Anti-family with sequence similarity 19, member A5 antibodies and method of use thereof
The present disclosure provides antibodies that specifically bind to human FAM19A5 and compositions comprising such antibodies. In a specific aspect, antibodies are deimmunized to reduce immunogenicity in a human subject. In some embodiments, the anti-FAM19A5 antibodies can modulate FAM19A5 activity, e.g., inhibit, suppress, reduce, or reverse the onset of reactive gliosis and/or excessive proliferation of reactive astrocytes, utilizing such antibodies. The present disclosure also provides methods for treating disorders, such as central nervous system damage, a degenerative brain disorder, a neuropathic pain, or a cancer, by administering an antibody that specifically binds to human FAM19A5.
1. An isolated antibody, or antigen-binding portion thereof, which specifically binds a human family with sequence similarity 19, member A5 (FAM19A5) protein (anti-FAM19A5 antibody), comprising a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3, wherein:
(1) (i) the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 5; (ii) the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 6; (iii) the heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 7; (iv) the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 13; (v) the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14; and (vi) the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 10;
(2) (i) the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 5; (ii) the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 27; (iii) the heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 7; (iv) the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 13; (v) the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 29; and (vi) the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 10; or
(3) (i) the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 5; (ii) the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 28; (iii) the heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 7; (iv) the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 13; (v) the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 29; and (vi) the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 10.
2. The anti-FAM19A5 antibody of claim 1 , wherein:
(i) the VH comprises the amino acid sequence set forth in SEQ ID NO: 30, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 32;
(ii) the VH comprises the amino acid sequence set forth in SEQ ID NO: 31, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 32; or
(iii) the VH comprises the amino acid sequence set forth in SEQ ID NO: 17, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 18.
3. The anti-FAM19A5 antibody of claim 1 , which is selected from the group consisting of an IgGI, IgG2, IgG3, IgG4, a variant thereof, and any combination thereof.
4. The anti-FAM19A5 antibody of claim 1 , which is a chimeric antibody or a humanized antibody.
5. The anti-FAM19A5 antibody of claim 1 , which comprises an Fab, an Fab′, an F(ab′)2, an Fv, or a single chain Fv (scFv).
6. The anti-FAM19A5 antibody of claim 5 , wherein the scFv comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 17, 30, or 31, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 18 or 32.
7. The anti-FAM19A5 antibody of claim 1 , which exhibits one or more of the following properties:
(a) binds to soluble human FAM19A5 with a KD of 10 nM or less as measured by enzyme-linked immunosorbent assay (ELISA);
(b) binds to membrane bound human FAM19A5 with a KD of 10 nM or less as measured by ELISA;
(c) reduces, reverses, and/or delays an onset of reactive gliosis;
(d) suppresses an excessive proliferation of reactive astrocytes;
(e) decreases expression of chondroitin sulfate proteoglycans;
(f) increases expression of c-fos and pERK in the nucleus of neurons;
(g) promotes survival of neurons;
(h) increases expression of GAP43 in neurons;
(i) promotes regrowth of an axon;
(j) induces normalization of blood vessels;
(k) suppresses growth of a tumor;
(l) enhances infiltration of immune cells into a tumor;
(m) enhances infiltration of neuronal cells into a tumor;
(n) enhances phagocytic activity of a macrophage or a microglia;
(o) increases a mitochondrial membrane potential of a macrophage or a microglia;
(p) reduces recruitment of myeloid-derive suppressor cells (MDSCs) to a tumor;
(q) reduces necrosis and edema in a tumor;
(r) reduces tissue permeability of a tumor;
(s) increases a blood flow rate in a tumor;
(t) cross-competes with the reference antibody for binding to a FAM19A5 protein; or
(u) any combination thereof 21.
8. A nucleic acid encoding the anti-FAM19A5 antibody of claim 1 .
9. A vector comprising the nucleic acid of claim 8 .
10. A cell comprising the vector of claim 9 .
11. A method of producing an antibody which specifically binds to a human FAM19A5 protein, comprising culturing the cell of claim 10 under suitable conditions and isolating the antibody.
12. A composition comprising the anti-FAM19A5 antibody of claim 1 and a carrier.
13. A method of treating a disease or condition associated with an increased expression and/or activity of FAM19A5 in a subject in need thereof comprising administering to the subject the anti-FAM19A5 antibody of claim 1 .
14. The method of claim 13 , wherein the disease or condition comprises a tumor, a fibrosis, a glaucoma, a mood disorder, a neurodegenerative disease, a stroke, a neuropathic pain, or any combination thereof.
15. The method of claim 14 , wherein the neurodegenerative disease comprises an Alzheimer's disease.