Compositions comprising antibodies to LINGO or fragments thereof
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.
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 .