POLYOMAVIRUS NEUTRALIZING ANTIBODIES

• US 20180079799A1
• Filed: 12/01/2017
• Published: 03/22/2018
• Est. Priority Date: 09/16/2015
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: ABEND, Johanna, DRAGIC, Zorica, FEIRE, Adam Lloyd, KNAPP, Mark, KOVACS, Steven, TRAGGIAI, Elisabetta, WANG, Lichun, WANG, Yongqiang, WU, Danqing, WU, Qilong, XU, Fangmin
• Granted Patent: US 10,435,460 B2
• Time in Patent Office: Days
• 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: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• 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 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 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/084 Papovaviridae, e.g. papillomavirus, polyomavirus, SV40, BK virus, JC virus
• CPC Class Codes: C07K 2317/20 characterized by taxonomic origin
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• 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

The present invention relates to anti-VP1 antibodies, antibody fragments, and their uses for the prevention and treatment of polyoma virus infection and associated diseases.

Claims

1. An isolated antibody or antigen binding fragment thereof, wherein said antibody or antigen binding fragment thereof comprises:

(i) a heavy chain variable region that comprises (a) a HCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO;

186, (b) a HCDR2 of SEQ ID NO;

187, (c) a HCDR3 of SEQ ID NO;

188; and

a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

196, (e) a LCDR2 of SEQ ID NO;

197, and (f) a LCDR3 of SEQ ID NO;

198;

or

(ii) a heavy chain variable region that comprises;

(a) a HCDR1 of SEQ ID NO;

206, (b) a HCDR2 of SEQ ID NO;

207, (c) a HCDR3 of SEQ ID NO;

208; and

a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

216, (e) a LCDR2 of SEQ ID NO;

217, and (f) a LCDR3 of SEQ ID NO;

218.

2. The antibody of claim 1 wherein one or two amino acids within a CDR have been modified, deleted or substituted.

3. The antibody of claim 1, wherein the antibody contains the modifications in Table 3.

4. The antibody of claim 1 that retains at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identity over either the variable heavy chain region or the variable light chain region.

5. The antibody of claim 1 wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a human antibody, a single chain antibody(scFv) or an antibody fragment.

10. The antibody of claim 1 or 6 wherein the antibody or fragment thereof has reduced glycosylation or no glycosylation or is hypofucosylated.

11. A pharmaceutical composition comprising the antibody or fragment thereof, of any of the preceding claims further comprising a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutically acceptable carrier contains histadine or a sugar.

13. The pharmaceutical composition of claim 12, wherein the sugar is sucrose.

14. A pharmaceutical composition comprising a plurality of an antibody or antigen binding fragment of any of the preceding claims, wherein at least 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 5% or more or more of the antibodies in the composition have an α

2,3-linked sialic acid residue.

15. A pharmaceutical composition comprising a plurality of an antibody or antigen binding fragment of any of the preceding claims, wherein none of the antibodies comprise a bisecting GlcNAc.

16. The pharmaceutical composition comprising the antibody or fragment thereof, of any of the preceding claims, wherein the composition is prepared as a lyophilisate.

17. A method of neutralizing a BK virus or JC virus infection comprising administering via injection or infusion to a patient in need an effective amount of the antibody or the pharmaceutical composition of claim 1 or claim 6.

18. The method of claim 17, wherein the patient in need is diagnosed with BK viruria or BK viremia.

19. A method of treating or reducing the likelihood of a BK virus or JC virus associated disorder, comprising administering via injection or infusion to a patient in need an effective amount of the antibody or the pharmaceutical composition of claim 1 or claim 6, and wherein the disorder is:

nephropathy, BKVAN, hemorrhagic cystitis (HC), Progressive Multifocal Leukoencephalopathy (PML), granule cell neuronopathy (GCN), interstitial kidney disease, ureteral stenosis, vasculitis, colitis, retinitis, meningitis, and immune reconstitution inflammatory syndrome (IRIS).

20. The method of claim 17 or 19, wherein the antibody or composition is reconstituted prior to injection or infusion.

21. The method of claim 17 or 19, wherein the antibody or the pharmaceutical composition is administered in combination with another therapeutic agent.

22. The method of claim 21, wherein the therapeutic agent is an immunosuppressive agent.

23. The method of claim 22, wherein the immune suppressive agent is:

a monophosphate dehydrogenase inhibitor, a purine synthesis inhibitor, a calcineurin inhibitor or an mTOR inhibitor.

24. The method of claim 23, wherein the immunosuppressive agent is mycophenolate mofetil (MMF), mycophenolate sodium, azathioprine, tacrolimus, sirolimus or cyclosporine.

25. The method of claim 24, wherein the therapeutic agent is an additional anti-VP1 antibody.

26. A nucleic acid that encodes the antibody or antigen binding fragment of claim 1 or claim 6.

27. A vector comprising the nucleic acid of claim 26.

28. A host cell comprising the vector of claim 27.

30. A diagnostic reagent comprising the antibody or antigen binding fragment thereof of claim 1 or claim 6 which is labeled.

31. The diagnostic reagent of claim 30, wherein the label is selected from the group consisting of a radiolabel, a fluorophore, a chromophore, an imaging agent, and a metal ion.

6. An isolated antibody or antigen binding fragment thereof, wherein said antibody or antigen binding fragment thereof comprises:

(i) a heavy chain variable region (vH) that comprises SEQ ID NO;

192, and a light chain variable region (vL) that comprises SEQ ID NO;

202;

or

(ii) a heavy chain variable region (vH) that comprises SEQ ID NO;

212, and a light chain variable region (vL) that comprises SEQ ID NO;

222.

7. The antibody or fragment thereof, of claim 6 that retains at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identity over either the variable light or variable heavy region.

8. The antibody of claim 6, wherein one, two, three, four or five, but less than 10 amino acids within the variable light or variable heavy region have been modified, deleted or substituted.

9. The antibody of claim 6 wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a human antibody, a single chain antibody(scFv) or an antibody fragment.

29. A process for producing an antibody or antigen binding fragment comprising cultivating the host cell and recovering the antibody from the culture.