Recombinant human antibodies for therapy and prevention of polyomavirus-related diseases

• US 9,771,413 B2
• Filed: 01/02/2014
• Issued: 09/26/2017
• Est. Priority Date: 12/31/2012
• Status: Active Grant

• Current Assignee: Neurimmune Holding AG, University of Zurich
• Original Assignee: Neurimmune Holding AG, University of Zurich
• Inventors: Grimm, Jan, Martin, Roland, Combaluzier, Benoit, Jelcic, Ivan
• Primary Examiner(s): Zou, Nick
• Application Number:
  US14/758,615
• Publication Number:
  US 20160052996A1
• Time in Patent Office: 1,363 Days
• Field of Search: None
• CPC Class Codes: A61K 39/42 viral
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C07K 16/081 from DNA viruses
• CPC Class Codes: C07K 16/084 Papovaviridae, e.g. papillomavirus, polyomavirus, SV40, BK virus, JC virus
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C12N 2710/22022 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: G01N 2333/025 : Papovaviridae, e.g. papillomavirus, polyomavirus, SV40, BK virus, JC virus
• CPC Class Codes: G01N 33/56983 : Viruses
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided are novel human-derived antibodies specifically recognizing polyomavirus polypeptides, preferably capable of binding to polyomaviruses of the type of JC virus (JCV) and/or BK virus (BKV) as well as methods related thereto. Furthermore, assays and kits related to antibodies specific for polyomaviruses, polyomavirus VP1 and or polyomavirus VP1 Virus-Like Particles (VLPs), preferably of the type of JCV and/or BKV, are disclosed. The human-derived antibodies as well as binding fragments, derivatives and variants thereof can be used in pharmaceutical and diagnostic compositions for polyomavirus targeted immunotherapy and diagnostics.

Claims

1. A complementary DNA (cDNA) molecule encoding an antibody or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment thereof is capable of binding to a polyomavirus or an antigen thereof, wherein the polyomavirus is a JC virus (JCV) and wherein the antibody or antigen-binding fragment thereof comprises in its variable region:

(a) the complementarity determining regions (CDRs) 1, 2, and 3 of;

(i) the V_H variable region amino acid sequence of SEQ ID NO;

110, and

(ii) the V_L variable region amino acid sequence of SEQ ID NO;

112;

or

(b) an amino acid sequence of the V_H variable region set forth in SEQ ID NO;

110 and the V_L variable region set forth in SEQ ID NO;

112.

2. The cDNA molecule of claim 1, wherein the antibody or antigen-binding fragment thereof is capable of binding VP1 protein or a fragment thereof.

3. The cDNA molecule of claim 1, wherein the antibody or antigen-binding fragment thereof is capable of recognizing an epitope exposed on the surface of the virus.

4. The cDNA molecule of claim 1, wherein the antibody or antigen-binding fragment thereof does not substantially recognize serum albumin.

5. The cDNA molecule of claim 4, wherein the serum albumin is bovine serum albumin (BSA).

6. The cDNA molecule of claim 1, wherein the antibody or antigen-binding fragment thereof recognizes progressive multifocal leukoencephalopathy (PML)-associated VP1 mutants.

7. An isolated host cell comprising one or more cDNA molecule(s) of claim 1.

8. The host cell of claim 7, which is a prokaryotic or eukaryotic host cell.

9. A composition comprising the cDNA molecule of claim 1.

10. The composition of claim 9, wherein the composition:

(a) is a pharmaceutical composition and further comprises a pharmaceutical acceptable carrier, or

(b) is a diagnostic composition, and further comprises reagents conventionally used in immune- or nucleic acid-based diagnostic methods.

11. The composition of claim 10 further comprising an immunomodulatory agent.

12. The composition of claim 10, wherein the pharmaceutical composition is used for the prophylactic or therapeutic treatment of a disease, wherein the disease is Progressive Multifocal Leukoencephalopathy (PML), infection of granule neurons, hyperchromatic nuclei, granule cell neuronopathy, cerebral autothrophy, encephalopathy, meningitis, Polyoma-induced tumors, immune reconstitution inflammatory syndrome (IRIS), hemorrhagic cystitis, pneumonia, retinitis, colitis, vasculitis, interstitial kidney disease, infections of respiratory tract, JCV nephropathy, BKV nephropathy, meningitis, Merkel cell carcinoma, trichodysplasia spinulosa or malignant pleural mesothelioma and/or the agent is natalizumab, efalizumab, rituximab, infliximab, ocrelizumab, alemtuzumab, bentuximab, or vedotin.

13. A kit useful in the diagnosis or monitoring of the progression of Progressive Multifocal Leukoencephalopathy (PML) and/or transplant rejection following clinical bone marrow, kidney, and other solid organs transplantations, said kit comprising the cDNA molecule of claim 1.

14. The kit of claim 13 further comprising reagents and/or instructions for use.

15. One or more vector(s) comprising one or more cDNA molecule(s) of claim 1.

16. The vector(s) of claim 15, wherein the vector is an expression vector.

17. The vector(s) of claim 15, wherein the cDNA molecule is operatively linked to an expression control sequence allowing transcription of the cDNA into a translatable mRNA in prokaryotic and eukaryotic cells.

18. An isolated host cell comprising one or more vector(s) of claim 15.

19. The host cell of claim 18, which is a prokaryotic or eukaryotic host cell.

20. A polynucleotide linked to a heterologous nucleic acid, wherein the polynucleotide is selected from the group consisting of:

(a) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH variable region comprising CDRs 1, 2, and 3 of the VH variable region amino acid sequence of SEQ ID NO;

110 wherein the VH variable region when paired with a VL variable region comprising the amino acid sequence set forth in SEQ ID NO;

112 binds to JCV and/or an antigen thereof;

(b) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL variable region comprising CDRs 1, 2, and 3 of the VL variable region amino acid sequence of SEQ ID NO;

112 wherein the VL variable region when paired with a VH variable region comprising the amino acid sequence set forth in SEQ ID NO;

110 binds to JCV and/or an antigen thereof;

(c) a polynucleotide encoding;

(i) an immunoglobulin heavy chain or a fragment thereof comprising a VH variable region comprising CDRs 1, 2, and 3 of the VH variable region amino acid sequence of SEQ ID NO;

110; and

(ii) an immunoglobulin light chain or a fragment thereof comprising a VL variable region comprising CDRs 1, 2, and 3 of the VL variable region amino acid sequence of SEQ ID NO;

112;

(d) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH variable region comprising the amino acid sequence set forth in SEQ ID NO;

110, wherein the VH variable region when paired with a VL variable region comprising the amino acid sequence set forth in SEQ ID NO;

112, binds to JCV and/or an antigen thereof;

(e) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL variable region comprising the amino acid sequence set forth in SEQ ID NO;

112, wherein the VL variable region when paired with a VH variable region comprising the amino acid sequence set forth in SEQ ID NO;

110, binds to JCV and/or an antigen thereof; and

(f) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH variable region comprising the amino acid sequence set forth in SEQ ID NO 110 and an immunoglobulin light chain or a fragment thereof comprising a VL variable region comprising the amino acid sequence set forth in SEQ ID NO;

112.

21. One or more vector(s) comprising one or more polynucleotide(s) of claim 20.

22. The vector(s) of claim 21, wherein the vector is an expression vector.

23. An isolated host cell comprising one or more polynucleotide(s) of claim 20.

24. An isolated host cell comprising one or more vector(s) of claim 21.

25. The host cell of claim 23, which is a prokaryotic or eukaryotic host cell.

26. The host cell of claim 24, which is a prokaryotic or eukaryotic host cell.

27. A composition comprising the polynucleotide of claim 20.

28. The composition of claim 27, wherein the composition:

(a) is a pharmaceutical composition and further comprises a pharmaceutical acceptable carrier, or

(b) is a diagnostic composition, and further comprises reagents conventionally used in immune- or nucleic acid-based diagnostic methods.

29. The composition of claim 28 further comprising an immunomodulatory agent.

30. The composition of claim 28, wherein the pharmaceutical composition is used for the prophylactic or therapeutic treatment of a disease, wherein the disease is Progressive Multifocal Leukoencephalopathy (PML), infection of granule neurons, hyperchromatic nuclei, granule cell neuronopathy, cerebral autothrophy, encephalopathy, meningitis, Polyoma-induced tumors, immune reconstitution inflammatory syndrome (IRIS), hemorrhagic cystitis, pneumonia, retinitis, colitis, vasculitis, interstitial kidney disease, infections of respiratory tract, JCV nephropathy, BKV nephropathy, meningitis, Merkel cell carcinoma, trichodysplasia spinulosa or malignant pleural mesothelioma and/or the agent is natalizumab, efalizumab, rituximab, infliximab, ocrelizumab, alemtuzumab, bentuximab, or vedotin.

31. A kit useful in the diagnosis or monitoring of the progression of Progressive Multifocal Leukoencephalopathy (PML) and/or transplant rejection following clinical bone marrow, kidney, and other solid organs transplantations, said kit comprising the polynucleotide of claim 20.

32. The kit of claim 31 further comprising reagents and/or instructions for use.