Anti-TGF-beta antibodies and their use
The invention provides an improved pan-TGF-β antibody for treatment of conditions that are mediated by TGF-β, including autoimmune diseases, fibrotic conditions, and cancers. Also provided are methods and uses of the antibody in conjunction with other immunomodulatory agents such as an anti-PD-1 antibody.
1. An isolated nucleic acid molecule encoding a monoclonal antibody that binds specifically to human TGF-β1, TGF-β2, and TGF-β3, comprising the heavy chain complementarity-determining regions (CDR) 1-3 in SEQ ID NO: 1 and the light chain CDR1-3 in SEQ ID NO:2, wherein the antibody comprises a human IgG 4 constant region having a proline at position 228 (EU numbering).
2. The isolated nucleic acid molecule of claim 1 , wherein the antibody comprises a heavy chain variable domain (VH) amino acid sequence corresponding to residues 1-120 of SEQ ID NO: 1 and a light chain variable domain (VL) amino acid sequence corresponding to residues 1-108 of SEQ ID NO:2.
3. The isolated nucleic acid molecule of claim 1 , wherein the antibody has one or more of the following properties:
a) inhibits the differentiation of CD4 + T cells into inducible regulatory T cells (iTreg);
b) increases CD8 + T cell proliferation;
c) increases clustering of natural killer (NK) cells;
d) increases the level of MIP-2; and
e) increases the level of KC/GRO.
4. A vector comprising the nucleic acid molecule of claim 1 .
5. A mammalian host cell comprising nucleotide sequences encoding both the heavy and light chains of the antibody of claim 1 .
6. A method of producing an antibody, comprising
culturing the mammalian host cell of claim 5 under conditions that allow expression of the nucleotide sequences; and
isolating the antibody from the culture.
7. An isolated nucleic acid molecule encoding a monoclonal antibody, wherein the amino acid sequences of the heavy and light chains comprise SEQ ID NOs: 1 and 2, respectively.
8. A vector comprising the nucleic acid molecule of claim 7 .
9. A mammalian host cell comprising nucleotide sequences encoding both the heavy and light chains of the antibody of claim 7 .
10. A method of producing an antibody, comprising culturing the mammalian host cell of claim 9 under conditions that allow expression of the nucleotide sequences; and
isolating the antibody from the culture.