Compositions comprising antibodies to LINGO or fragments thereof

• US 9,745,375 B2
• Filed: 05/26/2016
• Issued: 08/29/2017
• Est. Priority Date: 07/09/2008
• Status: Active Grant

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen MA Inc. (Biogen, Inc.)
• Inventors: Mi, Sha, Pepinsky, R. Blake, Graff, Christilyn
• Primary Examiner(s): BALLARD, KIMBERLY
• Application Number:
  US15/165,279
• Publication Number:
  US 20160368984A1
• Time in Patent Office: 460 Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6879 the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/35 Valency
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 : Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/54 : F(ab')2
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C07K 2319/01 : containing a localisation/targetting motif

Abstract

Endogenous LINGO-1 is a negative regulator for neuronal survival, axon regeneration, oligodendrocyte differentiation and myelination. Molecules that block endogenous LINGO-1 function, such anti-LINGO-1 antibodies can be used as therapeutics for the treatment of neuron and oligodendrocyte dysfunction. The present invention provides antibodies specific for LINGO-1, and methods of using such antibodies as antagonists of endogenous LINGO-1 function. The invention further provides specific hybridoma and phage library-derived monoclonal antibodies, nucleic acids encoding these antibodies, and vectors and host cells comprising these antibodies. The invention further provides methods of promoting oligodendrocyte survival and myelination in a vertebrate, comprising administering to a vertebrate in need of such treatment an effective amount of an anti-LINGO-1 antibody.

Claims

1. An isolated antibody or antigen-binding fragment thereof that specifically binds to a human LINGO-1 polypeptide, wherein the antibody or antigen-binding fragment comprises:

an immunoglobulin heavy chain variable region (VH) comprising a complementarity determining region (CDR) 1, a CDR2, and a CDR3, wherein the CDR1 and the CDR2 of the VH are identical to the amino acid sequences of SEQ ID NO;

6 and SEQ ID NO;

7, respectively, and the CDR3 of the VH is identical to an amino acid sequence selected from the group consisting of SEQ ID NOs;

35-49;

an immunoglobulin light chain variable region (VL) comprising a CDR1, a CDR2, and a CDR3, wherein the CDR1, the CDR2, and the CDR3 of the VL are identical to the amino acid sequences of SEQ ID NO;

14, SEQ ID NO;

15 and SEQ ID NO;

16, respectively.

2. The antibody or antigen-binding fragment of claim 1, wherein the VH CDR3 is identical to an amino acid sequence selected from the group consisting of SEQ ID NOs:

43-49.

3. The antibody or antigen-binding fragment of claim 1, wherein the VL comprises the amino acid sequence of SEQ ID NO:

13.

4. The antibody or antigen-binding fragment of claim 1, wherein the VH comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

71-85.

5. The antibody or antigen-binding fragment of claim 3, wherein the VH comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

71-85.

6. The antibody or antigen-binding fragment of claim 1, further comprising a heterologous polypeptide fused thereto.

7. The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment is conjugated to an agent selected from the group consisting of a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a virus, a lipid, a biological response modifier, a pharmaceutical agent, and polyethylene glycol.

8. The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment is fused to a brain targeting moiety.

9. The antibody or antigen-binding fragment of claim 8, wherein the brain targeting moiety is selected from the group consisting of:

(i) the single domain antibody FC5, (ii) mAB 83-14, (iii) the B2 peptide, (iv) the B6 peptide, (v) the B8 peptide, and (vi) the OX26 monoclonal antibody.

10. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier.

11. A host cell comprising:

(a) two expression vectors, wherein the first expression vector encodes the VH of the antibody or antigen-binding fragment of claim 1 and the second expression vector encodes the VL of the antibody or antigen-binding fragment of claim 1;

or

(b) a single expression vector that encodes both the VH of the antibody or antigen-binding fragment of claim 1 and the VL of the antibody or antigen-binding fragment of claim 1.

12. An in vitro method of producing an anti-LINGO-1 antibody or antigen-binding fragment comprising culturing the host cell of claim 11 in a culture, and recovering the antibody or antigen-binding fragment from the culture.

13. A method of treating a CNS injury in a human subject in need thereof, the method comprising administering to the subject the antibody or antigen-binding fragment of claim 1.

14. The method of claim 13, wherein the CNS injury is multiple sclerosis.

15. The method of claim 13, wherein the CNS injury is ischemic optic neuropathy.

16. The method of claim 13, wherein the antibody or antigen-binding fragment is co-administered with an additional therapeutic agent for treatment of the CNS injury.

17. An isolated antibody or antigen-binding fragment thereof that specifically binds to a human LINGO-1 polypeptide, wherein the antibody or antigen-binding fragment comprises:

an immunoglobulin heavy chain variable region (VH) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs.;

242-249, 260-262, and 267; and

an immunoglobulin light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO;

9.

18. The antibody or antigen-binding fragment of claim 17, further comprising a heterologous polypeptide fused thereto.

19. The antibody or antigen-binding fragment of claim 17, wherein the antibody or antigen-binding fragment is fused to a brain targeting moiety.

20. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 17 and a pharmaceutically acceptable carrier.

21. A method of treating a CNS injury in a human subject in need thereof, the method comprising administering to the subject the antibody or antigen-binding fragment of claim 17.