Claims for Patent: 9,896,504

Summary for Patent: 9,896,504

Title:	Human anti-alpha-synuclein antibodies
Abstract:	Provided are human alpha-synuclein-specific autoantibodies as well as fragments, derivatives and variants thereof as well as methods related thereto. Assays, kits, and solid supports related to antibodies specific for .alpha.-synuclein are also disclosed. The antibody, immunoglobulin chain(s), as well as binding fragments, derivatives and variants thereof can be used in pharmaceutical and diagnostic compositions for .alpha.-synuclein targeted immunotherapy and diagnosis, respectively.
Inventor(s):	Weihofen; Andreas (Zurich, CH), Grimm; Jan (Duebendorf, CH), Nitsch; Roger (Zumikon, CH), Hock; Christoph (Erlenbach, CH)
Assignee:	Biogen International Neuroscience GmbH (Zug, CH) University of Zurich (Zurich, CH)
Application Number:	15/005,948
Patent Claims:	1. An expression vector comprising a promoter operably linked to a polynucleotide encoding a polypeptide comprising: an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:13 binds to human alpha-synuclein; an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:10 binds to human alpha-synuclein; an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:3, residues 50-66 of SEQ ID NO:3, and residues 99-110 of SEQ ID NO:3, respectively, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:7 binds to human alpha-synuclein; an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:6, residues 49-55 of SEQ ID NO:6, and residues 88-98 of SEQ ID NO:6, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:4 binds to human alpha-synuclein; an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:15, residues 50-66 of SEQ ID NO:15, and residues 99-112 of SEQ ID NO:15, respectively, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:19 binds to human alpha-synuclein; an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 24-34 of SEQ ID NO:18, residues 50-56 of SEQ ID NO:18, and residues 89-96 of SEQ ID NO:18, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:16 binds to human alpha-synuclein; or an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 24-34 of SEQ ID NO:21, residues 50-56 of SEQ ID NO:21, and residues 89-97 of SEQ ID NO:21, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:16 binds to human alpha-synuclein. 2. The expression vector of claim 1, wherein the promoter is a heterologous promoter. 3. The expression vector of claim 2, wherein the heterologous promoter is a cytomegalovirus, simian virus 40, or retroviral promoter. 4. The expression vector of claim 2, wherein the heterologous promoter is the cytomegalovirus immediate early promoter. 5. The expression vector of claim 4, wherein the expression vector comprises cytomegalovirus intron-A. 6. The expression vector of claim 1, wherein the polypeptide comprises a signal peptide. 7. The expression vector of claim 6, wherein the signal peptide is a heterologous signal peptide. 8. The expression vector of claim 1, wherein the polypeptide comprises: an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:10; an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in SEQ ID NO:13; an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:4; an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in SEQ ID NO:7; an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:16; an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in SEQ ID NO:19; or an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in SEQ ID NO:22. 9. The expression vector of claim 1, wherein the polynucleotide comprises the nucleic acid sequence set forth in: SEQ ID NO:8; or SEQ ID NO:11. 10. The expression vector of claim 1, wherein the expression vector is a plasmid, phage, virus, or retrovirus. 11. An expression vector comprising: a first polynucleotide encoding a first polypeptide comprising an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively; and a second polynucleotide encoding a second polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively, wherein the immunoglobulin heavy chain or fragment thereof when paired with the immunoglobulin light chain or fragment thereof forms an anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof. 12. The expression vector of claim 11, wherein the immunoglobulin heavy chain comprises a human IgG1 heavy chain constant region and the immunoglobulin light chain comprises a human lambda light chain constant region. 13. The expression vector of claim 11, wherein: the VH consists of the amino acid sequence set forth in SEQ ID NO:10; and the VL consists of the amino acid sequence set forth in SEQ ID NO:13. 14. The expression vector of claim 11, wherein: the first polynucleotide comprises the nucleic acid sequence set forth in SEQ ID NO:8; and the second polynucleotide comprises the nucleic acid sequence set forth in SEQ ID NO:11. 15. The expression vector of claim 11, wherein the expression vector is a plasmid, phage, virus, or retrovirus. 16. A cDNA comprising a polynucleotide encoding a polypeptide comprising: an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:13 binds to human alpha-synuclein; an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:10 binds to human alpha-synuclein; an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:3, residues 50-66 of SEQ ID NO:3, and residues 99-110 of SEQ ID NO:3, respectively, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:7 binds to human alpha-synuclein; an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:6, residues 49-55 of SEQ ID NO:6, and residues 88-98 of SEQ ID NO:6, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:4 binds to human alpha-synuclein; an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:15, residues 50-66 of SEQ ID NO:15, and residues 99-112 of SEQ ID NO:15, respectively, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:19 binds to human alpha-synuclein; an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 24-34 of SEQ ID NO:18, residues 50-56 of SEQ ID NO:18, and residues 89-96 of SEQ ID NO:18, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:16 binds to human alpha-synuclein; or an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 24-34 of SEQ ID NO:21, residues 50-56 of SEQ ID NO:21, and residues 89-97 of SEQ ID NO:21, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:16 binds to human alpha-synuclein. 17. A host cell comprising: a first expression vector comprising a first polynucleotide encoding a first polypeptide comprising an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively; and a second expression vector comprising a second polynucleotide encoding a second polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively, wherein the immunoglobulin heavy chain or fragment thereof when paired with the immunoglobulin light chain or fragment thereof forms an anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof. 18. The host cell of claim 17, wherein the immunoglobulin heavy chain comprises a human IgG1 heavy chain constant region and the immunoglobulin light chain comprises a human lambda light chain constant region. 19. The host cell of claim 17, wherein the host cell is a mammalian host cell. 20. The host cell of claim 17, wherein the host cell is a Chinese Hamster Ovary (CHO) cell, a HEK 293 cell, or a NSO cell. 21. A host cell comprising an expression vector comprising: a first polynucleotide encoding a first polypeptide comprising an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively; and a second polynucleotide encoding a second polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively, wherein the immunoglobulin heavy chain or fragment thereof when paired with the immunoglobulin light chain or fragment thereof forms an anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof. 22. The host cell of claim 21, wherein the immunoglobulin heavy chain comprises a human IgG1 heavy chain constant region and the immunoglobulin light chain comprises a human lambda light chain constant region. 23. The host cell of claim 21, wherein the host cell is a mammalian host cell. 24. The host cell of claim 21, wherein the host cell is a Chinese Hamster Ovary (CHO) cell, a HEK 293 cell, or a NSO cell. 25. A method for preparing an anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof, the method comprising: culturing the host cell of claim 17 in a cell culture; and isolating the anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof from the cell culture. 26. The method of claim 25, further comprising formulating the anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof into a sterile pharmaceutical composition suitable for administration to a human subject. 27. The method of claim 26, wherein the pharmaceutical composition is suitable for intravenous or subcutaneous administration. 28. A method for preparing an anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof, the method comprising: culturing the host cell of claim 21 in a cell culture; and isolating the anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof from the cell culture. 29. The method of claim 28, further comprising formulating the anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof into a sterile pharmaceutical composition suitable for administration to a human subject. 30. The method of claim 29, wherein the pharmaceutical composition is suitable for intravenous or subcutaneous administration. 31. A method of preparing a pharmaceutical composition, the method comprising formulating an anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof into a sterile pharmaceutical composition suitable for administration to a human subject, wherein the anti-human alpha-synuclein antibody or human alpha-synuclein-binding fragment thereof comprises (i) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively. 32. The method of claim 31, wherein (i) the VH consists of the amino acid sequence set forth in SEQ ID NO:10; and (ii) the VL consists of the amino acid sequence set forth in SEQ ID NO:13. 33. The method of claim 32, wherein the immunoglobulin heavy chain comprises a human IgG1 heavy chain constant region and the immunoglobulin light chain comprises a human lambda light chain constant region. 34. The method of claim 33, wherein the pharmaceutical composition is suitable for intravenous or subcutaneous administration. 35. The expression vector of claim 1, wherein the polypeptide comprises: an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising VH CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:13 binds to human alpha-synuclein. 36. The expression vector of claim 1, wherein the polypeptide comprises: an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:10 binds to human alpha-synuclein. 37. The expression vector of claim 1, wherein the polypeptide comprises: an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:10. 38. The expression vector of claim 1, wherein the polypeptide comprises: an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in SEQ ID NO:13. 39. The expression vector of claim 10, wherein the expression vector is a plasmid. 40. The expression vector of claim 15, wherein the expression vector is a plasmid. 41. The cDNA of claim 16, wherein the polypeptide comprises: an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising VH CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:13 binds to human alpha-synuclein. 42. The cDNA of claim 16, wherein the polypeptide comprises: an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:10 binds to human alpha-synuclein. 43. The cDNA of claim 16, wherein the polypeptide comprises: an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:10. 44. The cDNA of claim 16, wherein the polypeptide comprises: an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in SEQ ID NO:13. 45. The cDNA of claim 43, which is in an expression vector. 46. The cDNA of claim 44, which is in an expression vector. 47. The host cell of claim 17, wherein: the VH consists of the amino acid sequence set forth in SEQ ID NO:10; and the VL consists of the amino acid sequence set forth in SEQ ID NO:13. 48. The host cell of claim 47, wherein the immunoglobulin heavy chain comprises a human IgG1 heavy chain constant region and the immunoglobulin light chain comprises a human lambda light chain constant region. 49. A method for preparing an anti-human alpha-synuclein antibody, the method comprising: culturing the host cell of claim 48 in a cell culture; and isolating the anti-human alpha-synuclein antibody from the cell culture. 50. The method of claim 49, further comprising formulating the anti-human alpha-synuclein antibody into a sterile pharmaceutical composition suitable for administration to a human subject. 51. The method of claim 50, wherein the pharmaceutical composition is suitable for intravenous or subcutaneous administration. 52. The host cell of claim 17, wherein the first expression vector is a plasmid, phage, or virus, and the second expression vector is a plasmid, phage, or virus. 53. The host cell of claim 17, wherein the first expression vector is a retrovirus, and the second expression vector is a retrovirus. 54. The host cell of claim 17, wherein the first expression vector comprises a first heterologous promoter operably linked to the first polynucleotide, and the second expression vector comprises a second heterologous promoter operably linked to the second polynucleotide. 55. The host cell of claim 54, wherein the first heterologous promoter is a cytomegalovirus, simian virus 40, or retroviral promoter, and the second heterologous promoter is a cytomegalovirus, simian virus 40, or retroviral promoter. 56. The host cell of claim 54, wherein the first heterologous promoter is the cytomegalovirus immediate early promoter and the second heterologous promoter is the cytomegalovirus immediate early promoter. 57. The host cell of claim 21, wherein the expression vector is a plasmid, phage, or virus. 58. The host cell of claim 21, wherein the expression vector is a retrovirus. 59. The host cell of claim 21, wherein: the VH consists of the amino acid sequence set forth in SEQ ID NO:10; and the VL consists of the amino acid sequence set forth in SEQ ID NO:13. 60. The host cell of claim 59, wherein the immunoglobulin heavy chain comprises a human IgG1 heavy chain constant region and the immunoglobulin light chain comprises a human lambda light chain constant region. 61. A method for preparing an anti-human alpha-synuclein antibody, the method comprising: culturing the host cell of claim 60 in a cell culture; and isolating the anti-human alpha-synuclein antibody from the cell culture. 62. The method of claim 61, further comprising formulating the anti-human alpha-synuclein antibody into a sterile pharmaceutical composition suitable for administration to a human subject. 63. The method of claim 62, wherein the pharmaceutical composition is suitable for intravenous or subcutaneous administration. 64. A polynucleotide linked to a heterologous nucleic acid, wherein the polynucleotide is selected from the group consisting of: a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:13 binds to human alpha-synuclein; a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:10 binds to human alpha-synuclein; a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:3, residues 50-66 of SEQ ID NO:3, and residues 99-110 of SEQ ID NO:3, respectively, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:7 binds to human alpha-synuclein; a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:6, residues 49-55 of SEQ ID NO:6, and residues 88-98 of SEQ ID NO:6, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:4 binds to human alpha-synuclein; a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:15, residues 50-66 of SEQ ID NO:15, and residues 99-112 of SEQ ID NO:15, respectively, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:19 binds to human alpha-synuclein; a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 24-34 of SEQ ID NO:18, residues 50-56 of SEQ ID NO:18, and residues 89-96 of SEQ ID NO:18, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:16 binds to human alpha-synuclein; and a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 24-34 of SEQ ID NO:21, residues 50-56 of SEQ ID NO:21, and residues 89-97 of SEQ ID NO:21, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:16 binds to human alpha-synuclein. 65. The polynucleotide of claim 64, wherein: the polynucleotide encodes an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising VH CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 31-35 of SEQ ID NO:9, residues 50-68 of SEQ ID NO:9, and residues 101-102 of SEQ ID NO:9, respectively, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:13 binds to human alpha-synuclein. 66. The polynucleotide of claim 64, wherein: the polynucleotide encodes an immunoglobulin light chain or a fragment thereof comprising a VL comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in residues 23-33 of SEQ ID NO:12, residues 49-55 of SEQ ID NO:12, and residues 88-98 of SEQ ID NO:12, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:10 binds to human alpha-synuclein. 67. The polynucleotide of claim 64, wherein: the polynucleotide encodes an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:10. 68. The polynucleotide of claim 64, wherein: the polynucleotide encodes an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in SEQ ID NO:13. 69. The polynucleotide of claim 64, wherein the heterologous nucleic acid is a regulatory element. 70. The polynucleotide of claim 69, wherein the regulatory element is a promoter, an enhancer, a ribosome binding site, or a transcription terminator. 71. The polynucleotide of claim 64, wherein the heterologous nucleic acid is a secretory signal peptide. 72. The polynucleotide of claim 71, wherein the secretory signal peptide is a mammalian signal peptide. 73. The polynucleotide of claim 72, wherein the mammalian signal peptide is from tissue plasminogen activator. 74. A host cell comprising the polynucleotide of claim 64. 75. The host cell of claim 74, wherein the host cell is a Chinese Hamster Ovary (CHO) cell.

Details for Patent 9,896,504

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2028-12-19
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2028-12-19
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2028-12-19