Anti-TNF-/anti-IL-23 bispecific antibodies
Bispecific antibodies are provided that bind Tumor Necrosis Factor alpha (TNFα) and the p19 subunit of Interleukin-23 (IL-23p19) and are characterized as having high affinity and strong simultaneous neutralizing properties to both TNFα and IL-23. The bispecific antibodies of the invention are useful for treating various autoimmune diseases including Inflammatory Bowel Disease, such as Crohn's Disease and Ulcerative Colitis, Axial Spondyloarthropathy, Rheumatoid Arthritis and Psoriatic Arthritis.
1. A bispecific antibody comprising an immunoglobulin G antibody (IgG) that binds tumor necrosis factor alpha (TNFα) conjugated to two single chain variable fragments (scFv) that bind the p19 subunit of IL-23 (IL23p19) wherein,
a.) said IgG comprises two heavy chains (HC) and two light chains (LC), each HC comprises a heavy chain variable region (HCVR1) comprising heavy chain CDRs (HCDR) 1-3 and each LC comprises a light chain variable region (LCVR1) comprising light chain CDRs (LCDR) 1-3, wherein the amino acid sequence of HCDR1 is SEQ ID NO:9, the amino acid sequence of HCDR2 is SEQ ID NO:10, the amino acid sequence of HCDR3 is SEQ ID NO:11, the amino acid sequence of LCDR1 is SEQ ID NO:15, the amino acid sequence of LCDR2 is SEQ ID NO:16, and the amino acid sequence of LCDR3 is SEQ ID NO:17; and
b.) each scFv comprises a heavy chain variable region (HCVR2) and a light chain variable region (LCVR2), the HCVR2 comprising HCDRs 4-6 and the LCVR2 comprising LCDRs 4-6, wherein the amino acid sequence of HCDR4 is SEQ ID NO:12, the amino acid sequence of HCDR5 is SEQ ID NO:13, the amino acid sequence of HCDR6 is SEQ ID NO:14, the amino acid sequence of LCDR4 is SEQ ID NO:18, the amino acid sequence of LCDR5 is SEQ ID NO:19, and the amino acid sequence of LCDR6 is SEQ ID NO:20,
wherein each scFv is independently conjugated to said IgG antibody via a polypeptide linker (L1) covalently attached to the C-terminus of each IgG HC and the N-terminus of HCVR2 of each scFv, and the HCVR2 of each scFv is covalently attached to the LCVR2 of the same scFv via a second polypeptide linker (L2) covalently attached to the C-terminus of the HCVR2 and the N-terminus of the LCVR2 of the same scFv.
2. The bispecific antibody of claim 1 , wherein the amino acid sequence of HCVR1 of each HC is SEQ ID NO:5, the amino acid sequence of LCVR1 of each LC is SEQ ID NO:7, the amino acid sequence of HCVR2 of each scFv is SEQ ID NO:6, and the amino acid sequence of LCVR2 of each scFv is SEQ ID NO:8.
3. The bispecific antibody of claim 1 , wherein the amino acid sequence of each HC is SEQ ID NO:23, the amino acid sequence of each LC is SEQ ID NO:2, the amino acid sequence of HCVR2 of each scFv is SEQ ID NO:6, the amino acid sequence of LCVR2 of each scFv is SEQ ID NO:8, the amino acid sequence of L1 is SEQ ID NO:21, and the amino acid sequence of L2 is SEQ ID NO:22.
4. A method of treating ulcerative colitis or rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a bispecific antibody of claim 1 .
5. The method of claim 4 , wherein the amino acid sequence of each HC of the bispecific antibody is SEQ ID NO:23, the amino acid sequence of each LC of the bispecific antibody is SEQ ID NO:2, the amino acid sequence of HCVR2 of each scFv of the bispecific antibody is SEQ ID NO:6, the amino acid sequence of LCVR2 of each scFv of the bispecific antibody is SEQ ID NO:8, the amino acid sequence of L1 of the bispecific antibody is SEQ ID NO:21, and the amino acid sequence of L2 of the bispecific antibody is SEQ ID NO:22.
6. A pharmaceutical composition comprising a bispecific antibody of claim 1 and one or more pharmaceutically acceptable carriers, diluents, or excipients.
7. The pharmaceutical composition of claim 6 , wherein the amino acid sequence of each HC of the bispecific antibody is SEQ ID NO:23, the amino acid sequence of each LC of the bispecific antibody is SEQ ID NO:2, the amino acid sequence of HCVR2 of each scFv of the bispecific antibody is SEQ ID NO:6, the amino acid sequence of LCVR2 of each scFv of the bispecific antibody is SEQ ID NO:8, the amino acid sequence of L1 of the bispecific antibody is SEQ ID NO:21, and the amino acid sequence of L2 of the bispecific antibody is SEQ ID NO:22.
8. A DNA molecule comprising a polynucleotide sequence encoding a polypeptide chain of a bispecific antibody, said polypeptide chain comprising one HC, one scFv, one polypeptide linker and one second polypeptide linker of the bispecific antibody wherein the amino acid sequence of the encoded polypeptide chain is SEQ ID NO:1.
9. The DNA molecule of claim 8 further comprising a polynucleotide sequence encoding a polypeptide chain of the bispecific antibody, said polypeptide chain comprising one LC, wherein the amino acid sequence of the encoded polypeptide chain is SEQ ID NO:2.