions (such as CDC or ADCC) are non-essential or deleterious, making this anti-Nogo-A antibody an ideal candidate for this application. Reduction/elimination of CDC and/or ADCC activity is confirmed by performing cytotoxicity assays in vitro and/or in vivo. For example, via Fc (FcR) binding assay to confirm that the antibody lacks FcγR binding ability (and therefore may lack ADCC activity) but still retains FcRn binding ability. Among the main cells that mediate ADCC, NK cells only express FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assessment of ADCC activity of target molecules are described in US Pat. No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986 ) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); US Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166 :1351-1361 (1987)). Alternatively, nonradioactive detection methods can be used (see, e.g., ACTI ™ Flow Cytometry Nonradioactive Cytotoxicity Assay (Cell Technology, Inc. Mountain View, Calif.) and CYTOTOX 96 ™ Nonradioactive Cell Toxicity assays (Promega, Madison, Wis.). Effector cells used in these assays include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, the ADCC activity of the target molecule is performed in vivo Detection, for example, in animal models, as described in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q , thereby lacking CDC activity. See, for example, C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay can be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). Determined using methods known in the art FcRn binding and clearance/half-life in vivo (see, eg, Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).
具有降低的效应功能的抗体，包括在Fc区残基238、265、269、270、297、327和329位进行一个或多个残基的取代(U.S.Pat.No.6,737,056)。这些Fc变体包括在265、269、270、297和327位进行两个或多个残基的取代的Fc变体，包括被称为“DANA”的Fc变体，其在265和297位残基取代为丙氨酸(U.S.Pat.No.7,332,581)。Antibodies with reduced effector function include substitution of one or more residues at residues 238, 265, 269, 270, 297, 327, and 329 of the Fc region (U.S. Pat. No. 6,737,056). These Fc variants include Fc variants with substitutions of two or more residues at positions 265, 269, 270, 297 and 327, including the Fc variant known as "DANA" which has substitutions at residues 265 and 297. The base is substituted with alanine (U.S. Pat. No. 7,332,581).
这类与FcRs结合能力提高或降低的抗体变体已有描述(参见例如U.S.Pat.No.6,737,056；WO2004/056312，和Shields et al.,J.Biol.Chem.9(2):6591-6604(2001))。Such antibody variants with increased or decreased binding ability to FcRs have been described (see, e.g., U.S. Pat. No. 6,737,056; WO2004/056312, and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001)).
在一些实施例中，提供一种抗Nogo-A抗体(例如全长的抗Nogo-A抗体)变体，其包含具有一个或多个能够增强ADCC效应的氨基酸取代的Fc区变体。在一些实施例中，Fc区变体包含一个或多个能够增强ADCC效应的氨基取代，这些取代的位置在Fc区的298、333和/或334位(EU残基编号)。在一些实施例中，所述抗Nogo-A抗体(例如，全长的抗Nogo-A抗体)变体包括在Fc区的S298A，E333A和K334A位氨基酸取代。In some embodiments, an anti-Nogo-A antibody (eg, a full-length anti-Nogo-A antibody) variant is provided that includes an Fc region variant with one or more amino acid substitutions capable of enhancing ADCC effects. In some embodiments, the Fc region variant contains one or more amino substitutions capable of enhancing the ADCC effect at positions 298, 333 and/or 334 (EU residue numbering) of the Fc region. In some embodiments, the anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) variant includes amino acid substitutions at positions S298A, E333A, and K334A in the Fc region.
在一些实施例中，Fc区的改变导致C1q结合和/或补体依赖性细胞毒作用(CDC)的改变(即增强或减弱)，参见U.S.Pat.No.6,194,551,WO 99/51642，和Idusogie et al.,J.Immunol.164:4178-4184(2000)中所述。In some embodiments, changes in the Fc region result in changes (i.e., enhancement or attenuation) of Clq binding and/or complement-dependent cytotoxicity (CDC), see U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. al., J. Immunol. 164:4178-4184 (2000).
在一些实施例中，提供一种抗Nogo-A抗体(例如全长的抗Nogo-A抗体)变体，其包含具有一个或多个氨基酸取代的Fc区变体，能够延长半衰期或增强与Fc受体(FcRn)的结合。具有延长半衰期和改善FcRn结合的抗体在US 2005/0014934A1(Hinton等)中有所描述。这些抗体Fc区 包含一个或多个氨基酸取代，增强了Fc区与FcRn的结合。这些Fc变体在Fc区包含238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434位的残基中的一个或多个取代，例如Fc区434位残基的取代(U.S.Pat.No.7,371,826)。In some embodiments, an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody) variant is provided that includes an Fc region variant with one or more amino acid substitutions capable of extending half-life or enhancing association with the Fc Receptor (FcRn) binding. Antibodies with extended half-life and improved FcRn binding are described in US 2005/0014934A1 (Hinton et al.). These antibody Fc regions Contains one or more amino acid substitutions that enhance the binding of the Fc region to FcRn. These Fc variants contain 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or One or more substitutions in residue 434, such as substitution of residue 434 in the Fc region (US Pat. No. 7,371,826).
同时参见Duncan&Winter,Nature 322:738-40(1988)；U.S.Pat.No.5,648,260；U.S.Pat.No.5,624,821和WO 94/29351中提供其它Fc区变体的例子。See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Pat. No. 5,648,260; U.S. Pat. No. 5,624,821 and WO 94/29351 for other examples of Fc region variants.
本申请考虑了包括本文所述的任一种Fc变体或其组合的抗Nogo-A抗体(例如全长抗Nogo-A抗体)。This application contemplates anti-Nogo-A antibodies (eg, full-length anti-Nogo-A antibodies) that include any of the Fc variants described herein, or combinations thereof.
糖基化变体Glycosylation variants
在一些实施例中，对本文所提供的抗Nogo-A抗体(例如全长抗Nogo-A抗体)进行改变，以增加或降低抗NGF抗体糖基化的程度。通过改变抗NGF抗体或其多肽部分的氨基酸序列以此来增加或去除一个或多个糖基化位点，可以方便地实现添加或删除抗Nogo-A抗体上的糖基化位点。In some embodiments, anti-Nogo-A antibodies provided herein (eg, full-length anti-Nogo-A antibodies) are altered to increase or decrease the extent of glycosylation of the anti-NGF antibody. Adding or deleting glycosylation sites on the anti-Nogo-A antibody can be easily accomplished by changing the amino acid sequence of the anti-NGF antibody or its polypeptide portion to add or remove one or more glycosylation sites.
其中抗Nogo-A抗体包含Fc区，可以改变与其连接的糖。由哺乳动物细胞产生的天然抗体通常包含分支的双触角寡糖，该寡糖通常通过N-连接与Fc区CH2结构域Asn297连接，参见例如Wright et al.，TIBTECH 15:26-32(1997)。所述寡糖可包含多种糖类，例如甘露糖、N-乙酰氨基葡萄糖苷(GlcNAc)、半乳糖和唾液酸，以及与双触角寡糖结构“茎”部的GlcNAc相连接的海藻糖。在一些实施例中，可对本申请的抗Nogo-A抗体进行寡糖修饰，从而产生具有某些改进特性的抗Nogo-A抗体变体。The anti-Nogo-A antibody contains an Fc region that can change the sugar attached to it. Natural antibodies produced by mammalian cells typically contain branched biantennary oligosaccharides that are often linked to the Fc region CH2 domain Asn297 via an N-link, see e.g. Wright et al., TIBTECH 15:26-32 (1997) . The oligosaccharides can include a variety of sugars, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as trehalose linked to GlcNAc in the "stem" portion of the biantennary oligosaccharide structure. In some embodiments, the anti-Nogo-A antibodies of the present application can be subjected to oligosaccharide modifications, thereby producing anti-Nogo-A antibody variants with certain improved properties.
与Fc区的CH2结构域连接的N-聚糖是异质的。CHO细胞中产生的抗体或Fc融合蛋白通过岩藻糖基转移酶活性被岩藻糖基化，参见Shoji-Hosaka et al.,J.Biochem.2006,140:777-83。通常，可以在人血清中检测出一小部分天然存在的非岩藻糖基化IgGs。Fc区的N-糖基化对于其与FcγR结合很重要；而非岩藻糖基化的N-聚糖增强了Fc与FcγRIIIa的结合能力。与FcRIIIa结合能力增强使得ADCC效应增强，这在需要细胞毒性的某些抗体治疗应用中是有利的。The N-glycans linked to the CH2 domain of the Fc region are heterogeneous. Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al., J. Biochem. 2006, 140:777-83. Typically, a small proportion of naturally occurring afucosylated IgGs can be detected in human serum. N-glycosylation of the Fc region is important for its binding to FcγR; afucosylated N-glycan enhances the binding ability of Fc to FcγRIIIa. The enhanced binding ability to FcRIIIa results in enhanced ADCC effect, which is advantageous in certain antibody therapeutic applications that require cytotoxicity.
在一些实施例中，当不需要Fc介导的细胞毒作用时，增强的效应功能可能是有害的。在一些实施例中，Fc片段或CH2结构域是非糖基化的。在一些实施例中，通过对CH2结构域中的N-糖基化位点进行突变以阻止其糖基化。In some embodiments, enhanced effector function may be detrimental when Fc-mediated cytotoxicity is not required. In some embodiments, the Fc fragment or CH2 domain is non-glycosylated. In some embodiments, glycosylation is prevented by mutating the N-glycosylation site in the CH2 domain.
在一些实施例中，提供抗Nogo-A抗体(例如全长的抗Nogo-A抗体)变体，其包含Fc区，其中连接于Fc区的糖类结构具有减少的岩藻糖或缺乏岩藻糖，这可能会增强ADCC功能。具体地，本文提供抗Nogo-A抗体，其相对于野生型CHO细胞产生的相同抗Nogo-A抗体具有减少的岩藻糖。也就是说，它们的特征在于，与天然CHO细胞(例如，产生天然糖基化形式的CHO细胞，含有天然FUT8基因的CHO细胞)产生的抗体相比，具有更少量的岩藻糖。在一些实施例中，所述抗Nogo-A抗体的N-连接聚糖具有少于50％、40％、30％、20％、10％或 5％的岩藻糖。例如，该抗Nogo-A抗体的岩藻糖含量可能是1％-80％、1％-65％、5％-65％或20％-40％。在一些实施例中，所述抗Nogo-A抗体的N-连接聚糖不包含岩藻糖，即，其中抗Nogo-A抗体完全不含岩藻糖， 或没有岩藻糖或是去岩藻糖基化。岩藻糖的含量是通过计算连接到Asn297上的糖链内岩藻糖平均含量相对于通过MALDI-TOF质谱测量的所有连接在Asn297上的糖结构(如复合、杂交或甘露糖结构)的总量来确定的，如WO 2008/077546所述。Asn297是指位于Fc区297位的天冬酰胺残基(EU Fc区残基编号体系)。然而，由于抗体的微小序列变化，Asn297也可位于297位的上游或下游±3个氨基酸，即在294和300位之间。这些岩藻糖基化变体可能具有增强的ADCC功能。参见例如US Patent Publication Nos.US 2003/0157108(Presta,L.)，US 2004/0093621(Kyowa Hakko Kogyo Co.,Ltd)。与“去岩藻糖基化”或“岩藻糖缺乏”的抗体变体相关的出版物的实例包括，US 2003/0157108；WO 2000/61739；WO 2001/29246；US 2003/0115614；US 2002/0164328；US 2004/0093621；US 2004/0132140；US 2004/0110704；US 2004/0110282；US 2004/0109865；WO 2003/085119；WO 2003/084570；WO 2005/035586；WO 2005/035778；WO 2005/053742；WO 2002/031140；Okazaki et al.J.Mol.Biol.336:1239-1249(2004)；Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004)。能够产生去岩藻糖基化抗体的细胞系包括缺乏蛋白岩藻糖基化功能的Lec13CHO细胞(Ripka et al.Arch.Biochem.Biophys.249:533-545(1986)；US Pat Appl No US 2003/0157108 A1,Presta,L；和WO 2004/056312 A1,Adams et al.,尤其是实施例11)，和基因敲除细胞系，例如α-1,6-岩藻糖基转移酶基因，FUT8基因敲除的CHO细胞(参见Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004)；Kanda,Y.et al.,Biotechnol.Bioeng.,94(4):680-688(2006)；和WO2003/085107)。In some embodiments, anti-Nogo-A antibody (e.g., full-length anti-Nogo-A antibody) variants are provided that comprise an Fc region, wherein the carbohydrate structure linked to the Fc region has reduced fucose or lacks fucose. Sugar, which may enhance ADCC function. Specifically, provided herein are anti-Nogo-A antibodies that have reduced fucose relative to the same anti-Nogo-A antibody produced by wild-type CHO cells. That is, they are characterized by having smaller amounts of fucose than antibodies produced by native CHO cells (e.g., CHO cells that produce the native glycosylated form, CHO cells that contain the native FUT8 gene). In some embodiments, the N-linked glycan of the anti-Nogo-A antibody has less than 50%, 40%, 30%, 20%, 10%, or 5% fucose. For example, the fucose content of the anti-Nogo-A antibody may be 1%-80%, 1%-65%, 5%-65%, or 20%-40%. In some embodiments, the N-linked glycans of the anti-Nogo-A antibody do not contain fucose, i.e., wherein the anti-Nogo-A antibody contains no fucose at all, Either without fucose or defucosylated. The fucose content is calculated by calculating the average fucose content within the sugar chain attached to Asn297 relative to the total of all sugar structures attached to Asn297 (such as complex, hybrid or mannose structures) measured by MALDI-TOF mass spectrometry. quantity, as described in WO 2008/077546. Asn297 refers to the asparagine residue located at position 297 of the Fc region (EU Fc region residue numbering system). However, due to minor sequence changes in the antibody, Asn297 can also be located ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. These fucosylation variants may have enhanced ADCC function. See, for example, US Patent Publication Nos. US 2003/0157108 (Presta, L.), US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to "afucosylated" or "fucose-deficient" antibody variants include, US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002 /0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/03558 6;WO 2005/035778;WO 2005 /053742; WO 2002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004). Cell lines capable of producing afucosylated antibodies include Lec13 CHO cells lacking protein fucosylation function (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003 /0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially Example 11), and gene knockout cell lines, such as α-1,6-fucosyltransferase gene, FUT8 Gene knockout CHO cells (see Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003/085107).
抗Nogo-A抗体(例如全长抗Nogo-A抗体)变体进一步提供二等分寡糖，例如，其中连接于抗Nogo-A抗体Fc区的双触角寡糖被GlcNAc等分。这种抗Nogo-A抗体(例如全长的抗Nogo-A抗体)变体可能具有减少的岩藻糖基化和/或增强的ADCC功能。这类抗体变体的实例在WO 2003/011878(Jean-Mairet et al.)；U.S.Pat.No.6,602,684(Umana et al.)；US 2005/0123546(Umana et al.)，和Ferrara et al.,Biotechnology and Bioengineering,93(5):851-861(2006)中有所描述。还提供抗Nogo-A抗体(例如全长的抗Nogo-A抗体)变体，其在与Fc区连接的寡糖中具有至少一个半乳糖残基。这类抗Nogo-A抗体变体可能具有增强的CDC功能。这类变体在例如WO1997/30087(Patel et al.)；WO 1998/58964(Raju,S.)；和WO 1999/22764(Raju,S.)中有所描述。Anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) variants further provide bisecting oligosaccharides, eg, wherein the biantennary oligosaccharide linked to the Fc region of the anti-Nogo-A antibody is bisected by GlcNAc. Such anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) variants may have reduced fucosylation and/or enhanced ADCC function. Examples of such antibody variants are in WO 2003/011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana et al.); US 2005/0123546 (Umana et al.), and Ferrara et al. Described in ,Biotechnology and Bioengineering, 93(5):851-861(2006). Also provided are anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) variants having at least one galactose residue in the oligosaccharide linked to the Fc region. Such anti-Nogo-A antibody variants may have enhanced CDC function. Such variants are described, for example, in WO1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
在一些实施例中，所述抗Nogo-A抗体(例如全长抗Nogo-A抗体)变体包含能与FcγRIII结合的Fc区。在一些实施例中，包含Fc区的所述抗Nogo-A抗体(例如全长抗Nogo-A抗体)变体在人效应细胞(例如T细胞)存在下具有ADCC活性，或者与具有人野生型IgG1Fc区的其他相同抗Nogo-A抗体(例如全长抗Nogo-A抗体)相比，在人效应细胞存在下，具有增强的ADCC活性。In some embodiments, the anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) variant comprises an Fc region capable of binding FcyRIII. In some embodiments, the anti-Nogo-A antibody (e.g., full-length anti-Nogo-A antibody) variant comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells), or is identical to a human wild-type The Fc region of IgG1 has enhanced ADCC activity in the presence of human effector cells compared to other identical anti-Nogo-A antibodies (eg, full-length anti-Nogo-A antibodies).
半胱氨酸工程变体Cysteine engineered variants
在一些实施例中，需要制备半胱氨酸工程化的抗Nogo-A抗体(例如全长抗Nogo-A抗体)，在该抗体中一个或多个氨基酸残基被半胱氨酸残基取代。在一些实施例中，取代残基出现在抗 Nogo-A抗体的可及位点。通过用半胱氨酸取代那些残基，具有活性的巯基基团位于抗Nogo-A抗体的可及位点，可以用于将该抗Nogo-A抗体与其它部分偶联，例如药物部分或接头-药物部分，来制备如本文中进一步描述的抗Nogo-A免疫偶联物。半胱氨酸工程化的抗Nogo-A抗体(例如，全长抗Nogo-A抗体)可以按照例如U.S.Pat.No.7,521,541所述进行制备。In some embodiments, it is desirable to prepare a cysteine-engineered anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody) in which one or more amino acid residues are replaced with cysteine residues . In some embodiments, the substituted residue occurs in the anti- Accessible sites for Nogo-A antibodies. By replacing those residues with cysteine, reactive thiol groups are located in accessible sites of the anti-Nogo-A antibody and can be used to couple the anti-Nogo-A antibody to other moieties, such as drug moieties or linkers. - a drug moiety to prepare an anti-Nogo-A immunoconjugate as further described herein. Cysteine-engineered anti-Nogo-A antibodies (eg, full-length anti-Nogo-A antibodies) can be prepared, for example, as described in US Pat. No. 7,521,541.
衍生物derivative
在一些实施例中，本文所提供的抗Nogo-A抗体(例如全长抗Nogo-A抗体)可进一步修饰以包含本领域已知并且容易获得的其它非蛋白部分。适用于衍生化抗Nogo-A抗体的部分包括，但不限于，水溶性聚合物。水溶性聚合物的非限制性实例包括，但不限于，聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纤维素、右旋糖酐、聚乙烯醇、聚乙烯吡咯烷酮、聚-1,3-二氧戊烷、聚-1,3,6-三氧杂环已烷、乙烯/马来酸酐共聚物、聚氨基酸(均聚物或无规共聚物)、右旋糖酐或聚(n-乙烯基吡咯烷酮)聚乙二醇、丙二醇均聚物、环氧丙烷/环氧乙烷共聚物、聚氧乙基化多元醇(例如甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛由于其在水中的稳定性，在制造中具有优势。聚合物可以具有任意分子量，可以是支链或非支链的。连接在抗Nogo-A抗体上的聚合物数量可以变化，并且如果连接多于一个多聚物，它们可以是相同的或不同的分子。通常，用于衍生化的聚合物的数量和/或类型可基于以下考虑因素来确定，包括但不限于，需要改进抗Nogo-A抗体的特性或功能，抗Nogo-A抗体衍生物是否用于特定条件下的治疗等。In some embodiments, anti-Nogo-A antibodies (eg, full-length anti-Nogo-A antibodies) provided herein can be further modified to include other non-protein moieties known in the art and readily available. Suitable moieties for derivatizing anti-Nogo-A antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymer, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1 , 3-dioxopentane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer), dextran or poly(n- vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymer, propylene oxide/ethylene oxide copolymer, polyoxyethylated polyols (such as glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde offers advantages in manufacturing due to its stability in water. The polymers can be of any molecular weight and can be branched or unbranched. The number of polymers attached to the anti-Nogo-A antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. Generally, the amount and/or type of polymer used for derivatization can be determined based on considerations including, but not limited to, the need to improve the properties or functionality of the anti-Nogo-A antibody, whether the anti-Nogo-A antibody derivative is used Treatment for specific conditions, etc.
药物组合物pharmaceutical composition
本文还提供包含任一种抗Nogo-A抗体(例如全长抗Nogo-A抗体)、编码抗体的核酸、包含编码抗体的核酸的载体或者包含本文所述的核酸或载体的宿主细胞的组合物(例如药物组合物，在这里也称为制剂)。在一些实施例中，提供一种药物组合物，包含本文所述的任一种抗Nogo-A抗体和药学上可接受的载体。Also provided herein are compositions comprising any anti-Nogo-A antibody (eg, a full-length anti-Nogo-A antibody), a nucleic acid encoding the antibody, a vector comprising a nucleic acid encoding an antibody, or a host cell comprising a nucleic acid or vector described herein (For example, pharmaceutical compositions, also referred to herein as formulations). In some embodiments, a pharmaceutical composition is provided comprising any of the anti-Nogo-A antibodies described herein and a pharmaceutically acceptable carrier.
可通过混合具有所需纯度的抗Nogo-A抗体与任选的药学上可接受的载体、赋形剂或稳定剂(Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))获得合适的抗Nogo-A抗体制剂，制备成冻干制剂或液体制剂形式。可接受的载体、赋形剂或稳定剂在所用剂量和浓度下对接受者无毒，包括缓冲剂如：磷酸盐、柠檬酸和其它有机酸；抗氧化剂，包括抗坏血酸和蛋氨酸；防腐剂(例如十八烷基二甲基苄基氯化铵；六甲基氯化铵；苯扎氯铵；苄索氯铵；苯酚；丁醇或苄醇；对羟基苯甲酸烷基酯，如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯；邻苯二酚；间苯二酚；环己醇；3-戊醇和间甲酚)；低分子量(少于10个残基)多肽；蛋白质，例如血清白蛋白、明胶或免疫球蛋白；亲水性聚合物，如聚乙烯吡咯烷酮；氨基酸，例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸；单糖、二糖和其它碳水化合物，包括葡萄糖、甘露糖或糊精；螯合剂如EDTA；糖类，如蔗糖、甘露醇、海藻糖或山梨糖醇；成盐反离子如钠；金属复合物(如锌-蛋白复合物)；和/或非离子表面活性剂如TWEENTM，PLURONICSTM或聚乙二醇(PEG)；示例性制剂如WO98/56418中所述，并通过引用明确并入本文。适合皮下给药的冻干制剂在 WO97/04801中有所描述。这类冻干制剂可通过合适的稀释剂重构成高蛋白浓度的制剂，并且重构的制剂可以通过皮下给药的方式给予本文中待治疗个体。阳离子脂质体或脂质体可以用于将本申请中的抗Nogo-A抗体递送至细胞。A suitable antibody can be obtained by mixing an anti-Nogo-A antibody of the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)) Anti-Nogo-A antibody preparations are prepared in the form of lyophilized preparations or liquid preparations. Acceptable carriers, excipients or stabilizers are non-toxic to the recipient at the doses and concentrations used and include buffers such as phosphates, citric acid and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g. Octadecyldimethylbenzyl ammonium chloride; hexamethylammonium chloride; benzalkonium chloride; benzethonium chloride; phenol; butanol or benzyl alcohol; alkyl parabens, such as p-hydroxybenzoate Methyl formate or propyl parahydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than 10 residues) peptides; proteins, e.g. serum Albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes such as zinc-protein complex); and/or non-ionic surfactants such as TWEEN ™ , PLURONICS ™ or polyethylene glycol (PEG); exemplary formulations are as described in WO98/56418, expressly incorporated herein by reference. Lyophilized formulations suitable for subcutaneous administration are available in Described in WO97/04801. Such lyophilized formulations can be reconstituted with appropriate diluents into high protein concentration formulations, and the reconstituted formulations can be administered subcutaneously to the individuals to be treated herein. Cationic liposomes or liposomes can be used to deliver the anti-Nogo-A antibodies of the present application to cells.
本文所述的制剂除包含抗Nogo-A抗体(例如全长抗Nogo-A抗体)之外，还可以包含一种或多种治疗特定病症所必要的其它活性物质，优选具有活性互补且彼此无不良反应的物质。例如，除了抗Nogo-A抗体之外，可能需要进一步包含皮质类固醇，神经营养因子如NGF、BDNF，或其他用于神经退化疾病的药物如ExelonTM、Levodopa等。这些分子以对预期目的有效的量组合存在。其它物质的有效量取决于制剂中的抗Nogo-A抗体的含量，疾病或病症或治疗的类型，以及如上所述的其它因素。这些药物通常以与本文描述的相同剂量和给药途径使用，或者以目前应用剂量的1％至99％使用。The formulations described herein, in addition to anti-Nogo-A antibodies (eg, full-length anti-Nogo-A antibodies), may also contain one or more other active substances necessary for the treatment of a specific disorder, preferably with complementary and mutually exclusive activities. adverse reaction substances. For example, in addition to anti-Nogo-A antibodies, it may be necessary to further include corticosteroids, neurotrophic factors such as NGF, BDNF, or other drugs for neurodegenerative diseases such as Exelon ™ , Levodopa, etc. These molecules are present in combination and in amounts effective for the intended purpose. Effective amounts of other substances will depend on the amount of anti-Nogo-A antibody in the formulation, the type of disease or condition or treatment, and other factors as discussed above. These drugs are typically used at the same dosages and routes of administration as described herein, or at 1% to 99% of currently used doses.
所述抗Nogo-A抗体(例如，全长抗Nogo-A抗体)也可以包埋在例如通过凝聚技术和界面聚合制备的微胶囊中，例如分别在胶体药物递送系统(例如，脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊)中或粗乳液中的羟甲基纤维素或明胶-微胶囊和聚(甲基丙烯酸甲酯)微胶囊。可以制备缓释制剂。The anti-Nogo-A antibody (e.g., full-length anti-Nogo-A antibody) can also be embedded in microcapsules prepared, for example, by coacervation techniques and interfacial polymerization, such as in colloidal drug delivery systems (e.g., liposomes, Hydroxymethylcellulose or gelatin-microcapsules and poly(methyl methacrylate) microcapsules in albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Sustained release formulations can be prepared.
可以制备抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的缓释制剂。缓释制剂的适合的实例包括含有抗体(或其片段)的固体疏水聚合物半透性基质，这些基质是成型制品的形式，例如，薄膜或微胶囊。缓释基质的实例包括聚酯、水凝胶(例如，聚(2-羟乙基甲基丙烯酸酯)或聚(乙烯醇))、聚乳酸(U.S.Pat.No.3,773,919)，L-谷氨酸和L-谷氨酸乙酯共聚物，不可降解的乙烯-醋酸乙烯酯，可降解的乳酸-乙醇酸共聚物如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林组成的可注射微球)以及聚-D(-)-3-羟基丁酸。虽然诸如乙烯-醋酸乙烯酯和乳酸-乙醇酸之类的聚合物可以使分子的释放超过100天，某些水凝胶可以在更短的时间内释放蛋白质。当包封的抗体在体内长时间停留时，它们会因暴露于37℃的潮湿环境中发生变性或聚集，可能导致生物活性的丧失或免疫原性的改变。可以根据相应的机制，设计合理的策略来稳定抗Nogo-A抗体。例如，如果发现聚集机制是通过硫代二硫化物交换形成分子间S-S键，则可以通过修饰巯基残基、在酸性溶液中冻干、控制含水量、使用适当的添加剂、以及开发特定的聚合物基质组合物来实现稳定化。Sustained release formulations of anti-Nogo-A antibodies (eg, full-length anti-Nogo-A antibodies) can be prepared. Suitable examples of sustained release formulations include solid hydrophobic polymeric semipermeable matrices containing the antibodies (or fragments thereof) in the form of shaped articles, for example, films or microcapsules. Examples of sustained-release matrices include polyester, hydrogel (eg, poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid (U.S. Pat. No. 3,773,919), L-glutamine Acid and L-glutamic acid ethyl ester copolymer, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer such as LUPRON DEPOTTM (a biodegradable product composed of lactic acid-glycolic acid copolymer and leuprolide acetate) injection microspheres) and poly-D(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic-glycolic acid can release molecules over 100 days, certain hydrogels can release proteins in much shorter time periods. When encapsulated antibodies stay in the body for a long time, they will denature or aggregate due to exposure to a humid environment at 37°C, which may lead to loss of biological activity or changes in immunogenicity. Reasonable strategies can be designed to stabilize anti-Nogo-A antibodies based on the corresponding mechanisms. For example, if the aggregation mechanism is found to be through thiodisulfide exchange to form intermolecular S-S bonds, this can be achieved by modifying sulfhydryl residues, lyophilizing in acidic solutions, controlling water content, using appropriate additives, and developing specific polymers. matrix composition to achieve stabilization.
在一些实施例中，所述抗Nogo-A抗体(例如全长抗Nogo-A抗体)配制在含有柠檬酸盐、氯化钠、乙酸盐、琥珀酸盐、甘氨酸、聚山梨酯80(吐温80)或上述任何组合的缓冲液中。In some embodiments, the anti-Nogo-A antibody (e.g., full-length anti-Nogo-A antibody) is formulated in a solution containing citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 80) or any combination of the above buffers.
用于体内给药的制剂必须是无菌的。这可以通过例如应用无菌过滤膜过滤而容易地实现。Preparations for in vivo administration must be sterile. This can be easily achieved, for example, by applying sterile filtration membrane filtration.
使用抗Nogo-A抗体的治疗方法Treatment using anti-Nogo-A antibodies
抗Nogo-A抗体(例如，全长的抗Nogo-A抗体)和/或本申请所述的组合物可以施用于个体(例如，哺乳动物，如人类)来治疗Nogo-A信号通路失调导致的疾病和/或病症(例如，中枢神经系统和/或外周神经系统疾病或创伤)，这些疾病包括但不限于神经退行性疾病如阿尔兹海默 病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。因此，本申请在一些实施例中，提供一种治疗患有Nogo-A信号通路失调导致的疾病和/或病症(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向个体施用有效量的包含抗Nogo-A抗体(例如，全长的抗Nogo-A抗体)的组合物(例如，药物组合物)，例如本文所述的任一种抗Nogo-A抗体(例如，全长的抗Nogo-A抗体)，在一些实施例中，所述个体是人类。Anti-Nogo-A antibodies (e.g., full-length anti-Nogo-A antibodies) and/or compositions described herein can be administered to individuals (e.g., mammals, such as humans) to treat disorders resulting from dysregulation of the Nogo-A signaling pathway. Diseases and/or conditions (e.g., central nervous system and/or peripheral nervous system disease or trauma), including but not limited to neurodegenerative diseases such as Alzheimer's disease Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, other common dementias, post-traumatic disorders of the head, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, Monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease, pontine myelmolysis, adrenoleukodystrophy, Pelizois-Metzbach disease, spongiform disease Encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabb's disease, degenerative visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration , diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's vitelliform retinal degeneration, Leber's congenital amaurosis and other inherited retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric disorders such as schizophrenia and depression. Therefore, the present application, in some embodiments, provides a method of treating individuals suffering from diseases and/or conditions caused by dysregulation of the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system diseases or trauma), Comprised of administering to an individual an effective amount of a composition (e.g., a pharmaceutical composition) comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), such as any of the anti-Nogo-A antibodies described herein ( For example, a full-length anti-Nogo-A antibody), in some embodiments, the individual is a human.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含特异性结合人Nogo-A上表位的Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述表位包含人Nogo-A的位氨基酸残基。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The individual is administered an effective amount of a pharmaceutical composition comprising a Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody) that specifically binds to an epitope on human Nogo-A, wherein the epitope comprises an amino acid of human Nogo-A Residues. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYGMH(SEQ ID NO:1)；HC-CDR2，其包含SISHTGKTVFYGESVKG(SEQ ID NO:3)；和HC-CDR3，其包含TELGGDNWFDV(SEQ ID NO:5)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含TGSSSNIGGYDVY(SEQ ID NO:7)；LC-CDR2，其包含DNNKRPS(SEQ ID NO:9)；和LC-CDR3，其包含AAWDDSLYGYI(SEQ ID NO:11)。在一些实施例中，所述抗Nogo-A抗体是全 长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), a heavy chain variable domain ( VH ) comprising: a heavy chain complementarity determining region ( HC-CDR)1, which contains DYGMH (SEQ ID NO:1); HC-CDR2, which contains SISHTGKTVFYGESVKG (SEQ ID NO:3); and HC-CDR3, which contains TELGGDNWFDV (SEQ ID NO:5); and light Chain variable domain (V L ), the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes TGSSSNIGGYDVY (SEQ ID NO: 7); LC-CDR2, which includes DNKRPS (SEQ ID NO :9); and LC-CDR3, which contains AAWDDSLYGYI (SEQ ID NO:11). In some embodiments, the anti-Nogo-A antibody is fully long antibodies. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:1所示的氨基酸序列，HC-CDR2，其包含SEQ ID NO:3所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NO:5所示的氨基酸序列，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:7所示的氨基酸序列，LC-CDR2，其包含SEQ ID NO:9所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NO:11所示的氨基酸序列，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody includes VH , and the VH includes: HC-CDR1, which includes the amino acid sequence shown in SEQ ID NO: 1, HC-CDR2, which includes The amino acid sequence shown in SEQ ID NO:3, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:5, or a variant of the V H whose HC-CDRs include up to about 5 amino acids. Substitution; and VL , the VL includes: LC-CDR1, which includes the amino acid sequence shown in SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO:9, and LC-CDR3 , which includes the amino acid sequence shown in SEQ ID NO: 11, or a variant of said V L , which contains at most about 5 amino acid substitutions in its LC-CDRs.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，所述VH包含SEQ ID NOs:13-16中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:13-16中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，所述VL包含SEQ ID NOs:18-19中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:18-19中任一所示的氨基酸序列具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence shown in any one of SEQ ID NOs: 13-16 or a variant thereof, the variant A body having at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 13-16; and a V L comprising an amino acid sequence shown in any one of SEQ ID NOs: 18-19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 18-19.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:3，和HC-CDR3，其包含氨基酸序列SEQ ID NO:5，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包 含：LC-CDR1，其包含氨基酸序列SEQ ID NO:7，LC-CDR2，其包含氨基酸序列SEQ ID NO:9，和LC-CDR3，其包含氨基酸序列SEQ ID NO:11，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody includes: VH , the VH includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 5, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L bag Containing: LC-CDR1, which includes the amino acid sequence SEQ ID NO:7, LC-CDR2, which includes the amino acid sequence SEQ ID NO:9, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:11, or the V L Variants containing up to about 5 amino acid substitutions in their LC-CDRs.
在一些实施例中，本文所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:13或其变体，所述变体与氨基酸序列SEQ ID NO:13具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:18或其变体，所述变体与氨基酸序列SEQ ID NO:18具有至少约80％序列同一性。在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof that is at least the same as the amino acid sequence SEQ ID NO: 13 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 18 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 18. In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，本文所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:14或其变体，所述变体与氨基酸序列SEQ ID NO:14具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof that is at least the same as the amino acid sequence SEQ ID NO: 14 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 19. In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，本文所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:15或其变体，所述变体与氨基酸序列SEQ ID NO:15具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof that is at least the same as the amino acid sequence SEQ ID NO: 15 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 19. In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，本文所述抗Nogo-A抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:16或其变体，所述变体与氨基酸序列SEQ ID NO:16具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒 定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof that is at least the same as the amino acid sequence SEQ ID NO: 16 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 19. In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant The defined region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:4，和HC-CDR3，其包含氨基酸序列SEQ ID NO:6，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:8，LC-CDR2，其包含氨基酸序列SEQ ID NO:10，和LC-CDR3，其包含氨基酸序列SEQ ID NO:12，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:2, HC-CDR2, which includes the amino acid sequence SEQ ID NO:4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:6, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 8, LC- CDR2, which includes the amino acid sequence of SEQ ID NO: 10, and LC-CDR3, which includes the amino acid sequence of SEQ ID NO: 12, or a variant of the V L whose LC-CDRs include substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，所述VH包含SEQ ID NO:17所示的氨基酸序列或其变体，所述变体与SEQ ID NO:17所示的氨基酸序列具有至少约80％序列同一性；以及VL，所述VL包含SEQ ID NO:20所示的氨基酸序列或其变体，所述变体与SEQ ID NO:20所示的氨基酸序列具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence shown in SEQ ID NO: 17 or a variant thereof, the variant being identical to SEQ ID NO : The amino acid sequence shown in 17 has at least about 80% sequence identity; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:20 or a variant thereof, which variant is identical to SEQ ID NO:20 The amino acid sequences shown have at least about 80% sequence identity.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A 抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYGMH(SEQ ID NO:28)；HC-CDR2，其包含VIWYHGSKKYYADSVKD(SEQ ID NO:48)；和HC-CDR3，其包含SIAETTDYGLDS(SEQ ID NO:65)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLLYRGGKTFLY(SEQ ID NO:85)；LC-CDR2，其包含ELSNRAS(SEQ ID NO:100)；和LC-CDR3，其包含MQGIQLPWT(SEQ ID NO:111)。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual with a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual Contains an effective amount of anti-Nogo-A Pharmaceutical compositions of antibodies (e.g., full-length anti-Nogo-A antibodies), wherein the antibodies comprise: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1, which contains SYGMH (SEQ ID NO:28); HC-CDR2, which contains VIWYHGSKKYYADSVKD (SEQ ID NO:48); and HC-CDR3, which contains SIAETTDYGLDS (SEQ ID NO:65); and light chain variable structures Domain (V L ), the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes RSSQSLLYRGGKTFLY (SEQ ID NO:85); LC-CDR2, which includes ELSNRAS (SEQ ID NO:100); and LC-CDR3, which contains MQGIQLPWT (SEQ ID NO: 111). In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:28所示的氨基酸序列，HC-CDR2，其包含SEQ ID NO:48所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NO:65所示的氨基酸序列，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:85所示的氨基酸序列，LC-CDR2，其包含SEQ ID NO:100所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NO:111所示的氨基酸序列，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。In some embodiments, a method for treating a subject with a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the subject an effective amount A composition comprising an anti-Nogo-A antibody, wherein the antibody comprises VH , and the VH comprises: HC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO:28, HC-CDR2, which comprises SEQ ID The amino acid sequence shown in NO:48, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:65, or a variant of the V H whose HC-CDRs include substitutions of up to about 5 amino acids; and VL , said VL comprising: LC-CDR1, which includes the amino acid sequence shown in SEQ ID NO:85, LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO:100, and LC-CDR3, which Comprising the amino acid sequence shown in SEQ ID NO: 111, or a variant of the VL , the LC-CDRs of which comprise at most about 5 amino acid substitutions.
在一些实施例中，提供一种用于治疗与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含SEQ ID NOs:127-128中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:127-128中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NOs:150-151中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:150-151中任一所示的氨基酸序列具有至少约80％序列同一性。In some embodiments, a method for treating a subject with a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the subject an effective amount A composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence shown in any one of SEQ ID NOs: 127-128 or a variant thereof, the variant being identical to SEQ ID NOs : The amino acid sequence shown in any one of SEQ ID NOs: 127-128 has at least about 80% sequence identity; and VL , which includes the amino acid sequence shown in any one of SEQ ID NOs: 150-151 or a variant thereof, the variant The entity has at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 150-151.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或 由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or It consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，本文所述抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:127或其变体，所述变体与氨基酸序列SEQ ID NO:127具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性。在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 127 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 127 Sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 150 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 150. In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，本文所述抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:151或其变体，所述变体与氨基酸序列SEQ ID NO:151具有至少约80％序列同一性。在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 128 Sequence identity; and VL comprising the amino acid sequence SEQ ID NO:151 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:151. In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
在一些实施例中，本文所述抗Nogo-A抗体包含：VH，其包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性。在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, the anti-Nogo-A antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 128 Sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 150 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 150. In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:29，HC-CDR2，其包含氨基酸序列SEQ ID NO:49，和HC-CDR3，其包含氨基酸序列SEQ ID NO:66，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:86，LC-CDR2，其包含氨基酸序列SEQ ID NO:101，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112，或者所述VL的变体，其LC-CDRs中包含至多约 5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 29, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 49, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 66, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 86, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 101, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 112, or a variant of said V L whose LC-CDRs comprise at most about 5 amino acid substitutions. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含SEQ ID NO:129所示的氨基酸序列或其变体，所述变体与SEQ ID NO:129所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:152所示的氨基酸序列或其变体，所述变体与SEQ ID NO:152所示的氨基酸序列具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence shown in SEQ ID NO: 129 or a variant thereof, which variant is identical to that shown in SEQ ID NO: 129 The amino acid sequence shown has at least about 80% sequence identity; and V L includes the amino acid sequence shown in SEQ ID NO: 152 or a variant thereof, which variant has the same amino acid sequence as the amino acid sequence shown in SEQ ID NO: 152 At least about 80% sequence identity.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:30，HC-CDR2，其包含氨基酸序列SEQ ID NO:50，和HC-CDR3，其包含氨基酸序列SEQ ID NO:67，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:87，LC-CDR2，其包含氨基酸序列SEQ ID NO:102，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓 炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:30, HC-CDR2, which includes the amino acid sequence SEQ ID NO:50, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:67, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 87, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 102, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 113, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic disease of the head, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, cerebrospinal inflammation, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease, pontine myelmolysis, adrenoleukodystrophy, Pellizois-Metzbach disease, spongiform encephalopathy, Alexander disease, spongiform white matter Degenerative diseases, metachromatic leukodystrophy and Krabb's disease, degenerative visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, macular cyst Edema (CME), retinitis pigmentosa, Skoda's disease, Best's vitelliform retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degenerations, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric disorders Diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:153具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 130 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 153 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 153.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:68，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病 和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 31, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 68, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 114, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric disorders such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:131或其变体，所述变体与氨基酸序列SEQ ID NO:131具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:154或其变体，所述变体与氨基酸序列SEQ ID NO:154具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 131 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 131 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 154 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 154.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:32，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:69，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:32, HC-CDR2, which includes the amino acid sequence SEQ ID NO:51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:69, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 114, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic disease of the head, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pellizois-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:132或其变体，所述变体 与氨基酸序列SEQ ID NO:132具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:155或其变体，所述变体与氨基酸序列SEQ ID NO:155具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 132 or a variant thereof, the variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 132; and V L comprising the amino acid sequence SEQ ID NO: 155 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 155 80% sequence identity.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:33，HC-CDR2，其包含氨基酸序列SEQ ID NO:52，和HC-CDR3，其包含氨基酸序列SEQ ID NO:70，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:89，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:115，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:33, HC-CDR2, which includes the amino acid sequence SEQ ID NO:52, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:70, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 89, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 115, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:133或其变体，所述变体与氨基酸序列SEQ ID NO:133具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:156或其变体，所述变体与氨基酸序列SEQ ID NO:156具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 133 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 133 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 156 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 156.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或 由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or It consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:34，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:71，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 34, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 71, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 114, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:134或其变体，所述变体与氨基酸序列SEQ ID NO:134具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:157或其变体，所述变体与氨基酸序列SEQ ID NO:157具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 134 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 134 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 157 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 157.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域 (VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:35，HC-CDR2，其包含氨基酸序列SEQ ID NO:54，和HC-CDR3，其包含氨基酸序列SEQ ID NO:72，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:90，LC-CDR2，其包含氨基酸序列SEQ ID NO:105，和LC-CDR3，其包含氨基酸序列SEQ ID NO:116，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain (V H ), the V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 35, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 54, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 72, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ), the V L comprising: LC-CDR1, which Comprising the amino acid sequence SEQ ID NO: 90, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 105, and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 116, or a variant of said V L whose LC- The CDRs contain substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:135或其变体，所述变体与氨基酸序列SEQ ID NO:135具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:158或其变体，所述变体与氨基酸序列SEQ ID NO:158具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 135 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 135 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 158 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 158.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:36，HC-CDR2，其包含氨基酸序列SEQ ID NO:55，和HC-CDR3，其包含氨基酸序列SEQ ID NO:73，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117，或者所述VL的变体，其LC-CDRs中包含至多约 5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO:36, HC-CDR2, which includes the amino acid sequence SEQ ID NO:55, and HC-CDR3, which includes the amino acid sequence SEQ ID NO:73, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 91, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 106, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 117, or a variant of said V L whose LC-CDRs comprise at most about 5 amino acid substitutions. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 136 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 159 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 159.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:37，HC-CDR2，其包含氨基酸序列SEQ ID NO:56，和HC-CDR3，其包含氨基酸序列SEQ ID NO:74，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧 症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 37, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 56, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 74, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 91, LC- CDR2, which includes the amino acid sequence of SEQ ID NO: 106, and LC-CDR3, which includes the amino acid sequence of SEQ ID NO: 117, or a variant of the V L whose LC-CDRs include substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenal white matter deoxygenation disease, Pellizois-Mertzbach disease, spongiform encephalopathies, Alexander disease, spongiform degeneration, metachromatic leukodystrophy, and Krabbe disease, degenerative visual diseases such as general ischemic retinopathy , Anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skullard's disease, Best's vitelliform retinal degeneration, Leber's congenital amaurosis disease and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 137 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 159 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 159.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:31，HC-CDR2，其包含氨基酸序列SEQ ID NO:57，和HC-CDR3，其包含氨基酸序列SEQ ID NO:75，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:92，LC-CDR2，其包含氨基酸序列SEQ ID NO:107，和LC-CDR3，其包含氨基酸序列SEQ ID NO:118，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病 和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 31, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 57, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 75, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 92, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 107, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 118, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric disorders such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:138或其变体，所述变体与氨基酸序列SEQ ID NO:138具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:160或其变体，所述变体与氨基酸序列SEQ ID NO:160具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 138 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 138 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 160 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 160.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:38，HC-CDR2，其包含氨基酸序列SEQ ID NO:58，和HC-CDR3，其包含氨基酸序列SEQ ID NO:76，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:93，LC-CDR2，其包含氨基酸序列SEQ ID NO:108，和LC-CDR3，其包含氨基酸序列SEQ ID NO:119，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 38, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 58, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 76, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 93, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 108, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 119, or a variant of said V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:139或其变体，所述变体 与氨基酸序列SEQ ID NO:139具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:161或其变体，所述变体与氨基酸序列SEQ ID NO:161具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 139 or a variant thereof, the variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 139; and V L comprising the amino acid sequence SEQ ID NO: 161 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 161 80% sequence identity.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:39，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:77，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 39, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 77, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 120, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:140或其变体，所述变体与氨基酸序列SEQ ID NO:140具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:162或其变体，所述变体与氨基酸序列SEQ ID NO:162具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 140 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 140 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 162 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 162.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或 由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or It consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:40，HC-CDR2，其包含氨基酸序列SEQ ID NO:59，和HC-CDR3，其包含氨基酸序列SEQ ID NO:78，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:94，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:121，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 40, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 59, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 78, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 94, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 121, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:141或其变体，所述变体与氨基酸序列SEQ ID NO:141具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:163或其变体，所述变体与氨基酸序列SEQ ID NO:163具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 141 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 141 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 163 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 163.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域 (VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:41，HC-CDR2，其包含氨基酸序列SEQ ID NO:60，和HC-CDR3，其包含氨基酸序列SEQ ID NO:79，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain (V H ), the V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 41, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 60, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 79, or a variant of the V H containing at most about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ), the V L comprising: LC-CDR1, which Comprising the amino acid sequence SEQ ID NO: 88, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 103, and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 114, or a variant of said V L whose LC- The CDRs contain substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:142或其变体，所述变体与氨基酸序列SEQ ID NO:142具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:164或其变体，所述变体与氨基酸序列SEQ ID NO:164具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 142 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 142 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 164 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 164.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:42，HC-CDR2，其包含氨基酸序列SEQ ID NO:51，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:88，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:120，或者所述VL的变体，其LC-CDRs中包含至多约 5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 42, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 51, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 88, LC- CDR2, which includes the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 120, or a variant of said V L , whose LC-CDRs include at most about 5 amino acid substitutions. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:143或其变体，所述变体与氨基酸序列SEQ ID NO:143具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:165或其变体，所述变体与氨基酸序列SEQ ID NO:165具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 143 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 143 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 165 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 165.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:122，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧 症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 95, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 109, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 122, or a variant of said V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenal white matter deoxygenation disease, Pellizois-Mertzbach disease, spongiform encephalopathies, Alexander disease, spongiform degeneration, metachromatic leukodystrophy, and Krabbe disease, degenerative visual diseases such as general ischemic retinopathy , Anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skullard's disease, Best's vitelliform retinal degeneration, Leber's congenital amaurosis disease and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:144或其变体，所述变体与氨基酸序列SEQ ID NO:144具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:166或其变体，所述变体与氨基酸序列SEQ ID NO:166具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 144 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 144 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 166 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 166.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:44，HC-CDR2，其包含氨基酸序列SEQ ID NO:62，和HC-CDR3，其包含氨基酸序列SEQ ID NO:82，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:96，LC-CDR2，其包含氨基酸序列SEQ ID NO:110，和LC-CDR3，其包含氨基酸序列SEQ ID NO:123，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病 和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 44, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 62, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 82, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 96, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 110, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 123, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric disorders such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:145或其变体，所述变体与氨基酸序列SEQ ID NO:145具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:167或其变体，所述变体与氨基酸序列SEQ ID NO:167具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 145 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 145 about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:167 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:167.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:45，HC-CDR2，其包含氨基酸序列SEQ ID NO:63，和HC-CDR3，其包含氨基酸序列SEQ ID NO:83，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:97，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:124，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 45, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 63, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 83, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 97, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 104, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 124, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体 与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:168或其变体，所述变体与氨基酸序列SEQ ID NO:168具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof, the variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 146; and V L comprising the amino acid sequence SEQ ID NO: 168 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 168 80% sequence identity.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:46，HC-CDR2，其包含氨基酸序列SEQ ID NO:53，和HC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:98，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 46, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 53, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 80, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 98, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 114, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:169或其变体，所述变体与氨基酸序列SEQ ID NO:169具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 147 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 147 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 169 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 169.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或 由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:21. In some embodiments, the heavy chain constant region comprises or It consists of the amino acid sequence SEQ ID NO:22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:47，HC-CDR2，其包含氨基酸序列SEQ ID NO:64，和HC-CDR3，其包含氨基酸序列SEQ ID NO:84，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:99，LC-CDR2，其包含氨基酸序列SEQ ID NO:103，和LC-CDR3，其包含氨基酸序列SEQ ID NO:125，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain ( VH ), the VH comprising: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 47, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 64, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 84, or a variant of the V H A body comprising up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain ( VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 99, LC- CDR2, which comprises the amino acid sequence SEQ ID NO: 103, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 125, or a variant of the V L whose LC-CDRs comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:170或其变体，所述变体与氨基酸序列SEQ ID NO:170具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 148 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 148 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 170 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 170.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgGl or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
例如，在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体(例如，全长抗Nogo-A抗体)的药物组合物，其中所述抗体包含：重链可变结构域 (VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:43，HC-CDR2，其包含氨基酸序列SEQ ID NO:61，和HC-CDR3，其包含氨基酸序列SEQ ID NO:81，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:95，LC-CDR2，其包含氨基酸序列SEQ ID NO:109，和LC-CDR3，其包含氨基酸序列SEQ ID NO:126，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗Nogo-A抗体是全长抗体。在一些实施例中，所述全长抗Nogo-A抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。在一些实施例中，所述个体是人类。For example, in some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising providing said The subject is administered an effective amount of a pharmaceutical composition comprising an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), wherein the antibody comprises: a heavy chain variable domain (V H ), the V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 43, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 61, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 81, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and a light chain variable domain (V L ), the V L comprising: LC-CDR1, which Comprising the amino acid sequence SEQ ID NO: 95, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 109, and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 126, or a variant of said V L whose LC- The CDRs contain substitutions of up to about 5 amino acids. In some embodiments, the anti-Nogo-A antibody is a full-length antibody. In some embodiments, the full-length anti-Nogo-A antibody is an IgGl or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, others Common dementia, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami disease , pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, degeneration Visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's yolk Similar retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression. In some embodiments, the individual is a human.
在一些实施例中，提供一种用于治疗患有与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)的个体的方法，包括向所述个体施用有效量的包含抗Nogo-A抗体的组合物，其中所述抗体包含：VH，其包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:171或其变体，所述变体与氨基酸序列SEQ ID NO:171具有至少约80％序列同一性。In some embodiments, a method for treating an individual suffering from a disease associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma) is provided, comprising administering to the individual An effective amount of a composition comprising an anti-Nogo-A antibody, wherein the antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 149 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 149 about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:171 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:171.
在一些实施例中，本文所述抗Nogo-A抗体是包含IgG1或IgG4恒定区的全长抗Nogo-A抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:21组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:22组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:23组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:24组成。In some embodiments, an anti-Nogo-A antibody described herein is a full-length anti-Nogo-A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 22. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 23. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 24.
在一些实施例中，所述个体是哺乳动物(例如人、非人灵长类、大鼠、小鼠、牛、马、猪、绵羊、山羊、狗、猫等)。在一些实施例中，所述个体是人类。在一些实施例中，所述个体是临床患者、临床试验志愿者、实验动物等。在一些实施例中，所述个体年龄小于60岁(包括例如小于50、40、30、25、20、15或10岁)。在一些实施例中，所述个体年龄大于60岁(包括例如大于70、80、90或100岁)。在一些实施例中，所述个体是被诊断为或在遗传角度上易患本文所描述的一种或多种疾病或病症(例如中枢神经系统和/或外周神经系统疾病或创伤)。在一些实施例中，所述个体具有一种或多种与本文所述的一种或多种疾病或病症相关的风险因子。 In some embodiments, the subject is a mammal (eg, human, non-human primate, rat, mouse, cow, horse, porcine, sheep, goat, dog, cat, etc.). In some embodiments, the individual is a human. In some embodiments, the individual is a clinical patient, clinical trial volunteer, experimental animal, etc. In some embodiments, the individual is less than 60 years old (including, for example, less than 50, 40, 30, 25, 20, 15, or 10 years old). In some embodiments, the individual is older than 60 years old (including, for example, older than 70, 80, 90, or 100 years old). In some embodiments, the individual is diagnosed with or genetically predisposed to one or more diseases or conditions described herein (eg, central nervous system and/or peripheral nervous system disease or trauma). In some embodiments, the individual has one or more risk factors associated with one or more diseases or conditions described herein.
在一些实施例中，本申请提供一种向个体中在其表面表达Nogo-A的细胞递送抗Nogo-A抗体(例如本文所述的任一种抗Nogo-A抗体，例如分离的抗Nogo-A抗体)的方法，所述方法包括向该个体施用包含抗Nogo-A抗体的组合物。In some embodiments, the application provides a method of delivering an anti-Nogo-A antibody (e.g., any of the anti-Nogo-A antibodies described herein, e.g., an isolated anti-Nogo-A antibody) to cells in an individual that express Nogo-A on their surface. A antibody), the method comprising administering to the individual a composition comprising an anti-Nogo-A antibody.
中枢神经系统和/或外周神经系统疾病或创伤或其它任何表现出Nogo-A异常表达的疾病的许多诊断方法和这些疾病的临床描述在本领域是已知的。这类方法包括，但不限于，例如免疫组化、PCR以及荧光原位杂交(FISH)。Many diagnostic methods for central nervous system and/or peripheral nervous system disease or trauma or any other disease exhibiting abnormal expression of Nogo-A and the clinical description of these diseases are known in the art. Such methods include, but are not limited to, immunohistochemistry, PCR, and fluorescence in situ hybridization (FISH), for example.
在一些实施例中，本申请所述抗Nogo-A抗体(例如全长抗Nogo-A抗体)和/或组合物与第二、第三或第四药剂(包括例如皮质类固醇，神经营养因子如NGF、BDNF，或其他用于神经退化疾病的药物如ExelonTM、Levodopa)联合使用来治疗与Nogo-A信号通路相关的疾病。In some embodiments, the anti-Nogo-A antibodies (eg, full-length anti-Nogo-A antibodies) and/or compositions described herein are combined with a second, third, or fourth agent (including, for example, corticosteroids, neurotrophic factors such as NGF, BDNF, or other drugs used for neurodegenerative diseases (such as Exelon TM , Levodopa) are used in combination to treat diseases related to the Nogo-A signaling pathway.
采用例如神经突数量、再生芽的存在和密度、CST纤维数量、细胞铺展活性、蛋白表达水平和/或活性来评估脊髓损伤的治疗。可以采用确定治疗效果的方法，包括例如，通过免疫荧光染色、放射成像、解剖学实验或行为学实验来检测是否响应。Treatment of spinal cord injury is evaluated using, for example, neurite number, presence and density of regenerative sprouts, CST fiber number, cell spreading activity, protein expression levels and/or activity. Methods of determining treatment efficacy may be employed, including, for example, detection of response by immunofluorescent staining, radiographic imaging, anatomical experiments, or behavioral experiments.
在一些实施例中，治疗的效果以神经突数量增加百分率(％)来评估，使用等式100-(T/C×100)来计算，其中T是已治疗脊髓损伤的神经突数量，C是未治疗治疗脊髓损伤的神经突数量。在一些实施例中，百分率(％)约为10％、20％、30％、40％、50％、60％、70％、80％、90％、91％、92％、93％、94％、95％或超过95％。In some embodiments, the effect of treatment is evaluated as a percent increase (%) in neurite number, calculated using the equation 100 - (T/C × 100), where T is the number of neurites in the treated spinal cord injury and C is Number of neurites in untreated spinal cord injury. In some embodiments, the percentage (%) is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94% , 95% or more than 95%.
在一些实施例中，治疗效果通过脊髓损伤患者中再生芽的存在和密度水平来评估，通过与施用抗体前相比再生芽数量变化率来计算。在一些实施例中，再生芽的存在和密度恢复至少约1％、2％、5％、10％、15％、20％、25％、30％或35％。In some embodiments, therapeutic efficacy is assessed by the presence and density level of regenerative shoots in patients with spinal cord injury, calculated as the rate of change in the number of regenerative shoots compared to before administration of the antibody. In some embodiments, the presence and density of regenerated shoots is restored by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, or 35%.
在一些实施例中，治疗效果通过脊髓损伤患者中CST纤维数量来评估。在一些实施例中，CST纤维数量恢复至少约10％、20％、30％、40％、50％、60％、70％、80％、90％、91％、92％、93％、94％、95％或超过95％。In some embodiments, therapeutic efficacy is assessed by CST fiber number in patients with spinal cord injury. In some embodiments, the CST fiber count is restored by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94% , 95% or more than 95%.
抗Nogo-A抗体的给药剂量和方法Dosage and methods of administration of anti-Nogo-A antibodies
施用于个体(例如人)的抗Nogo-A抗体(例如分离的抗Nogo-A抗体)组合物的剂量可能因特定组合物、给药方式和治疗疾病类型的不同而不同。在一些实施例中，组合物(例如，包含抗Nogo-A抗体的组合物)的量可在中枢神经系统和/或外周神经系统疾病或创伤治疗中有效产生客观响应(例如，部分响应或完全响应)。在一些实施例中，抗Nogo-A抗体组合物的量足以在个体中产生完全响应。在一些实施例中，抗Nogo-A抗体组合物的量足以在个体中产生部分响应。在一些实施例中，抗Nogo-A抗体组合物的给药剂量(例如当单独施用时)足以在使用抗Nogo-A抗体组合物治疗的个体群体中产生高于20％、25％、30％、35％、40％、45％、50％、55％、60％、64％、65％、70％、75％、80％、85％或90％的总响应率。个体对本文所述治疗方法的响应可通过，例如，神经损伤部位的萌芽，受损轴突的再生，受损神经突的神经突增生来确定。The dosage of an anti-Nogo-A antibody (eg, isolated anti-Nogo-A antibody) composition administered to an individual (eg, a human) may vary depending on the particular composition, the mode of administration, and the type of disease being treated. In some embodiments, the amount of the composition (e.g., a composition comprising an anti-Nogo-A antibody) is effective to produce an objective response (e.g., a partial response or a complete response) in the treatment of central nervous system and/or peripheral nervous system disease or trauma. response). In some embodiments, the amount of anti-Nogo-A antibody composition is sufficient to produce a complete response in an individual. In some embodiments, the amount of anti-Nogo-A antibody composition is sufficient to produce a partial response in an individual. In some embodiments, the anti-Nogo-A antibody composition is administered at a dose (e.g., when administered alone) sufficient to produce greater than 20%, 25%, 30% in a population of individuals treated with the anti-Nogo-A antibody composition , 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90% overall response rate. An individual's response to the treatment methods described herein can be determined by, for example, sprouting at the site of nerve injury, regeneration of damaged axons, and neurite outgrowth of damaged neurites.
在一些实施例中，组合物(例如包含分离的抗Nogo-A抗体的组合物)的量足以延长个体的无进展生存期。在一些实施例中，组合物的量足以延长个体的总体生存期。在一些实施例中，在使 用抗Nogo-A抗体组合物治疗的个体群体中，组合物的量(例如当单独施用时)足以产生高于50％、60％、70％或77％的临床益处。In some embodiments, the amount of the composition (eg, a composition comprising an isolated anti-Nogo-A antibody) is sufficient to prolong progression-free survival in an individual. In some embodiments, the amount of the composition is sufficient to prolong the overall survival of the subject. In some embodiments, using The amount of the composition (eg, when administered alone) is sufficient to produce greater than 50%, 60%, 70%, or 77% of the clinical benefit in a population of individuals treated with the anti-Nogo-A antibody composition.
在一些实施例中，组合物(例如包含分离的抗Nogo-A抗体的组合物)的量，单独使用或与第二，第三、和/或第四药剂联合使用时，是指在治疗前或与未接受治疗的其他受试者的相应活性相比，足以控制症状和减少病情加重的风险的量。可以采用标准方法来测量该疗效的大小，例如纯化酶的体外检测、基于细胞的检测、动物模型或人体试验。In some embodiments, the amount of a composition (eg, a composition comprising an isolated anti-Nogo-A antibody), alone or in combination with a second, third, and/or fourth agent, is before treatment. or an amount sufficient to control symptoms and reduce the risk of exacerbation of the condition as compared to the corresponding activity in other subjects not receiving treatment. The magnitude of this effect can be measured using standard methods, such as in vitro assays of purified enzymes, cell-based assays, animal models, or human trials.
在一些实施例中，当将组合物施用于个体时，组合物中抗Nogo-A抗体(例如全长的抗Nogo-A抗体)的量低于引起毒性效应(即，一种高于临床可接受毒性水平的效应)的水平，或者处于潜在副作用可以控制或耐受的水平。In some embodiments, the amount of anti-Nogo-A antibody (e.g., full-length anti-Nogo-A antibody) in the composition is less than the amount that causes a toxic effect (i.e., an amount greater than clinically acceptable) when the composition is administered to an individual. Toxic levels of effects), or at a level where potential side effects can be controlled or tolerated.
在一些实施例中，遵循相同的给药方案，组合物的量接近的组合物的最大耐受剂量(MTD)。在一些实施例中，组合物的量高于MTD的80％、90％、95％或98％。In some embodiments, following the same dosing regimen, the amount of the composition approximates the maximum tolerated dose (MTD) of the composition. In some embodiments, the amount of the composition is greater than 80%, 90%, 95%, or 98% of the MTD.
在一些实施例中，组合物中抗Nogo-A抗体(例如全长的抗Nogo-A抗体)的含量在0.001μg到1000μg的范围之内。In some embodiments, the amount of anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) in the composition ranges from 0.001 μg to 1000 μg.
在如上所述任一个实施例中，组合物中的抗Nogo-A抗体(例如全长的抗Nogo-A抗体)的有效量，按照体重时计算，为0.1μg/kg到100mg/kg的范围之内。In any of the above embodiments, the effective amount of anti-Nogo-A antibody (eg, full-length anti-Nogo-A antibody) in the composition is in the range of 0.1 μg/kg to 100 mg/kg based on body weight. within.
抗Nogo-A抗体组合物可通过多种途径施用于个体(如人类)，包括，例如静脉注射、动脉内给药、腹腔注射、肺内给药、口服给药、吸入给药、血管内给药、肌肉注射、气管内给药、皮下注射、眼内给药、鞘内给药、粘膜给药或经皮给药。在一些实施例中，使用组合物的缓释制剂。在一些实施例中，组合物通过静脉给药。在一些实施例中，组合物通过动脉给药。在一些实施例中，组合物通过腹膜内给药。在一些实施例中，组合物通过肝内给药。在一些实施例中，组合物通过肝动脉输注给药。在一些实施例中，组合物施用于远离第一病灶的部位。Anti-Nogo-A antibody compositions can be administered to an individual (e.g., a human) by a variety of routes, including, for example, intravenous injection, intraarterial administration, intraperitoneal injection, intrapulmonary administration, oral administration, inhalation administration, intravascular administration medicine, intramuscular injection, intratracheal administration, subcutaneous injection, intraocular administration, intrathecal administration, mucosal administration or transdermal administration. In some embodiments, a sustained release formulation of the composition is used. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered intraarterially. In some embodiments, the composition is administered intraperitoneally. In some embodiments, the composition is administered intrahepatically. In some embodiments, the composition is administered by hepatic artery infusion. In some embodiments, the composition is administered to a site distal to the first lesion.
制品及试剂盒Products and kits
在本申请的一些实施例中，提供一种制品，所述制品包含一种物质，所述物质能够用于治疗与Nogo-A信号通路相关的疾病(例如，中枢神经系统和/或外周神经系统疾病或创伤)，或者用于递送抗Nogo-A抗体(例如一种全长抗Nogo-A抗体)到表面表达Nogo-A的细胞。所述制品可以包括一种容器以及在容器上或随该容器附带的标签或包装说明书。合适的容器包括，例如瓶子、小瓶、注射器等。容器可以由多种材料制成，例如玻璃或塑料。通常，该容器内装有能够有效治疗本文所述疾病或病症的组合物，并且具有一个无菌端口(例如该容器可以是一个静脉输液袋或是一个具有皮下注射针头可刺穿盖子的小瓶)。组合物中的至少一种活性物质即为本申请所述的抗Nogo-A抗体。标签或包装说明书标示了该组合物可以用于治疗的特定病症。标签或包装说明书进一步包含给患者施用抗Nogo-A抗体组合物的说明书。包括联合治疗的制品和试剂盒均在本文的考虑范围之内。 In some embodiments of the present application, an article of manufacture is provided, the article of manufacture comprising a substance that can be used to treat diseases associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system disease or trauma), or for delivering an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody) to cells expressing Nogo-A on their surface. The article of manufacture may include a container and a label or package insert on or accompanying the container. Suitable containers include, for example, bottles, vials, syringes, and the like. Containers can be made from a variety of materials, such as glass or plastic. Typically, the container contains a composition effective for treating the disease or condition described herein and has a sterile port (eg, the container may be an IV bag or a vial with a hypodermic needle-pierceable cap). At least one active substance in the composition is the anti-Nogo-A antibody described in this application. The label or package insert identifies the specific condition for which the composition is used to treat. The label or package insert further contains instructions for administering the anti-Nogo-A antibody composition to a patient. Articles and kits including combination therapies are considered within the scope of this article.
包装说明书是指通常包含在治疗产品的商业包装内的说明书，其包含关于与这些治疗产品使用有关的适应症、用法、剂量、施用、禁忌症和/或警告信息。在一些实施例中，包装说明书标明该组合物可以用于治疗与Nogo-A信号通路相关的疾病(例如中枢神经系统和/或外周神经系统疾病或创伤)。在一些实施例中，包装说明书标明该组合物可以用于治疗以下的疾病，包括神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病，其他普通痴呆，颅、脑或脊髓创伤后疾病，中风，脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病，退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病，精神病疾病如精神分裂症、抑郁症。Package insert means the instructions usually included in the commercial packaging of therapeutic products that contain information on indications, usage, dosage, administration, contraindications and/or warnings relevant to the use of these therapeutic products. In some embodiments, the package insert states that the composition can be used to treat diseases associated with the Nogo-A signaling pathway (eg, central nervous system and/or peripheral nervous system diseases or trauma). In some embodiments, the package insert states that the composition can be used to treat neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy Body-like diseases, other common dementias, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis , Marchiafava-Bignami disease, pontine myelmolysis, adrenoleukodystrophy, Pelizoys-Metzbach disease, spongiform encephalopathies, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Gram Labware disease, degenerative visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Sigmoiditis Dalton syndrome, Best's vitelliform retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression.
此外，所述制品还可以包括第二容器，其包含药学上可接受的缓冲液，例如抑菌性注射用水(BWFI)、磷酸盐缓冲液、格林氏溶液或葡萄糖溶液。还可以包括从商业和用户角度而言所需的其他材料，包括其他缓冲液、稀释液、过滤器、针头和注射器。Additionally, the article of manufacture may further include a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffer, Green's solution, or dextrose solution. Other materials required from a commercial and user perspective may also be included, including additional buffers, diluents, filters, needles, and syringes.
同时还涉及可用于各种目的的试剂盒，例如用于治疗与Nogo-A信号通路相关的疾病(例如中枢神经系统和/或外周神经系统疾病或创伤)，或者用于递送抗Nogo-A抗体(例如全长抗Nogo-A抗体)到表面表达Nogo-A的细胞中，任选与制品组合。本申请的试剂盒包括一个或多个容器，其包含抗Nogo-A抗体组合物(或单剂量形式和/或制品)，并且在一些实施例中，进一步包含另一种药剂(例如本文所述的药剂)和/或与本文所述任一方法相一致的使用说明书。该试剂盒可进一步包括选择适合治疗个体的描述。本申请中试剂盒中所附带的使用说明书通常是标签或包装说明书上的书面说明(例如包含在试剂盒内的纸页)，机器可读的说明(例如，磁性或光学储存光盘上的说明)也是可以接受的。Also contemplated are kits that can be used for various purposes, such as for the treatment of diseases associated with the Nogo-A signaling pathway (such as central nervous system and/or peripheral nervous system diseases or trauma), or for the delivery of anti-Nogo-A antibodies. (e.g., full-length anti-Nogo-A antibody) into cells expressing Nogo-A on their surface, optionally in combination with a preparation. Kits of the present application include one or more containers containing an anti-Nogo-A antibody composition (or single dose form and/or article of manufacture) and, in some embodiments, further comprising another agent (e.g., as described herein agent) and/or instructions for use consistent with any of the methods described herein. The kit may further include instructions for selecting individuals suitable for treatment. Instructions for use accompanying the kit in this application are usually written instructions on the label or package insert (e.g., a sheet of paper included in the kit), machine-readable instructions (e.g., instructions on a magnetic or optical storage disc) Also acceptable.
例如，在一些实施例中，试剂盒包括一种包含抗Nogo-A抗体(例如全长的抗Nogo-A抗体)的组合物。在一些实施例中，试剂盒包括：a)包含本文所述的任一种抗Nogo-A抗体的组合物，和b)至少一种有效量的其它药剂，其能够增强抗Nogo-A抗体的效果(如治疗效果、检测效果)。在一些实施例中，试剂盒包括：a)包含本文所述的任一种抗Nogo-A抗体的组合物，和b)向个体施用抗Nogo-A抗体组合物用于治疗与Nogo-A信号通路相关的疾病(例如中枢神经系统和/或外周神经系统疾病或创伤)的使用说明书。在一些实施例中，试剂盒包括：a)包含本文所述的任一种抗Nogo-A抗体的组合物，和b)至少一种有效量的其它药剂，其能够增强抗Nogo-A抗体的效果(如治疗效果、检测效果)和c)向个体施用抗Nogo-A抗体组合物和其它物质用于治疗与Nogo-A信号通路相关的疾病(例如中枢神经系统和/或外周神经系统疾病或创伤)的使用说明书。所述抗Nogo-A抗体和其他物质可以存在于独立的容器或同一个容器中。例如，该试剂盒可以包括一种特 定组合物或两种或更多种组合物，其中一种组合物包括抗Nogo-A抗体，另一种组合物包括另一种药剂。For example, in some embodiments, the kit includes a composition comprising an anti-Nogo-A antibody (eg, a full-length anti-Nogo-A antibody). In some embodiments, a kit includes: a) a composition comprising any one of the anti-Nogo-A antibodies described herein, and b) an effective amount of at least one other agent capable of enhancing the anti-Nogo-A antibody's Effect (such as treatment effect, detection effect). In some embodiments, the kit includes: a) a composition comprising any one of the anti-Nogo-A antibodies described herein, and b) administering to the individual the anti-Nogo-A antibody composition for treating Nogo-A signaling Instructions for use in pathway-related disorders (e.g., central nervous system and/or peripheral nervous system disease or trauma). In some embodiments, a kit includes: a) a composition comprising any one of the anti-Nogo-A antibodies described herein, and b) an effective amount of at least one other agent capable of enhancing the anti-Nogo-A antibody's effects (e.g., therapeutic effects, detection effects) and c) administering anti-Nogo-A antibody compositions and other substances to individuals for the treatment of diseases associated with the Nogo-A signaling pathway (e.g., central nervous system and/or peripheral nervous system diseases or trauma) instructions for use. The anti-Nogo-A antibody and other substances may be present in separate containers or in the same container. For example, the kit may include a specific A specific composition or two or more compositions, one of which includes an anti-Nogo-A antibody and the other of which includes another pharmaceutical agent.
在一些实施例中，试剂盒包含一种(或一组)编码抗Nogo-A抗体(例如全长的抗Nogo-A抗体)的核酸。在一些实施例中，试剂盒包含：a)一种(或一组)编码抗Nogo-A抗体(例如全长的抗Nogo-A抗体)的核酸，和b)一种表达核酸(或一组核酸)的宿主细胞。在一些实施例中，试剂盒包含：a)一种(或一组)编码抗Nogo-A抗体(例如全长的抗Nogo-A抗体)的核酸，和b)使用说明书，适用于：i)在宿主细胞中表达抗Nogo-A抗体，ii)制备包含抗Nogo-A抗体的组合物，和iii)向个体施用包含抗Nogo-A抗体的组合物来治疗与Nogo-A信号通路相关的疾病(例如中枢神经系统和/或外周神经系统疾病或创伤)。在一些实施例中，试剂盒包括：a)一种(或一组)编码抗Nogo-A抗体(例如全长的抗Nogo-A抗体)的核酸，b)一种表达核酸(或一组核酸)的宿主细胞，和c)使用说明书，适用于：i)在宿主细胞中表达抗Nogo-A抗体，ii)制备包含抗Nogo-A抗体的组合物，和iii)向个体施用包含抗Nogo-A抗体的组合物来治疗与Nogo-A信号通路相关的疾病(例如中枢神经系统和/或外周神经系统疾病或创伤)。In some embodiments, the kit includes a nucleic acid (or a set of nucleic acids) encoding an anti-Nogo-A antibody (eg, a full-length anti-Nogo-A antibody). In some embodiments, the kit comprises: a) a nucleic acid (or a set of) encoding an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), and b) an expression nucleic acid (or a set of nucleic acid) host cells. In some embodiments, the kit comprises: a) one (or a set of) nucleic acids encoding an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), and b) instructions for use, suitable for: i) expressing an anti-Nogo-A antibody in a host cell, ii) preparing a composition comprising the anti-Nogo-A antibody, and iii) administering the composition comprising the anti-Nogo-A antibody to an individual to treat a disease associated with the Nogo-A signaling pathway (e.g. central nervous system and/or peripheral nervous system disease or trauma). In some embodiments, the kit includes: a) a nucleic acid (or a set of nucleic acids) encoding an anti-Nogo-A antibody (e.g., a full-length anti-Nogo-A antibody), b) an expression nucleic acid (or a set of nucleic acids ), and c) instructions for use suitable for: i) expressing an anti-Nogo-A antibody in a host cell, ii) preparing a composition comprising an anti-Nogo-A antibody, and iii) administering to an individual a composition comprising an anti-Nogo-A antibody. A composition of antibodies to treat diseases related to the Nogo-A signaling pathway (such as central nervous system and/or peripheral nervous system diseases or trauma).
本申请所述的试剂盒以合适的形式进行包装。合适的包装包括，但不限于，小瓶、瓶子、广口瓶、软包装(例如密封的聚酯薄膜或塑料袋)等。试剂盒可以任选地提供其它的组分，例如缓冲液和说明信息。因此，本申请还提供制品，其包括小瓶、瓶子、广口瓶、软包装(例如密封的聚酯薄膜或塑料袋)等。The kits described in this application are packaged in a suitable form. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (eg, sealed mylar or plastic bags), and the like. Kits may optionally provide other components such as buffers and instructions. Accordingly, the present application also provides articles including vials, bottles, jars, flexible packaging (eg, sealed Mylar or plastic bags), and the like.
关于抗Nogo-A抗体组合物的使用说明书，通常包括一些信息，诸如，剂量，给药周期和给药途径等。容器可以是单位剂量的，大包装的(如，多剂量包装)或亚单位剂量的。例如，提供一种包含足够剂量的如本文所述的抗Nogo-A抗体(例如全长的抗Nogo-A抗体)的试剂盒以对个体进行长期有效的治疗，例如一周、8天、9天、10天、11天、12天、13天、2周、3周、4周、6周、8周、3个月、4个月、5个月、7个月、8个月、9个月或更长时间。试剂盒还可包含多单位剂量的抗Nogo-A抗体、药物组合物和使用说明书，并且以足够在药房中储存和使用的量进行包装，例如，医院药房和复方药房。Instructions for use of anti-Nogo-A antibody compositions generally include information such as dosage, administration period and administration route. Containers may be unit dose, bulk (eg, multi-dose packaging) or subunit dose. For example, a kit is provided that contains a sufficient dose of an anti-Nogo-A antibody as described herein (e.g., a full-length anti-Nogo-A antibody) to effectively treat an individual for a long period of time, such as one week, 8 days, 9 days , 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months months or more. The kit may also contain multiple unit doses of anti-Nogo-A antibody, a pharmaceutical composition, and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies, such as hospital pharmacies and compounding pharmacies.
本领域的技术人员将认识到在本申请的范围和宗旨内可能的若干实施例。现在将通过参考以下非限制性实施例来更详细地描述本申请。以下实施例进一步阐明本申请，但不应解释为以任何方式进行限制其范围。Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of this application. The application will now be described in more detail with reference to the following non-limiting examples. The following examples further illustrate this application but should not be construed as limiting its scope in any way.
具体实施方式Detailed ways
在下述公开的实施例中，适用如下缩写：Nogo-A(Neurite outgrowth inhibitor-A,轴突生长抑制因子A)；Bavih-hNiG(Biotin-hNiG-Avi-10His)。 In the following disclosed examples, the following abbreviations apply: Nogo-A (Neurite outgrowth inhibitor-A, neurite growth inhibitory factor A); Bavih-hNiG (Biotin-hNiG-Avi-10His).
实施例1：制备重组NiG抗原及Nogo-A抗体的筛选Example 1: Preparation of recombinant NiG antigen and screening of Nogo-A antibody
制备重组NiG抗原Preparation of recombinant NiG antigen
Nogo-A，分子量190kD，是网状内皮素RTN4基因的翻译产物。由Nogo-A独特的外显子3编码的由818个氨基酸(186-1004aa)组成的蛋白，称为NiG。分别合成密码子优化的人NiG(hNiG，186-1004aa)、恒河猴NiG(mkNiG，171-1049aa)、大鼠NiG(rNiG，174-979aa)的编码序列，并与His标签融合后构建到真核细胞表达载体pTTa1中。分别构建了如下表达载体：pTTa1-hNiG-10His，pTTa1-mkNiG-10His，pTTa1-rNiG-10His。其中“his或His”代表His标签，“Avi”代表亲和素标签。Nogo-A, with a molecular weight of 190kD, is the translation product of the reticuloendothelin RTN4 gene. The protein composed of 818 amino acids (186-1004aa) encoded by the unique exon 3 of Nogo-A is called NiG. Codon-optimized coding sequences of human NiG (hNiG, 186-1004aa), rhesus monkey NiG (mkNiG, 171-1049aa), and rat NiG (rNiG, 174-979aa) were synthesized and fused with His tags to construct In the eukaryotic cell expression vector pTTa1. The following expression vectors were constructed respectively: pTTa1-hNiG-10His, pTTa1-mkNiG-10His, and pTTa1-rNiG-10His. Among them, "his or His" represents the His tag, and "Avi" represents the avidin tag.
按照制造商的操作说明书，对上述重组NiG进行表达和纯化。简言之，将上述表达载体分别转染293F细胞，并将上述细胞在37℃、8％CO2、120rpm条件下培养5天。对于His-tag蛋白的纯化，收集细胞培养液，将上清装入Histrap柱，用含有0.25M NaCl和5mM咪唑(pH8.0)的20mM磷酸钠缓冲液(pH7.4)进行平衡，用含有0.25M NaCl和15mM咪唑(pH8.0)的20mM磷酸钠缓冲液(pH7.4)洗涤柱子，然后用含有0.25M NaCl和100mM咪唑(pH8.0)的20mM磷酸钠缓冲液(pH7.4)洗脱并收集目的蛋白。The above recombinant NiG was expressed and purified according to the manufacturer's instructions. Briefly, the above expression vectors were transfected into 293F cells respectively, and the above cells were cultured at 37°C, 8% CO 2 , and 120 rpm for 5 days. For purification of His-tag proteins, collect the cell culture fluid, load the supernatant into a Histrap column, equilibrate with 20mM sodium phosphate buffer (pH7.4) containing 0.25M NaCl and 5mM imidazole (pH8.0), and use The column was washed with 20mM sodium phosphate buffer (pH7.4) containing 0.25M NaCl and 15mM imidazole (pH8.0), followed by 20mM sodium phosphate buffer (pH7.4) containing 0.25M NaCl and 100mM imidazole (pH8.0). Elute and collect the protein of interest.
制备生物素化标记的hNiG抗原Preparation of biotinylated hNiG antigen
按照操作说明书，采用生物素化连接酶B0101A(GeneCopoeia)对hNiG-Avi-10His进行生物素化标记。简而言之，向hNiG-Avi-10His抗原中加入缓冲液A/B和BirA连接酶后在30℃下孵育2小时。生物素化的hNiG(即Biotin-hNiG-Avi-10His)被命名为Bavih-hNiG。通过ELISA方法检测生物素化效率。简而言之，将Bavih-hNiG起始浓度设置为500ng/ml，按1：2的比例进行倍比稀释，稀释之后包被ELISA板。采用SA-HRP来检测，用生物素化标准品做对照，Bavih-hNiG生物素化标记效率为70％。According to the operating instructions, biotinylation ligase B0101A (GeneCopoeia) was used to biotinylate hNiG-Avi-10His. Briefly, buffer A/B and BirA ligase were added to hNiG-Avi-10His antigen and incubated at 30°C for 2 hours. Biotinylated hNiG (ie Biotin-hNiG-Avi-10His) was named Bavih-hNiG. Biotinylation efficiency was detected by ELISA method. Briefly, the starting concentration of Bavih-hNiG was set to 500ng/ml, diluted at a ratio of 1:2, and then coated on the ELISA plate after dilution. SA-HRP was used for detection and biotinylated standards were used as controls. The Bavih-hNiG biotinylation labeling efficiency was 70%.
筛选Nogo-A抗体Screening for Nogo-A antibodies
构建scFv抗体酵母展示文库：使用hNiG-10His作为抗原，与等份(v/v)佐剂一起免疫食蟹猴。收集免疫后的猴血清，ELISA检测上述血清中的总IgG滴度。取最高滴度的猴血样本，提取RNA，经逆转录获得cDNA，采用VH和VL特异性引物扩增VH和VL片段，经过胶回收纯化后，连接VH和VL，构建scFv，并将其克隆到酵母展示质粒PYD1中，随后，将该质粒电转至酵母菌中，获得scFv抗体酵母展示文库。Construction of scFv antibody yeast display library: hNiG-10His was used as antigen and cynomolgus monkeys were immunized with equal parts (v/v) of adjuvant. The monkey serum after immunization was collected, and the total IgG titer in the above serum was detected by ELISA. Take the monkey blood sample with the highest titer, extract RNA, obtain cDNA through reverse transcription, use V H and V L specific primers to amplify the V H and V L fragments, and after gel recovery and purification, connect V H and V L to construct scFv and clone it into the yeast display plasmid PYD1. Subsequently, the plasmid is electroporated into yeast to obtain a scFv antibody yeast display library.
筛选抗NiG单链抗体(scFv)：从上述酵母展示文库中分离识别hNiG的scFv。简而言之，采用MACS磁珠分选对表达scFv的酵母细胞进行富集。将1000OD的酵母细胞，在2500g下离心5分钟。获得的细胞沉淀，按照OD600＝1的起始浓度，用1L SGCAA培养基进行重悬，并于20℃、250rpm培养条件下诱导表达40-48小时。将细胞培养液离心，并用PBSM溶液清洗后，用5-10倍体积含有1μM Bavih-hNiG的PBSM溶液重悬细胞沉淀，4℃孵育1小时。经过离心和PBSM洗涤后，未结合的抗原被PBSM溶液洗去。加入磁珠后，充分混匀，随后被置于4℃悬转仪上孵育30分钟。 2500g离心5分钟，弃去上清，用5-10倍体积的PBSM溶液重悬沉淀。每次取7ml细胞悬液加入到柱子上，直到所有的细胞悬液流穿柱子。收集结合到柱子上的细胞，并进一步培养以提取质粒。Screening of anti-NiG single chain antibodies (scFv): scFv that recognizes hNiG was isolated from the above yeast display library. Briefly, scFv-expressing yeast cells were enriched using MACS magnetic bead sorting. Centrifuge 1000OD yeast cells at 2500g for 5 minutes. The obtained cell pellet was resuspended in 1L SGCAA medium at a starting concentration of OD600=1, and expression was induced for 40-48 hours under culture conditions of 20°C and 250 rpm. Centrifuge the cell culture medium and wash it with PBSM solution. Resuspend the cell pellet in 5-10 times the volume of PBSM solution containing 1 μM Bavih-hNiG, and incubate at 4°C for 1 hour. After centrifugation and washing with PBSM, unbound antigen is washed away with PBSM solution. After adding the magnetic beads, mix thoroughly and then place on a 4°C suspension incubator and incubate for 30 minutes. Centrifuge at 2500g for 5 minutes, discard the supernatant, and resuspend the pellet in 5-10 times the volume of PBSM solution. Add 7ml of cell suspension to the column at a time until all the cell suspension flows through the column. Cells bound to the column were collected and further cultured to extract plasmid.
制备既可展示又可分泌IgG抗体的CHO-IgG文库并筛选IgG抗体：采用设计的引物从酵母库中获得的质粒进行两轮PCR扩增，将获得的VL-CL-2A-VH片段经AgeI和NheI酶切克隆到CHO-IgG展示分泌载体pFLP-In-TM中，连接完成后的质粒通过PEI试剂与POG44辅助质粒(Thermofisher，cat#V600520)共转染至CHO-FRT细胞(Thermofisher，cat#R75807)中，经过潮霉素(Sigma,cat#31282-04-9)筛选获得CHO-IgG抗体展示文库。经过3-4轮的FACS筛选，从展示文库中分离获得特异性结合hNiG的IgG抗体。简而言之，通过每轮降低抗原浓度来进行FACS分选获得细胞群，再将最后一轮的细胞群进行FACS单克隆分选至96孔板培养，两周后取上清进行ELISA鉴定，挑选结合力强的克隆进行测序，获得候选先导抗体L82、mkNG-22、mkNG-3、mkNG-26、mkNG-38、mkNG-258、mkNG-267、mkNG-272、mkNG-325、mkNG-327、mkNG-333、mkNG-360、mkNG-362、mkNG-375、mkNG-378、mkNG-379、mkNG-381、mkNG-388、mkNG-398、mkNG-401、mkNG-405、mkNG-407、mkNG-412、mkNG-416。候选先导抗体L82、mkNG-22的重链和轻链的可变结构域序列如表2和表3所示。候选先导抗体mkNG-3、mkNG-26、mkNG-38、mkNG-258、mkNG-267、mkNG-272、mkNG-325、mkNG-327、mkNG-333、mkNG-360、mkNG-362、mkNG-375、mkNG-378、mkNG-379、mkNG-381、mkNG-388、mkNG-398、mkNG-401、mkNG-405、mkNG-407、mkNG-412、mkNG-416的重链和轻链的可变结构域序列如表2A和表3A所示。Prepare a CHO-IgG library that can both display and secrete IgG antibodies and screen IgG antibodies: Use the designed primers to perform two rounds of PCR amplification on the plasmid obtained from the yeast library, and then pass the obtained VL-CL-2A-VH fragment through AgeI and NheI digestion and cloned into the CHO-IgG display secretion vector pFLP-In-TM. The ligated plasmid was co-transfected into CHO-FRT cells (Thermofisher, cat. #R75807), a CHO-IgG antibody display library was obtained through hygromycin (Sigma, cat#31282-04-9) screening. After 3-4 rounds of FACS screening, IgG antibodies that specifically bind hNiG were isolated from the display library. In short, the cell population is obtained by FACS sorting by reducing the antigen concentration in each round, and then the final round of cell population is FACS monoclonal sorted and cultured in a 96-well plate. Two weeks later, the supernatant is taken for ELISA identification. Select clones with strong binding capacity for sequencing and obtain candidate lead antibodies L82, mkNG-22, mkNG-3, mkNG-26, mkNG-38, mkNG-258, mkNG-267, mkNG-272, mkNG-325, mkNG-327 , mkNG-333, mkNG-360, mkNG-362, mkNG-375, mkNG-378, mkNG-379, mkNG-381, mkNG-388, mkNG-398, mkNG-401, mkNG-405, mkNG-407, mkNG -412, mkNG-416. The variable domain sequences of the heavy and light chains of candidate lead antibodies L82 and mkNG-22 are shown in Tables 2 and 3. Candidate lead antibodies mkNG-3, mkNG-26, mkNG-38, mkNG-258, mkNG-267, mkNG-272, mkNG-325, mkNG-327, mkNG-333, mkNG-360, mkNG-362, mkNG-375 , variable structures of heavy and light chains of mkNG-378, mkNG-379, mkNG-381, mkNG-388, mkNG-398, mkNG-401, mkNG-405, mkNG-407, mkNG-412, mkNG-416 Domain sequences are shown in Table 2A and Table 3A.
实施例2：制备和表征全长抗Nogo-A抗体Example 2: Preparation and characterization of full-length anti-Nogo-A antibodies
制备全长的抗Nogo-A抗体Preparation of full-length anti-Nogo-A antibodies
将最有潜力的Fab抗体构建成具有人IgG1或IgG4的重链恒定区和人kappa或lambda轻链恒定区的人IgG1或IgG4抗体分子。扩增VL和VH，分别构建入真核表达载体pTTa1-K1(包含kappa恒定区)或pTTa1-L(包含lambda恒定区)，以及pTTa1-H1(包含IgG1重链恒定区)或pTTa1-H4(包含IgG4重链恒定区)中。分别提取表达轻/重链的质粒，共转染293F细胞，37℃、5％CO2、120rpm培养6天，用蛋白A亲和层析柱纯化培养液。简而言之，首先采用6倍柱体积的PBS缓冲液(pH7.2-7.4)以150cm/h的流速平衡蛋白A柱。培养液上清(调节pH至7.2)以150cm/h流速流穿柱子。在进行进一步平衡之后，采用含0.1M甘氨酸、0.15M氯化钠，pH3.2的溶液洗脱，收集洗脱液，加入适量的1M Tirs(pH9.0)溶液调节pH至中性，超滤浓缩换液至PBS中。超滤浓缩后测定IgG浓度，获得全长的抗Nogo-A抗体。The most promising Fab antibodies are constructed as human IgG1 or IgG4 antibody molecules with the heavy chain constant region of human IgG1 or IgG4 and the human kappa or lambda light chain constant region. Amplify V L and V H and construct them into eukaryotic expression vectors pTTal-K1 (containing kappa constant region) or pTTal-L (containing lambda constant region), and pTTal-H1 (containing IgG1 heavy chain constant region) or pTTal- H4 (containing the IgG4 heavy chain constant region). Plasmids expressing light and heavy chains were extracted respectively, co-transfected into 293F cells, cultured at 37°C, 5% CO 2 , and 120 rpm for 6 days, and the culture medium was purified using a protein A affinity chromatography column. Briefly, the protein A column was first equilibrated with 6 column volumes of PBS buffer (pH 7.2-7.4) at a flow rate of 150 cm/h. The culture supernatant (pH adjusted to 7.2) flows through the column at a flow rate of 150cm/h. After further equilibration, use a solution containing 0.1M glycine, 0.15M sodium chloride, pH3.2 to elute, collect the eluate, add an appropriate amount of 1M Tirs (pH9.0) solution to adjust the pH to neutral, and perform ultrafiltration Concentrate and change the medium into PBS. After ultrafiltration and concentration, the IgG concentration was measured to obtain the full-length anti-Nogo-A antibody.
抗Nogo-A全长抗体的表征Characterization of anti-Nogo-A full-length antibodies
抗Nogo-A先导抗体全长形式(包括抗体L82、mkNG-22、mkNG-3、mkNG-26、mkNG-38、mkNG-258、mkNG-267、mkNG-272、mkNG-325、mkNG-327、mkNG-333、mkNG-360、mkNG-362、mkNG-375、mkNG-378、mkNG-379、mkNG-381、mkNG-388、mkNG-398、mkNG-401、 mkNG-405、mkNG-407、mkNG-412、mkNG-416)的性质表征，包括亲和力、中和活性以及生物学活性的检测，详见以下实施例。Anti-Nogo-A lead antibody full-length form (including antibody L82, mkNG-22, mkNG-3, mkNG-26, mkNG-38, mkNG-258, mkNG-267, mkNG-272, mkNG-325, mkNG-327, mkNG-333, mkNG-360, mkNG-362, mkNG-375, mkNG-378, mkNG-379, mkNG-381, mkNG-388, mkNG-398, mkNG-401, mkNG-405, mkNG-407, mkNG-412, mkNG-416), including detection of affinity, neutralizing activity and biological activity, see the following examples for details.
实施例3:抗Nogo-A抗体的人源化Example 3: Humanization of anti-Nogo-A antibodies
抗Nogo-A抗体的人源化：以获得的先导抗体L82(人IgG4形式)的VH/VL的CDR典型结构为基础，将重、轻链可变区序列与抗体种系数据库中的序列进行比较，获得同源性高的人种系模板。将嵌合抗体的CDR区移植到选定的人种系模板上以产生人源化的可变区，再与相应的人IgG恒定区(优选为IgG4重链(LALA)和κ轻链)重组。随后，以嵌合抗体的三维结构为基础对包埋残基、与CDR区有直接相互作用的残基以及对VH和VL的构象有重要影响的残基进行回复突变，并优化CDR区化学不稳定的氨基酸残基，从而获得3个人源化分子H-L82-1，H-L82-2，H-L82-3。人源化抗体的重链和轻链的可变结构域序列如表2和表3所示。 Humanization of anti-Nogo-A antibody : Based on the obtained typical VH / VL CDR structure of the lead antibody L82 (human IgG4 form), combine the heavy and light chain variable region sequences with those in the antibody germline database The sequences are compared to obtain a human germline template with high homology. The CDR regions of the chimeric antibody are grafted onto a selected human germline template to generate humanized variable regions, which are then recombined with the corresponding human IgG constant regions (preferably IgG4 heavy chain (LALA) and kappa light chain) . Subsequently, based on the three-dimensional structure of the chimeric antibody, back mutations were performed on the embedded residues, residues that directly interact with the CDR region, and residues that have an important impact on the conformation of VH and VL , and the CDR region was optimized. Chemically unstable amino acid residues were used to obtain three humanized molecules H-L82-1, H-L82-2, and H-L82-3. The variable domain sequences of the heavy and light chains of humanized antibodies are shown in Tables 2 and 3.
按照如上所述的人源化方法，同样对先导抗体mkNG-362进行人源化，从而获得相应的人源化分子hum-mkNG362-1、hum-mkNG362-2。上述人源化抗体的重链和轻链的可变结构域序列如表2A和表3A所示。According to the humanization method as described above, the lead antibody mkNG-362 was also humanized to obtain the corresponding humanized molecules hum-mkNG362-1 and hum-mkNG362-2. The variable domain sequences of the heavy chain and light chain of the above-mentioned humanized antibodies are shown in Table 2A and Table 3A.
全长IgG形式的人源化抗Nogo-A抗体的制备根据实施例2所述的方法进行。The preparation of humanized anti-Nogo-A antibodies in the form of full-length IgG was performed according to the method described in Example 2.
实施例4：抗Nogo-A抗体结合活性检测Example 4: Anti-Nogo-A antibody binding activity detection
采用ELISA实验评价先导抗体L82、mkNG-22、mkNG-3、mkNG-26、mkNG-38、mkNG-327、mkNG-333、mkNG-362、mkNG-378、mkNG-398、mkNG-401、mkNG-405以及人源化抗体H-L82-1、H-L82-2、H-L82-3、hum-mkNG-362-1、hum-mkNG-362-2(重构为人IgG4)对hNiG的亲和力。简而言之，用1μg/mL的hNiG抗原包被96孔酶标板，4℃过夜。去除包被溶液，加入包含1％BSA的封闭缓冲液，室温孵育1小时。清洗板子3次，分别加入梯度稀释的待测抗体L82、H-L82-1、H-L82-2、H-L82-3、mkNG-22、mkNG-3、mkNG-26、mkNG-38、mkNG-327、mkNG-333、mkNG-362、mkNG-378、mkNG-398、mkNG-401、mkNG-405、hum-mkNG-362-1、hum-mkNG-362-2(重构为人IgG4)以及ATI-355(诺华公司)，其中ATI-355作为阳性对照，37℃反应1小时。清洗板子3次，加入100μL/孔HRP标记的羊抗人IgG Fab二抗(1:16000稀释，Jackson ImmunoResearch,cat#109-036-097)，37℃反应1小时。用清洗缓冲液洗涤5次。随后加入100μL/孔TMB室温显色10min，待显色完成后加入50μl 2M硫酸终止反应。读取OD450，并通过PRISM生成结合曲线，计算EC50值。ELISA experiment was used to evaluate the lead antibodies L82, mkNG-22, mkNG-3, mkNG-26, mkNG-38, mkNG-327, mkNG-333, mkNG-362, mkNG-378, mkNG-398, mkNG-401, mkNG- 405 and the affinity of humanized antibodies H-L82-1, H-L82-2, H-L82-3, hum-mkNG-362-1, hum-mkNG-362-2 (reconstituted as human IgG4) for hNiG. Briefly, a 96-well microplate was coated with 1 μg/mL hNiG antigen at 4°C overnight. Remove the coating solution, add blocking buffer containing 1% BSA, and incubate at room temperature for 1 hour. Wash the plate three times and add gradient dilutions of the antibodies to be tested: L82, H-L82-1, H-L82-2, H-L82-3, mkNG-22, mkNG-3, mkNG-26, mkNG-38, mkNG. -327, mkNG-333, mkNG-362, mkNG-378, mkNG-398, mkNG-401, mkNG-405, hum-mkNG-362-1, hum-mkNG-362-2 (reconstituted as human IgG4), and ATI -355 (Novartis), of which ATI-355 was used as a positive control, reacted at 37°C for 1 hour. Wash the plate three times, add 100 μL/well HRP-labeled goat anti-human IgG Fab secondary antibody (1:16000 dilution, Jackson ImmunoResearch, cat#109-036-097), and react at 37°C for 1 hour. Wash 5 times with wash buffer. Then add 100 μL/well TMB to develop color at room temperature for 10 min. After color development is completed, add 50 μl 2M sulfuric acid to terminate the reaction. Read the OD450 and generate a binding curve by PRISM to calculate the EC50 value.
结果如图1以及表5A-5B所示，抗Nogo-A抗体mkNG-22(图1A)，L82、H-L82-1、H-L82-2、H-L82-3(图1B)，mkNG-3、mkNG-26、mkNG-38、mkNG-327、mkNG-333、mkNG-362、mkNG-378、mkNG-398、mkNG-401、mkNG-405(表5A)均能够有效地结合hNiG，其结合活性优于阳性对照抗体ATI-355，或与之相当。 The results are shown in Figure 1 and Table 5A-5B, anti-Nogo-A antibodies mkNG-22 (Figure 1A), L82, H-L82-1, H-L82-2, H-L82-3 (Figure 1B), mkNG -3. mkNG-26, mkNG-38, mkNG-327, mkNG-333, mkNG-362, mkNG-378, mkNG-398, mkNG-401, mkNG-405 (Table 5A) can all effectively bind hNiG. The binding activity is better than or equivalent to the positive control antibody ATI-355.
表5A：抗Nogo-A抗体与人NiG的结合活性
Table 5A: Binding activity of anti-Nogo-A antibodies to human NiG
来源于先导抗体mkNG-362的人源化分子结合活性的结果如表5B所示，人源化抗Nogo-A抗体hum-mkNG-362-1、hum-mkNG-362-2的结合活性与其亲本抗体mkNG-362相当，表明人源化并没有改变抗Nogo-A抗体的结合活性。The results of the binding activity of humanized molecules derived from the lead antibody mkNG-362 are shown in Table 5B. The binding activities of humanized anti-Nogo-A antibodies hum-mkNG-362-1 and hum-mkNG-362-2 are similar to those of their parents. Antibody mkNG-362 was comparable, indicating that humanization did not alter the binding activity of the anti-Nogo-A antibody.
表5B：人源化抗Nogo-A抗体与人NiG的结合活性
Table 5B: Binding activity of humanized anti-Nogo-A antibody to human NiG
实施例5：抗Nogo-A抗体抑制hNiG与细胞膜上Nogo-A受体的结合试验Example 5: Anti-Nogo-A antibody inhibits the binding test of hNiG to Nogo-A receptors on cell membranes
采用细胞ELISA方法检测先导抗体L82、mkNG-22、mkNG-360、mkNG-362以及人源化抗体H-L82-1、H-L82-2、H-L82-3、hum-mkNG-362-1、hum-mkNG-362-2(重构为人IgG4)阻断hNiG与PC12或NIH 3T3细胞膜上Nogo-A受体的结合试验。简而言之，在96孔酶标板上分别包被PC12细胞(协和细胞中心，cat#1101RAT-PUMC000024)、NIH 3T3细胞(以下简称为3T3，来自协和细胞中心，cat#1101MOU-PUMC000018)，37℃培养过夜。之后采用4％的PFA固定，随后用1％BSA室温封闭1小时，洗板后，先后加入Bavih-hNiG和梯度稀释的待测抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3、mkNG-22、mkNG-360、mkNG-362、hum-mkNG-362-1、hum-mkNG-362-2以及ATI-355，其中ATI-355作为阳性对照，37℃反应1小时。之后加入100μL/孔HRP标记的链霉亲和素(1:10000)，37℃反应1小时。洗板后，加入100μL/孔TMB室温显色5-10min，随后加入2M硫酸终止显色。读取OD450，并通过PRISM生成结合曲线，计算IC50值。Cell ELISA method was used to detect lead antibodies L82, mkNG-22, mkNG-360, mkNG-362 and humanized antibodies H-L82-1, H-L82-2, H-L82-3, hum-mkNG-362-1 , hum-mkNG-362-2 (reconstructed into human IgG4) blocks the binding test of hNiG to Nogo-A receptor on PC12 or NIH 3T3 cell membrane. Briefly, PC12 cells (Concordia Cell Center, cat#1101RAT-PUMC000024) and NIH 3T3 cells (hereinafter referred to as 3T3, from Concordia Cell Center, cat#1101MOU-PUMC000018) were coated on 96-well microplates. Incubate overnight at 37°C. It was then fixed with 4% PFA, and then blocked with 1% BSA for 1 hour at room temperature. After washing the plate, Bavih-hNiG and gradient dilutions of the anti-Nogo-A antibodies to be tested L82, H-L82-1, H-L82- were added successively. 2. H-L82-3, mkNG-22, mkNG-360, mkNG-362, hum-mkNG-362-1, hum-mkNG-362-2 and ATI-355, of which ATI-355 is used as a positive control, 37℃ Reaction takes 1 hour. Then add 100 μL/well HRP-labeled streptavidin (1:10000) and react at 37°C for 1 hour. After washing the plate, add 100 μL/well TMB to develop color at room temperature for 5-10 min, and then add 2M sulfuric acid to terminate the color development. Read the OD450 and generate a binding curve by PRISM to calculate the IC50 value.
结果如表6和图2所示，示例性的抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3(表6A和图2A)、mkNG-360、mkNG-362(表6C)均能够有效地阻断hNiG与PC12细胞膜上Nogo-A受体的结合，其阻断活性优于阳性对照抗体ATI-355。The results are shown in Table 6 and Figure 2, exemplary anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 (Table 6A and Figure 2A), mkNG-360, mkNG -362 (Table 6C) can effectively block the binding of hNiG to the Nogo-A receptor on the PC12 cell membrane, and its blocking activity is better than the positive control antibody ATI-355.
抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3(表6B和图2B)，mkNG-360、mkNG-362(表6D)均能够有效地阻断hNiG与3T3细胞膜上Nogo-A受体的结合，其阻断活性优于阳性对照抗体ATI-355。 Anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 (Table 6B and Figure 2B), mkNG-360, mkNG-362 (Table 6D) can effectively block hNiG Binding to the Nogo-A receptor on the 3T3 cell membrane, its blocking activity is better than the positive control antibody ATI-355.
另外，mkNG-22、hum-mkNG-362-1、hum-mkNG-362-2也能够有效地阻断hNiG与PC12或3T3细胞膜上Nogo-A受体的结合，其阻断活性均优于阳性对照抗体ATI-355，且hum-mkNG-362-1、hum-mkNG-362-2的阻断活性与其亲本抗体mkNG-362基本相当(数据未显示)。In addition, mkNG-22, hum-mkNG-362-1, and hum-mkNG-362-2 can also effectively block the binding of hNiG to Nogo-A receptors on PC12 or 3T3 cell membranes, and their blocking activities are better than positive Control antibody ATI-355, and the blocking activities of hum-mkNG-362-1 and hum-mkNG-362-2 were basically equivalent to their parent antibody mkNG-362 (data not shown).
表6A：PC12细胞
Table 6A: PC12 cells
表6B：3T3细胞
Table 6B: 3T3 cells
表6C：PC12细胞
Table 6C: PC12 cells
表6D：3T3细胞
Table 6D: 3T3 cells
实施例6：抗Nogo-A抗体与不同种属Nogo-A的交叉结合活性检测Example 6: Detection of cross-binding activity of anti-Nogo-A antibodies to Nogo-A of different species
采用FACS方法检测抗Nogo-A抗体与不同种属(包括人、恒河猴、小鼠和大鼠)Nogo-A的交叉结合活性。简而言之，293T细胞离心计数后接种在6孔培养板中，37℃、5％CO2，过夜培养至密度约为80％～90％。将编码不同种属来源的Nogo-A蛋白的质粒pcmv3-人RTN4、pcmv3-恒河猴RTN4、pcmv3-大鼠RTN4、pcmv3-小鼠RTN4分别转染293T细胞，在37℃、5％CO2下培养48h。收取细胞后，加入梯度稀释的待测抗体L82、H-L82-1、H-L82-2、H-L82-3、mkNG-22、mkNG-360、mkNG-362、hum-mkNG-362-1、hum-mkNG-362-2、ATI-355以及IgG无关抗体(舒泰神)，其中ATI-355作为阳性对照，IgG无关抗体作为阴性对照，室温孵育1.5-2h。随后加入FC- PE标记的鼠抗人IgG，室温避光孵育60min。读取OD450，并通过PRISM生成结合曲线，计算EC50值。The FACS method was used to detect the cross-binding activity of anti-Nogo-A antibodies to Nogo-A of different species (including humans, rhesus monkeys, mice and rats). Briefly, 293T cells were centrifuged and counted and seeded in a 6-well culture plate at 37°C and 5% CO 2 overnight until the density was approximately 80% to 90%. The plasmids pcmv3-human RTN4, pcmv3-rhesus monkey RTN4, pcmv3-rat RTN4, and pcmv3-mouse RTN4 encoding Nogo-A proteins from different species were transfected into 293T cells respectively, and the cells were incubated at 37°C and 5% CO 2 Incubate for 48h. After collecting the cells, add serially diluted antibodies to be tested L82, H-L82-1, H-L82-2, H-L82-3, mkNG-22, mkNG-360, mkNG-362, hum-mkNG-362-1 , hum-mkNG-362-2, ATI-355 and IgG-irrelevant antibody (Sutaishen), in which ATI-355 is used as a positive control and IgG-irrelevant antibody is used as a negative control. Incubate at room temperature for 1.5-2h. Later joined FC- PE-labeled mouse anti-human IgG was incubated at room temperature in the dark for 60 minutes. Read the OD450 and generate a binding curve by PRISM to calculate the EC50 value.
结果如图3所示，抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3及mkNG-22(重构为人IgG4)不仅与人Nogo-A结合(图3A)，也与恒河猴Nogo-A(图3B)、大鼠Nogo-A(图3C)有较强的结合，但与小鼠Nogo-A的结合较弱(图3D)。The results are shown in Figure 3. Anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG-22 (reconstructed into human IgG4) not only bind to human Nogo-A (Figure 3A), also has strong binding to rhesus monkey Nogo-A (Fig. 3B) and rat Nogo-A (Fig. 3C), but the binding to mouse Nogo-A is weak (Fig. 3D).
另外，其他示例性的抗Nogo-A抗体mkNG-360、mkNG-362、hum-mkNG-362-1、hum-mkNG-362-2与恒河猴Nogo-A、大鼠Nogo-A、小鼠Nogo-A均有交叉结合活性(数据未显示)。Additionally, other exemplary anti-Nogo-A antibodies mkNG-360, mkNG-362, hum-mkNG-362-1, hum-mkNG-362-2 are related to rhesus monkey Nogo-A, rat Nogo-A, mouse Both Nogo-A have cross-binding activity (data not shown).
实施例7：表征抗Nogo-A抗体的结合亲和力以及解离常数(Kd)Example 7: Characterization of binding affinity and dissociation constant (Kd) of anti-Nogo-A antibodies
采用Biacore T200(GE)表征抗Nogo-A抗体(重构为人IgG4)的结合亲和力。将hNiG抗原固定在传感器芯片CM5上，检测不同浓度(包括0M、5.208E-10M、1.042E-9M、2.083E-9M、4.167E-9M、8.333E-9M)的抗Nogo-A抗体对hNiG抗原的亲和力。采用SPR技术测量抗体的结合率和解离率，并确定结合亲和力。Biacore T200 (GE) was used to characterize the binding affinity of anti-Nogo-A antibodies (reconstituted as human IgG4). The hNiG antigen was fixed on the sensor chip CM5, and anti-Nogo-A antibodies at different concentrations (including 0M, 5.208E-10M, 1.042E-9M, 2.083E-9M, 4.167E-9M, 8.333E-9M) were detected against hNiG Antigen affinity. SPR technology is used to measure the binding and dissociation rates of antibodies and determine binding affinity.
结果如表7所示，抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3与hNiG的亲和力均达到1.0E-13以上，其结合活性优于阳性对照抗体ATI-355。The results are shown in Table 7. The affinity of anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, and H-L82-3 to hNiG all reached above 1.0E-13, and their binding activity was better than that of the positive control. Antibody ATI-355.
表7
Table 7
实施例8：相对定量QPCR检测Nogo-A抗体活性Example 8: Detection of Nogo-A antibody activity by relative quantitative QPCR
Nogo-A是一种能够抑制神经生长与再生的蛋白，具有抑制神经细胞轴突生长与延伸的活性。GAP-43是一种轴突生长相关膜蛋白，与神经发育、突触形成和可塑性，特别是与神经再生密切相关。实验选择的传代PC12细胞系，是大鼠嗜鉻瘤细胞，源于神经外胚层嗜鉻组织的肿瘤。在NGF刺激下，该细胞能够表现出类神经细胞的轴突生长，且伴随GAP-43mRNA和蛋白质表达水平的上调；而Nogo-A能够抑制轴突生长，促使GAP-43mRNA水平降低。本实验基于Nogo-A的生物活性机制与GAP-43的生物学特性，采用体外培养的PC12细胞，检测Nogo-A对GAP-43转录水平的抑制活性，从而评价抗Nogo-A抗体的阻断效应。Nogo-A is a protein that can inhibit nerve growth and regeneration, and has the activity of inhibiting the growth and extension of nerve cell axons. GAP-43 is an axonal growth-related membrane protein that is closely related to neural development, synapse formation and plasticity, especially nerve regeneration. The passaged PC12 cell line selected for the experiment is rat pheochromoma cells, a tumor derived from neuroectodermal chromaffin tissue. Under NGF stimulation, the cells can exhibit neuronal cell-like axonal growth, accompanied by an upregulation of GAP-43 mRNA and protein expression levels; while Nogo-A can inhibit axonal growth and promote a decrease in GAP-43mRNA levels. This experiment is based on the biological activity mechanism of Nogo-A and the biological properties of GAP-43. PC12 cells cultured in vitro were used to detect the inhibitory activity of Nogo-A on the transcription level of GAP-43, thereby evaluating the blocking effect of anti-Nogo-A antibodies. effect.
简而言之，将NGF、待测抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3、mkNG-22、mkNG-3、mkNG-26、mkNG-258、mkNG-267、mkNG-272、mkNG-325、mkNG-327、mkNG-333、mkNG-360、mkNG-362、mkNG-375、mkNG-379、mkNG-381、mkNG-388、mkNG-405、mkNG-407、mkNG-412、mkNG-416、ATI-355和Nogo-A混合，加入至PC12细胞后孵育48h，其中空白对照组不加NGF(NGF-)，阴性对照组不加抗Nogo-A抗体(hNiG+NGF)，ATI-355作为阳性对照。随后提取各组细胞中的总RNA进行反转录，之后分别用GAP-43的引物和管家蛋白GAPDH 的引物进行相对荧光定量PCR，定量检测在抗原Nogo-A作用下GAP-43mRNA的变化水平，从而反映抗Nogo-A抗体的体外活性。Briefly, combine NGF, anti-Nogo-A antibody to be tested L82, H-L82-1, H-L82-2, H-L82-3, mkNG-22, mkNG-3, mkNG-26, mkNG-258 , mkNG-267, mkNG-272, mkNG-325, mkNG-327, mkNG-333, mkNG-360, mkNG-362, mkNG-375, mkNG-379, mkNG-381, mkNG-388, mkNG-405, mkNG -407, mkNG-412, mkNG-416, ATI-355 and Nogo-A were mixed, added to PC12 cells and incubated for 48 hours. The blank control group did not add NGF (NGF-), and the negative control group did not add anti-Nogo-A antibodies. (hNiG+NGF), ATI-355 was used as a positive control. Then the total RNA in each group of cells was extracted and reverse transcribed, and then the primers of GAP-43 and the housekeeping protein GAPDH were used respectively. The primers were used for relative fluorescence quantitative PCR to quantitatively detect the change level of GAP-43 mRNA under the action of the antigen Nogo-A, thereby reflecting the in vitro activity of the anti-Nogo-A antibody.
结果如图4所示，hNiG处理后的PC12细胞中GAP-43的表达水平下降，而经过抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3及mkNG-22(重构为人IgG4)处理后GAP-43的表达均得到显著升高，且活性优于阳性对照抗体ATI-355或与之相当，表明抗Nogo-A抗体能够阻断Nogo-A对GAP-43转录水平的抑制活性。The results are shown in Figure 4. The expression level of GAP-43 in PC12 cells after hNiG treatment decreased, while after treatment with anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H-L82-3 and mkNG The expression of GAP-43 was significantly increased after treatment with -22 (reconstructed into human IgG4), and its activity was better than or equivalent to the positive control antibody ATI-355, indicating that the anti-Nogo-A antibody can block the effect of Nogo-A on GAP -43 Inhibitory activity at the transcriptional level.
结果如表8所示，其他的18个示例性抗Nogo-A抗体mkNG-3、mkNG-26、mkNG-258、mkNG-267、mkNG-272、mkNG-325、mkNG-327、mkNG-333、mkNG-360、mkNG-362、mkNG-375、mkNG-379、mkNG-381、mkNG-388、mkNG-405、mkNG-407、mkNG-412、mkNG-416处理后的PC12细胞中GAP-43的表达均得到显著升高，且活性优于阳性对照抗体ATI-355，表明抗Nogo-A抗体能够有效阻断Nogo-A对GAP-43转录水平的抑制。The results are shown in Table 8. The other 18 exemplary anti-Nogo-A antibodies mkNG-3, mkNG-26, mkNG-258, mkNG-267, mkNG-272, mkNG-325, mkNG-327, mkNG-333, Expression of GAP-43 in PC12 cells treated with mkNG-360, mkNG-362, mkNG-375, mkNG-379, mkNG-381, mkNG-388, mkNG-405, mkNG-407, mkNG-412 and mkNG-416 All were significantly increased, and the activity was better than that of the positive control antibody ATI-355, indicating that the anti-Nogo-A antibody can effectively block Nogo-A's inhibition of GAP-43 transcription levels.
表8
Table 8
实施例9：抗Nogo-A抗体对hNiG抑制N1E-115细胞神经突生长的恢复作用Example 9: Restoration effect of anti-Nogo-A antibody on hNiG-inhibited neurite growth of N1E-115 cells
采用N1E-115细胞的形态学变化，评价抗Nogo-A抗体对hNiG抑制神经突生长的恢复作用。简而言之，将N1E-115细胞(ATCC)接种到96孔板中，37℃培养过夜。随后加入0.05％DMSO诱导神经突生长，同时加入hNiG以及相应浓度的待测抗Nogo-A抗体。孵育48h后，对细胞形态进行显微镜观察并拍照(图5A)，并采用Image J软件定量分析神经突生长情况(图5B-5C)。The morphological changes of N1E-115 cells were used to evaluate the restoration effect of anti-Nogo-A antibody on hNiG-inhibited neurite growth. Briefly, N1E-115 cells (ATCC) were seeded into 96-well plates and cultured at 37°C overnight. Then, 0.05% DMSO was added to induce neurite growth, and hNiG and corresponding concentrations of the anti-Nogo-A antibody to be tested were added at the same time. After incubation for 48 hours, the cell morphology was observed under a microscope and photographed (Figure 5A), and Image J software was used to quantitatively analyze neurite growth (Figures 5B-5C).
结果如图5A-5B所示，hNiG处理后的N1E-115细胞的神经突生长受到明显抑制，而抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3及mkNG-22(重构为人IgG4)均对神经突的生长抑制起到了明显的恢复作用，且恢复作用优于阳性对照抗体ATI-355。The results are shown in Figure 5A-5B. The neurite growth of N1E-115 cells treated with hNiG was significantly inhibited, while anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, and H-L82-3 and mkNG-22 (reconstructed into human IgG4) all significantly restored the inhibition of neurite growth, and the restoration effect was better than that of the positive control antibody ATI-355.
结果如图5C所示，其他示例性的抗Nogo-A抗体mkNG-362对神经突的生长抑制也起到了明显的恢复作用，且恢复作用优于阳性对照抗体11C7。The results are shown in Figure 5C. Other exemplary anti-Nogo-A antibody mkNG-362 also had a significant recovery effect on the inhibition of neurite growth, and the recovery effect was better than the positive control antibody 11C7.
实施例10：抗Nogo-A抗体对猴脊髓提取液抑制N1E-115细胞神经突生长的恢复作用Example 10: Restorative effect of anti-Nogo-A antibody on the inhibition of neurite growth of N1E-115 cells by monkey spinal cord extract
猴脊髓提取液中富含Nogo-A蛋白，能够抑制N1E-115细胞神经突的生长。采用N1E-115细胞的形态学变化，评价抗Nogo-A抗体对猴脊髓提取液(以下简称为Mk ex.)抑制神经突生长的恢复 作用。简而言之，将N1E-115细胞接种到96孔板中，37℃培养过夜。随后加入0.05％DMSO诱导神经突生长，同时加入猴脊髓提取液以及相应浓度的待测抗Nogo-A抗体。孵育48h后，对细胞形态进行显微镜观察并拍照(图6A)，采用Image J软件定量分析神经突生长情况(图6B)。Monkey spinal cord extract is rich in Nogo-A protein, which can inhibit the growth of neurites of N1E-115 cells. The morphological changes of N1E-115 cells were used to evaluate the recovery of neurite growth inhibited by anti-Nogo-A antibody in monkey spinal cord extract (hereinafter referred to as Mk ex.) effect. Briefly, N1E-115 cells were seeded into 96-well plates and cultured at 37°C overnight. Then, 0.05% DMSO was added to induce neurite growth, and monkey spinal cord extract and corresponding concentrations of the anti-Nogo-A antibody to be tested were added. After incubation for 48 hours, the cell morphology was observed under a microscope and photographed (Figure 6A), and the neurite growth was quantitatively analyzed using Image J software (Figure 6B).
结果如图6A-6B所示，猴脊髓提取液对N1E-115细胞的神经突生长有明显的抑制作用，而抗Nogo-A抗体L82、H-L82-1、H-L82-2、H-L82-3及mkNG-22(重构为人IgG4)均对神经突的生长起到了明显的恢复作用，且恢复作用优于阳性对照抗体ATI-355。The results are shown in Figure 6A-6B. Monkey spinal cord extract has a significant inhibitory effect on the neurite growth of N1E-115 cells, while anti-Nogo-A antibodies L82, H-L82-1, H-L82-2, H- Both L82-3 and mkNG-22 (reconstituted into human IgG4) significantly restored neurite growth, and the recovery effect was better than that of the positive control antibody ATI-355.
实施例11：抗Nogo-A抗体对hNiG抑制PC12细胞神经突生长的恢复作用Example 11: Restorative effect of anti-Nogo-A antibody on hNiG-inhibited neurite growth of PC12 cells
采用PC12细胞的形态学变化，评价抗Nogo-A抗体对hNiG抑制神经突生长的恢复作用。简而言之，将PC12细胞(协和)接种到多聚赖氨酸包被的96孔板中，37℃培养过夜。随后加入20ng/ml NGF诱导神经突生长2h，之后加入hNiG以及相应浓度的待测抗Nogo-A抗体。孵育5天后，对细胞形态进行显微镜观察并拍照(数据未显示)，并采用Image J软件定量分析神经突生长情况(图6C)。The morphological changes of PC12 cells were used to evaluate the restoration effect of anti-Nogo-A antibody on hNiG-inhibited neurite growth. Briefly, PC12 cells (Xiehe) were seeded into polylysine-coated 96-well plates and cultured at 37°C overnight. Then 20ng/ml NGF was added to induce neurite growth for 2 hours, and then hNiG and the corresponding concentration of the anti-Nogo-A antibody to be tested were added. After 5 days of incubation, the cell morphology was observed under a microscope and photographed (data not shown), and Image J software was used to quantitatively analyze neurite growth (Figure 6C).
结果如图6C所示，hNiG处理后的PC12细胞的神经突生长受到明显抑制，而示例性抗Nogo-A抗体mkNG-360、mkNG-362均对神经突的生长抑制起到了明显的恢复作用，且恢复作用优于阳性对照抗体ATI-355。The results are shown in Figure 6C. The neurite growth of PC12 cells after hNiG treatment was significantly inhibited, and the exemplary anti-Nogo-A antibodies mkNG-360 and mkNG-362 both significantly restored the inhibition of neurite growth. And the recovery effect is better than the positive control antibody ATI-355.
另外，其他示例性抗Nogo-A抗体hum-mkNG-362-1、hum-mkNG-362-2也对神经突的生长抑制起到了明显的恢复作用，且恢复作用与其亲本抗体mkNG-362基本相当，优于阳性对照抗体ATI-355(数据未显示)。In addition, other exemplary anti-Nogo-A antibodies hum-mkNG-362-1 and hum-mkNG-362-2 also significantly restored the inhibition of neurite growth, and the restoration effects were basically equivalent to their parent antibody mkNG-362. , better than the positive control antibody ATI-355 (data not shown).
实施例12：抗Nogo-A抗体在脊髓损伤小鼠模型中的体内药效学研究Example 12: In vivo pharmacodynamic study of anti-Nogo-A antibody in spinal cord injury mouse model
采用构建的脊髓损伤小鼠模型验证抗Nogo-A抗体的体内药效学。The constructed mouse model of spinal cord injury was used to verify the in vivo pharmacodynamics of anti-Nogo-A antibodies.
构建脊髓损伤(SCI)小鼠模型。简言之，根据分组前测定的体重，将13只检疫合格的9周龄C57BL/6雌性小鼠(北京华阜康生物科技股份有限公司)随机分为两组：模型对照组和供试品组，6～7只/组。将各组小鼠麻醉后脱毛、备皮，暴露T7～T10处脊椎，切除T7及T10处椎板，于T7～T8胸髓处行右过横半切，于T10～T11胸髓处行左横半切。缝合皮肤，单笼饲养。将手术当天定义为第0天。 Construction of spinal cord injury (SCI) mouse model . Briefly, according to the body weight measured before grouping, 13 quarantine-qualified 9-week-old C57BL/6 female mice (Beijing Huafukang Biotechnology Co., Ltd.) were randomly divided into two groups: model control group and test article. Group, 6 to 7 animals/group. The mice in each group were anesthetized and depilated and skin was prepared. The spine at T7 to T10 was exposed. The laminae at T7 and T10 were removed. A right transverse hemisection was performed at T7 to T8 thoracic cord, and a left transverse hemisection was performed at T10 to T11. Cut in half. The skin was sutured and kept in single cages. The day of surgery was defined as day 0.
抗Nogo-A抗体治疗：供试品组小鼠尾静脉注射抗Nogo-A抗体，给药剂量为10mg/kg，给药频率为第0、3、7、10天各给药一次。模型对照组以相同的给药频率注射等体积的PBS溶液。每日观察小鼠的生存状态，记录小鼠的死亡日期。采用专业摄像机分别于第7、14、21、28和35天拍摄不短于4分钟的小鼠自然状态下探索的视频，由同一专业人员按照BMS量表评分标准(详见表8)进行分析，并采用统计学软件SPSS和GraphPad Prism绘制动物BMS评分曲线。 Anti-Nogo-A antibody treatment : The mice in the test group were injected with anti-Nogo-A antibody into the tail vein at a dose of 10 mg/kg, and the administration frequency was once on days 0, 3, 7, and 10. The model control group was injected with an equal volume of PBS solution at the same administration frequency. Observe the survival status of the mice every day and record the death date of the mice. A professional camera was used to capture videos of mice exploring in their natural state for no less than 4 minutes on days 7, 14, 21, 28, and 35. The same professionals analyzed the videos in accordance with the BMS scale scoring standards (see Table 8 for details). , and used statistical software SPSS and GraphPad Prism to draw animal BMS score curves.
结果如图7所示，与模型对照(SCI)组相比，示例性抗Nogo-A抗体H-L82-3能够显著提高脊髓损伤小鼠的BMS评分，表明抗Nogo-A抗体在体内具有治疗脊髓损伤的效果。The results are shown in Figure 7. Compared with the model control (SCI) group, the exemplary anti-Nogo-A antibody H-L82-3 was able to significantly improve the BMS score of spinal cord injury mice, indicating that the anti-Nogo-A antibody has therapeutic effect in vivo Effects of spinal cord injury.
其他抗NogoA抗体L82、H-L82-1、H-L82-2、mkNG-22、mkNG-362、hum-mkNG-362-1、hum-mkNG-362-2也产生了类似的治疗脊髓损伤的效果(数据未显示)。 Other anti-NogoA antibodies L82, H-L82-1, H-L82-2, mkNG-22, mkNG-362, hum-mkNG-362-1, hum-mkNG-362-2 also produced similar therapeutic effects in spinal cord injury. effects (data not shown).
表8：BMS量表评分标准1
Table 8: BMS Scale Scoring Criteria 1
备注：1可被评估的步进：小鼠以匀速移动，且移动距离超过3个身长(不含尾部)。Notes: 1 Steps that can be evaluated: The mouse moves at a constant speed and the distance it moves exceeds 3 body lengths (excluding the tail).
2协调性：在可被评估的步进中，当前爪迈进一步，后爪随之迈进一步，且两个后爪交替前进。在整个评价过程中，至少产生3个可被评估的步进用来评价协调性，如果没有发生3个及以上可被评估的步进，则视为不协调。蹒跚不被视为协调。 2 Coordination: In the step that can be evaluated, the front paw takes one step, the hind paw takes one step, and the two hind paws advance alternately. During the entire evaluation process, at least 3 evaluable steps are generated to evaluate coordination. If 3 or more evaluable steps do not occur, it is regarded as incoordination. Staggering is not considered coordinated.
3极差的躯体稳定性：极差的躯体稳定性主要存在于以下两个方面之一：(1)后肢及臀部表现出极度异常的姿势(如明显的倾斜、蹒跚和/或在测试过程中后肢及臀部明显有塌陷的趋势)；(2)发生5次及以上臀部撞击地面、肌肉痉挛和/或脊柱侧弯，导致步进停止。 3 Extremely poor body stability: Extremely poor body stability mainly exists in one of the following two aspects: (1) The hind limbs and hips show extremely abnormal postures (such as obvious tilt, stagger and/or during the test There is a clear tendency for the hind limbs and buttocks to collapse); (2) The buttocks hit the ground 5 or more times, muscle spasm and/or scoliosis occurs, causing the step to stop.
4较好的躯体稳定性：少于5次的“极差的躯体稳定性”事件。臀部整体轻微摇摆和/或有塌陷的趋势。当小鼠尾巴上翘时，其远端三分之一会表现出左右摇摆。 4 Good Physical Stability: Less than 5 "Poor Physical Stability" events. The hips have an overall slight sway and/or a tendency to sag. When a mouse's tail is turned up, its distal third exhibits a side-to-side sway.
5正常的躯体稳定性：少于5次的“较好的躯体稳定性”事件，没有严重的姿势缺陷，臀部整体无倾斜或摇摆。运动时，小鼠尾巴的远端三分之一稳定、不摇摆。 5 Normal Body Stability: Less than 5 episodes of "good body stability", no serious postural deficiencies, and no overall hip tilt or sway. When moving, the distal third of the mouse's tail is stable and does not waver.

Claims (20)

  1. 一种分离的抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：An isolated anti-Nogo-A antibody, wherein the anti-Nogo-A antibody comprises:
    重链可变结构域(VH)，所述VH包含：Heavy chain variable domain (V H ), said V H comprising:
    重链互补决定区(HC-CDR)1，其包含SEQ ID NO:1所示的氨基酸序列；Heavy chain complementarity determining region (HC-CDR) 1, which contains the amino acid sequence shown in SEQ ID NO: 1;
    HC-CDR2，其包含SEQ ID NO:3所示的氨基酸序列；和HC-CDR2, which contains the amino acid sequence shown in SEQ ID NO:3; and
    HC-CDR3，其包含SEQ ID NO:5所示的氨基酸序列；以及HC-CDR3, which contains the amino acid sequence shown in SEQ ID NO:5; and
    轻链可变结构域(VL)，所述VL包含：Light chain variable domain (V L ), said V L comprising:
    轻链互补决定区(LC-CDR)1，其包含SEQ ID NO:7所示的氨基酸序列；Light chain complementarity determining region (LC-CDR) 1, which contains the amino acid sequence shown in SEQ ID NO:7;
    LC-CDR2，其包含SEQ ID NO:9所示的氨基酸序列；和LC-CDR2, which contains the amino acid sequence shown in SEQ ID NO: 9; and
    LC-CDR3，其包含SEQ ID NO:11所示的氨基酸序列。LC-CDR3, which contains the amino acid sequence shown in SEQ ID NO:11.
  2. 根据权利要求1中所述的分离的抗Nogo-A抗体，其包含：The isolated anti-Nogo-A antibody according to claim 1, comprising:
    (i)VH，其包含氨基酸序列SEQ ID NO:13或其变体，所述变体与氨基酸序列SEQ ID NO:13具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:18或其变体，所述变体与氨基酸序列SEQ ID NO:18具有至少约80％序列同一性；(i) V H comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 13; and V L comprising the amino acid sequence SEQ ID NO: 18 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 18;
    (ii)VH，其包含氨基酸序列SEQ ID NO:14或其变体，所述变体与氨基酸序列SEQ ID NO:14具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性；(ii) V H comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 14; and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 19;
    (iii)VH，其包含氨基酸序列SEQ ID NO:15或其变体，所述变体与氨基酸序列SEQ ID NO:15具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性；或(iii) V H comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 15; and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 19; or
    (iv)VH，其包含氨基酸序列SEQ ID NO:16或其变体，所述变体与氨基酸序列SEQ ID NO:16具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:19或其变体，所述变体与氨基酸序列SEQ ID NO:19具有至少约80％序列同一性。(iv) V H comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 16; and V L comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 19.
  3. 一种分离的抗Nogo-A抗体，其中所述抗Nogo-A抗体包含：An isolated anti-Nogo-A antibody, wherein the anti-Nogo-A antibody comprises:
    重链可变结构域(VH)，所述VH包含：Heavy chain variable domain (V H ), said V H comprising:
    重链互补决定区(HC-CDR)1，其包含SEQ ID NO:28所示的氨基酸序列；Heavy chain complementarity determining region (HC-CDR) 1, which contains the amino acid sequence shown in SEQ ID NO: 28;
    HC-CDR2，其包含SEQ ID NO:48所示的氨基酸序列；和 HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:48; and
    HC-CDR3，其包含SEQ ID NO:65所示的氨基酸序列；以及HC-CDR3, which contains the amino acid sequence shown in SEQ ID NO: 65; and
    轻链可变结构域(VL)，所述VL包含：Light chain variable domain (V L ), said V L comprising:
    轻链互补决定区(LC-CDR)1，其包含SEQ ID NO:85所示的氨基酸序列；Light chain complementarity determining region (LC-CDR) 1, which contains the amino acid sequence shown in SEQ ID NO: 85;
    LC-CDR2，其包含SEQ ID NO:100所示的氨基酸序列；和LC-CDR2, which contains the amino acid sequence shown in SEQ ID NO: 100; and
    LC-CDR3，其包含SEQ ID NO:111所示的氨基酸序列。LC-CDR3, which contains the amino acid sequence shown in SEQ ID NO:111.
  4. 根据权利要求3中所述的分离的抗Nogo-A抗体，其包含：The isolated anti-Nogo-A antibody according to claim 3, comprising:
    (i)VH，其包含氨基酸序列SEQ ID NO:127或其变体，所述变体与氨基酸序列SEQ ID NO:127具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性；(i) V H comprising the amino acid sequence SEQ ID NO: 127 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 127; and V L comprising the amino acid sequence SEQ ID NO:150 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:150;
    (ii)VH，其包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:151或其变体，所述变体与氨基酸序列SEQ ID NO:151具有至少约80％序列同一性；或(ii) V H comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 128; and V L comprising the amino acid sequence SEQ ID NO:151 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:151; or
    (iii)VH，其包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性。(iii) V H comprising the amino acid sequence SEQ ID NO: 128 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 128; and V L comprising the amino acid sequence SEQ ID NO:150 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:150.
  5. 一种分离的抗Nogo-A抗体，其包含：An isolated anti-Nogo-A antibody containing:
    (i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:4，和HC-CDR3，其包含氨基酸序列SEQ ID NO:6；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:8，LC-CDR2，其包含氨基酸序列SEQ ID NO:10，和LC-CDR3，其包含氨基酸序列SEQ ID NO:12；(i) V H comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 2, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 4 , and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 6; and V L comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO: 8, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 10 , and LC-CDR3 comprising Amino acid sequence SEQ ID NO: 12;
    (ii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:29，HC-CDR2，其包含氨基酸序列SEQ ID NO:49，和HC-CDR3，其包含氨基酸序列SEQ ID NO:66；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:86，LC-CDR2，其包含氨基酸序列SEQ ID NO:101，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112； (ii) V H comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 29, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 49, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 66; and V L comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO: 86, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 101 , and LC-CDR3 comprising Amino acid sequence SEQ ID NO: 112;
    (iii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:30，HC-CDR2，其包含氨基酸序列SEQ ID NO:50，和HC-CDR3，其包含氨基酸序列SEQ ID NO:67；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:87，LC-CDR2，其包含氨基酸序列SEQ ID NO:102，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113；(iii) VH , said VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 30, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 50, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:67; and VL comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:87, LC-CDR2 comprising the amino acid sequence SEQ ID NO:102, and LC-CDR3 comprising Amino acid sequence SEQ ID NO: 113;
    (iv)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:36，HC-CDR2，其包含氨基酸序列SEQ ID NO:55，和HC-CDR3，其包含氨基酸序列SEQ ID NO:73；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117；(iv) V H comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 36, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 55, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:73; and VL comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:91, LC-CDR2 comprising the amino acid sequence SEQ ID NO:106, and LC-CDR3 comprising Amino acid sequence SEQ ID NO: 117;
    (v)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:37，HC-CDR2，其包含氨基酸序列SEQ ID NO:56，和HC-CDR3，其包含氨基酸序列SEQ ID NO:74；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:91，LC-CDR2，其包含氨基酸序列SEQ ID NO:106，和LC-CDR3，其包含氨基酸序列SEQ ID NO:117；或(v) V H comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 37, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 56, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:74; and VL comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:91, LC-CDR2 comprising the amino acid sequence SEQ ID NO:106, and LC-CDR3 comprising Amino acid sequence SEQ ID NO: 117; or
    (vi)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:45，HC-CDR2，其包含氨基酸序列SEQ ID NO:63，和HC-CDR3，其包含氨基酸序列SEQ ID NO:83；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:97，LC-CDR2，其包含氨基酸序列SEQ ID NO:104，和LC-CDR3，其包含氨基酸序列SEQ ID NO:124。(vi) V H comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 45, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 63, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:83; and VL comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:97, LC-CDR2 comprising the amino acid sequence SEQ ID NO:104, and LC-CDR3 comprising Amino acid sequence SEQ ID NO:124.
  6. 根据权利要求5中所述的分离的抗Nogo-A抗体，其包含：The isolated anti-Nogo-A antibody according to claim 5, comprising:
    (i)VH，其包含氨基酸序列SEQ ID NO:17或其变体，所述变体与氨基酸序列SEQ ID NO:17具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:20或其变体，所述变体与氨基酸序列SEQ ID NO:20具有至少约80％序列同一性；(i) V H comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 17; and V L comprising the amino acid sequence SEQ ID NO:20 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:20;
    (ii)VH，其包含氨基酸序列SEQ ID NO:129或其变体，所述变体与氨基酸序列SEQ ID NO:129具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:152或其变体，所述变体与氨基酸序列SEQ ID NO:152具有至少约80％序列同一性； (ii) V H comprising the amino acid sequence SEQ ID NO: 129 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 129; and V L comprising the amino acid sequence SEQ ID NO:152 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:152;
    (iii)VH，其包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:153具有至少约80％序列同一性；(iii) V H comprising the amino acid sequence SEQ ID NO: 130 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 130; and V L comprising the amino acid sequence SEQ ID NO:153 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:153;
    (iv)VH，其包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性；(iv) V H comprising the amino acid sequence SEQ ID NO: 136 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 136; and V L comprising the amino acid sequence SEQ ID NO:159 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159;
    (v)VH，其包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性；或(v) V H comprising the amino acid sequence SEQ ID NO: 137 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 137; and V L comprising the amino acid sequence SEQ ID NO:159 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:159; or
    (vi)VH，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:168或其变体，所述变体与氨基酸序列SEQ ID NO:168具有至少约80％序列同一性。(vi) V H comprising the amino acid sequence SEQ ID NO: 146 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 146; and V L comprising the amino acid sequence SEQ ID NO:168 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:168.
  7. 根据权利要求1-6中任一项所述的分离的抗Nogo-A抗体，其中所述抗Nogo-A抗体与人Nogo-A结合的Kd值为约0.1pM至约10nM。The isolated anti-Nogo-A antibody of any one of claims 1-6, wherein the anti-Nogo-A antibody binds to human Nogo-A with a Kd value of about 0.1 pM to about 10 nM.
  8. 根据权利要求1-7中任一项的分离的抗Nogo-A抗体，其中所述抗Nogo-A抗体包含Fc片段。The isolated anti-Nogo-A antibody according to any one of claims 1-7, wherein said anti-Nogo-A antibody comprises an Fc fragment.
  9. 根据权利要求8中的分离的抗Nogo-A抗体，其中所述抗Nogo-A抗体是全长的IgA、IgD、IgE、IgG或IgM抗体。The isolated anti-Nogo-A antibody according to claim 8, wherein said anti-Nogo-A antibody is a full-length IgA, IgD, IgE, IgG or IgM antibody.
  10. 根据权利要求9中的分离的抗Nogo-A抗体，其中所述抗Nogo-A抗体是全长的IgG1、IgG2、IgG3或IgG4抗体。The isolated anti-Nogo-A antibody according to claim 9, wherein said anti-Nogo-A antibody is a full-length IgGl, IgG2, IgG3 or IgG4 antibody.
  11. 根据权利要求1-10中任一项的分离的抗Nogo-A抗体，其中所述抗Nogo-A抗体是嵌合的、人的或人源化的抗体。The isolated anti-Nogo-A antibody according to any one of claims 1-10, wherein said anti-Nogo-A antibody is a chimeric, human or humanized antibody.
  12. 根据权利要求1-7中任一项的分离的抗Nogo-A抗体，其中所述抗Nogo-A抗体是抗原结合片段，所述抗原结合片段选自Fab、Fab’、F(ab)’2、Fab’-SH、单链Fv(scFv)、Fv片段、dAb、Fd、纳米抗体(nanobody)、双链抗体(diabody)和线性抗体。 The isolated anti-Nogo-A antibody according to any one of claims 1-7, wherein the anti-Nogo-A antibody is an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab) ' , Fab'-SH, single chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, diabody and linear antibody.
  13. 一种分离的编码权利要求1-12中任一项所述的抗Nogo-A抗体的核酸分子。An isolated nucleic acid molecule encoding the anti-Nogo-A antibody of any one of claims 1-12.
  14. 一种包含权利要求13中所述的核酸分子的载体。A vector comprising the nucleic acid molecule of claim 13.
  15. 一种分离的宿主细胞，其包含权利要求1-12中任一项所述的抗Nogo-A抗体、权利要求13中所述的核酸分子或权利要求14中所述的载体。An isolated host cell comprising the anti-Nogo-A antibody of any one of claims 1-12, the nucleic acid molecule of claim 13, or the vector of claim 14.
  16. 一种制备抗Nogo-A抗体的方法，其包含：A method for preparing anti-Nogo-A antibodies, comprising:
    a)在能有效表达抗Nogo-A抗体的条件下培养权利要求15中所述的宿主细胞；和a) culturing the host cell described in claim 15 under conditions that can effectively express anti-Nogo-A antibodies; and
    b)从宿主细胞中获得表达的抗Nogo-A抗体。b) Obtain expressed anti-Nogo-A antibodies from host cells.
  17. 一种药物组合物，其包含权利要求1-12中任一项所述的抗Nogo-A抗体、权利要求13中所述的核酸分子、权利要求14中所述的载体、权利要求15中所述的分离的宿主细胞或由权利要求16中所述方法制备得到的抗体，以及药学上可接受的载体。A pharmaceutical composition comprising the anti-Nogo-A antibody described in any one of claims 1-12, the nucleic acid molecule described in claim 13, the vector described in claim 14, the vector described in claim 15 The isolated host cells described above or the antibody prepared by the method described in claim 16, and a pharmaceutically acceptable carrier.
  18. 权利要求1-12中任一项所述的抗体、权利要求13中所述的核酸分子、权利要求14中所述的载体、权利要求15中所述的宿主细胞、由权利要求16中所述方法制备得到的抗体、或权利要求17中所述的药物组合物在制备治疗有此需求的个体疾病或病症的药物中的用途。The antibody of any one of claims 1 to 12, the nucleic acid molecule of claim 13, the vector of claim 14, the host cell of claim 15, the nucleic acid molecule of claim 16 The use of the antibody prepared by the method or the pharmaceutical composition described in claim 17 in the preparation of drugs for treating individual diseases or conditions in need.
  19. 根据权利要求18中的用途，其中所述疾病或病症是Nogo-A信号通路失调导致的疾病和/或病症，例如中枢神经系统和/或外周神经系统疾病或创伤。The use according to claim 18, wherein the disease or condition is a disease and/or condition caused by dysregulation of the Nogo-A signaling pathway, such as central nervous system and/or peripheral nervous system disease or trauma.
  20. 根据权利要求19中的用途，其中所述疾病或病症选自神经退行性疾病如阿尔兹海默病、帕金森氏病、肌萎缩性脊髓侧索硬化症(ALS)、路易小体样疾病、其他普通痴呆、颅、脑或脊髓创伤后疾病、中风、脱髓鞘疾病如多发性硬化症、单相脱髓鞘、脑脊髓炎、多灶性脑白质炎、全脑炎、Marchiafava-Bignami氏症、脑桥myelmolysis、肾上腺脑白质失氧症、佩利措伊斯-梅茨巴赫病、海绵状脑病、亚历山大病、白质海绵状变性病、异染性脑白质营养不良和克腊伯氏病、退化视觉疾病如一般缺血性视网膜病、前部缺血型视神经病、视神经炎、老年黄斑变性、糖尿病视网膜病变、黄斑囊性水肿(CME)、色素性视网膜炎、斯格达氏症、Best's卵黄样视网膜退化、Leber's先天性黑蒙病和其他遗传性视网膜退化、病理性近视、早熟视网膜病和Leber's遗传性视神经病、精神病疾病如精神分裂症、抑郁症。 Use according to claim 19, wherein the disease or disorder is selected from neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Lewy body-like disease, Other common dementias, post-traumatic diseases of the brain, brain or spinal cord, stroke, demyelinating diseases such as multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalitis, panencephalitis, Marchiafava-Bignami's syndrome, pontine myelmolysis, adrenoleukodystrophy, Pellizois-Merzbach disease, spongiform encephalopathy, Alexander disease, leukospongiform degeneration, metachromatic leukodystrophy and Krabbe disease, Degenerative visual diseases such as general ischemic retinopathy, anterior ischemic optic neuropathy, optic neuritis, age-related macular degeneration, diabetic retinopathy, cystic macular edema (CME), retinitis pigmentosa, Skoda's disease, Best's Vitellite retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degeneration, pathological myopia, precocious retinopathy and Leber's hereditary optic neuropathy, psychiatric diseases such as schizophrenia and depression.
PCT/CN2023/113657 2022-08-22 2023-08-18 Antibody for specifically recognizing nogo-a and use thereof WO2024041450A1 (en)

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