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 - 221 . (canceled)
222 . 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:
a VH region comprising a CDR1 region, a CDR2 region, and a CDR3 region, wherein the CDR1 region and the CDR2 region of the VH region are identical to the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:7, respectively, and the CDR3 region of the VH region is identical to the amino acid sequence of SEQ ID NO:8, except for 1-5 amino acid substitutions;
a VL region comprising a CDR1 region, a CDR2 region, and a CDR3 region, wherein the CDR1 region, the CDR2 region and the CDR3 region of the VL region are identical to the amino acid sequences of SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, respectively.
223 . The antibody or antigen-binding fragment of claim 222 , wherein the VH CDR3 region is identical to an amino acid sequence selected from the group consisting of SEQ ID NOs:35-49.
224 . The antibody or antigen-binding fragment of claim 222 , wherein the VL region comprises the amino acid sequence of SEQ ID NO:13.
225 . The antibody or antigen-binding fragment of claim 222 , wherein the VH region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:71-85.
226 . The antibody or antigen-binding fragment of claim 224 , wherein the VH region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:71-85.
227 . The antibody or antigen-binding fragment of claim 222 , further comprising a heterologous polypeptide fused thereto.
228 . The antibody or antigen-binding fragment of claim 222 , 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.
229 . The antibody or antigen-binding fragment of claim 222 , wherein the antibody or antigen-binding fragment is fused to a brain targeting moiety.
230 . The antibody or antigen-binding fragment of claim 229 , 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.
231 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 222 and a pharmaceutically acceptable carrier.
232 . A host cell comprising:
(a) two expression vectors, wherein the first expression vector encodes the VH region of the antibody or antigen-binding fragment of claim 222 and the second expression vector encodes the VL region of the antibody or antigen-binding fragment of claim 222 ; or
(b) a single expression vector that encodes both the VH region of the antibody or antigen-binding fragment of claim 222 and the VL region of the antibody or antigen-binding fragment of claim 222 .
233 . An in vitro method of producing an anti-LINGO-1 antibody or antigen-binding fragment comprising culturing the host cell of claim 232 in a culture, and recovering the antibody or antigen-binding fragment from the culture.
234 . 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 222 .
235 . The method of claim 234 , wherein the CNS injury is multiple sclerosis.
236 . The method of claim 234 , wherein the CNS injury is ischemic optic neuropathy.
237 . The method of claim 234 , wherein the antibody or antigen-binding fragment is co-administered with an additional therapeutic agent for treatment of the CNS injury.