Anti-bk virus antibody molecules

Abstract

Anti-BK virus antibody molecules or binding fragments thereof are disclosed. These anti-BK virus antibody molecules or binding fragments can be used to treat or prevent BK virus infection and / or BK virus-associated conditions.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to anti-BK virus antibody molecules or binding fragments thereof. The present disclosure further relates to nucleic acids encoding the antibody molecules or binding fragments thereof, expression vectors, host cells, and methods of making the antibody molecules or binding fragments thereof. Pharmaceutical compositions comprising the antibody molecules or binding fragments thereof are also provided. The anti-BK virus antibody molecules or binding fragments thereof of the present disclosure, alone or in combination with other agents or treatment modalities, are useful for the treatment or prevention of BK virus infection and / or BK virus-associated conditions. Accordingly, the present disclosure further relates to the anti-BK virus antibody molecules or binding fragments thereof, or pharmaceutical compositions comprising the anti-BK virus antibody molecules or binding fragments thereof, for use in the treatment or prevention of BK virus infection and / or BK virus-associated conditions. Diagnostic compositions comprising the antibody molecules or binding fragments thereof are also provided. BACKGROUND

[0002] Immunosuppressive drugs are the standard of care treatment for transplant recipients to allow engraftment and prevent graft rejection. Immunosuppression can trigger reactivation of human BK polyomavirus in, for example, 40% to 50% of kidney transplant recipients (Hurdis et al., Structure, 2016 Apr 5;24(4):528-536), and in up to 10% of cases, this leads to BK virus (BKV)-associated nephropathy (BKVAN) (Bennett et al., Microbes Infect, 2012 Aug;14(9):672-83, Rinaldo et al., APMIS, 2013 Aug;121(8):728-45). BKVAN is a serious threat that can lead to loss of graft function or even loss of graft (Ramos et al., Transplantation, 2009 Mar 15;87(5):621-30). The use of antiviral drugs has yielded inconsistent efficacy results and is not considered a valuable treatment option (Santeusanio et al. Am J Health Syst Pharm, 2017 Dec 15;74(24):2037-2045; Kable et al., Transplant Direct, 2017 Mar 10;3(4):el42).

[0003] Accordingly, the standard of care for acute viremia is to reduce immunosuppression to allow the immune system to control the virus. However, this leads to a significant risk of short- and long-term graft dysfunction due to the host’s immune response to the graft, such as the formation of donor-specific antibodies.

[0004] In view of the continuing need for improved strategies for prophylactic or therapeutic therapies in immunosuppressed patients, there is a great desire for new compositions for neutralizing BK virus activity. SUMMARY

[0006] Aspect A

[0007] In one aspect Al, the present disclosure relates to an anti-BK virus antibody molecule, or an anti-BK virus binding fragment thereof.

[0008] Structural properties

[0009] In some embodiments of aspect Al, the present disclosure relates to an anti-BK virus antibody molecule, or an anti-BK virus binding fragment thereof, wherein the antibody molecule or binding fragment comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all CDRs) from a heavy chain variable region (VH) and / or a light chain variable region (VL) comprising the amino acid sequences set forth in Table 3, wherein one or more CDRs (or collectively all CDRs) can have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions), insertions or deletions, relative to the amino acid sequences set forth in Table 3.

[0010] In some embodiments of aspect Al, the present disclosure relates to an anti-BK virus antibody molecule, or an anti-BK virus binding fragment thereof, comprising:

[0011] a heavy chain variable region (VH) comprising one, two, or three of: a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 21 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 22 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 23 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions; and / or a light chain variable region (VL) comprising one, two, or three of: a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 24 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 25 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 26 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions.

[0012] In some embodiments of aspect Al, the disclosure relates to an anti-BK virus antibody molecule, or an anti-BK virus binding fragment thereof, comprising:

[0013] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 23, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions); and / or

[0014] a light chain variable region (VL) comprising a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 26, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions).

[0015] In some embodiments of aspect Al, the disclosure relates to an anti-BK virus antibody molecule, or an anti-BK virus binding fragment thereof, comprising:

[0016] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 21, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 22, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 23; and / or

[0017] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 24, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 25, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 26, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions).

[0018] In some embodiments of aspect Al, the disclosure relates to an anti-BK virus antibody molecule, or an anti-BK virus binding fragment thereof, comprising:

[0019] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 21, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 22, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 23; and / or

[0020] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 24, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 25, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 26, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions).

[0021] In some embodiments of aspect Al, the anti-BK virus antibody molecule, or an anti-BK virus binding fragment thereof, comprises:

[0022] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 21, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 22, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 23; and

[0023] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 24, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 25, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 26,

[0024] wherein one or two amino acids within a CDR have been inserted, deleted, or substituted.

[0025] In some embodiments of aspect A1, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises:

[0026] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 21, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 22, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 23; and

[0027] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 24, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 25, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 26.

[0028] In some embodiments of aspect A1, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 27, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 27.

[0029] In some embodiments of aspect A1, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises (i) a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 28, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 28; or (ii)

[0030] a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 27; and

[0031] In some embodiments of aspect Al, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises:

[0032] (i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 27; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 28, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 28; or

[0033] (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 27; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 31.

[0034] In some embodiments of aspect Al, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises:

[0035] (i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 27; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 28, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 28; or

[0036] (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 27; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 31.

[0037] Functional properties

[0038] In some embodiments of aspect Al, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) of the following properties:

[0039] (i) for example when tested as a bivalent molecule using ELISA, for example as described in Example 2, the antibody molecule or binding fragment thereof binds to BK virus serotype I VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, or 0.02 nM;

[0040] (ii) for example when tested as a bivalent molecule using ELISA, for example as described in Example 2, the antibody molecule or binding fragment thereof binds to BK virus serotype II VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, or 0.02 nM;

[0041] (iii) for example when tested as a bivalent molecule using ELISA, for example as described in Example 2, the antibody molecule or binding fragment thereof binds to BK virus serotype III VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, or 0.02 nM;

[0042] (iv) binds to a BK virus serotype IV VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, or 0.02 nM, e.g., when the antibody molecule or binding fragment thereof is tested as a bivalent molecule using an ELISA, e.g., as described in Example 2;

[0043] (v) does not bind to a JC virus VP1; e.g., as described in Example 6;

[0044] (vi) neutralizes a BK virus serotype I;

[0045] (vii) neutralizes a BK virus serotype II;

[0046] (viii) neutralizes a BK virus serotype III;

[0047] (ix) neutralizes a BK virus serotype IV.

[0048] In one aspect A2, the present disclosure relates to an antibody molecule or binding fragment thereof that competes for binding to a BK virus serotype I VP1, a BK virus serotype II VP1, a BK virus serotype III VP1, and / or a BK virus serotype IV VP1 with an antibody molecule or binding fragment thereof described herein. In some embodiments of aspect A2, the present disclosure relates to an antibody molecule or binding fragment thereof that competes for binding to a BK virus genotype I VP1, a BK virus genotype II VP1, a BK virus genotype III VP1, and / or a BK virus genotype IV VP1 with an antibody molecule or binding fragment thereof comprising a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VH CDR1) amino acid sequence of SEQ ID NO: 21, a heavy chain complementarity determining region 2 (VH CDR2) amino acid sequence of SEQ ID NO: 22, and a heavy chain complementarity determining region 3 (VH CDR3) amino acid sequence of SEQ ID NO: 23; and

[0049] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VL CDR1) amino acid sequence of SEQ ID NO: 24, a light chain complementarity determining region 2 (VL CDR2) amino acid sequence of SEQ ID NO: 25, and a light chain complementarity determining region 3 (VL CDR3) amino acid sequence of SEQ ID NO: 26.

[0050] In some embodiments of aspect A2, the present disclosure relates to an antibody molecule or binding fragment thereof which competes for binding to BK virus genotype I VP1, BK virus genotype II VP1, BK virus genotype III VP1, and / or BK virus genotype IV VP1 with an antibody molecule or binding fragment thereof comprising: (i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 28; or

[0051] (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 31.

[0052] In one aspect A3, the present disclosure relates to a pharmaceutical composition comprising an antibody molecule or binding fragment thereof described herein and a pharmaceutically acceptable carrier, excipient, or stabilizer.

[0053] In one aspect A4, the present disclosure relates to an anti-BK virus antibody molecule or binding fragment thereof described herein, or a pharmaceutical composition comprising an anti-BK virus antibody molecule or binding fragment thereof described herein, for use in the treatment or prevention of a BK virus infection and / or a BK virus-associated disorder. In some embodiments of aspect A4, the BK virus-associated disorder is selected from the group consisting of nephropathy, BK virus-associated nephropathy (BKVAN), hemorrhagic cystitis (HC).

[0054] In one aspect A5, the present disclosure relates to a nucleic acid encoding an antibody heavy chain variable region and / or a light chain variable region of an antibody molecule or binding fragment thereof described herein.

[0055] In one aspect A6, the present disclosure relates to an expression vector comprising a nucleic acid described herein.

[0056] In one aspect A7, the present disclosure relates to a host cell comprising a nucleic acid described herein or an expression vector described herein.

[0057] In one aspect A8, the present disclosure relates to a method of producing an antibody molecule, the method comprising culturing a host cell described herein under conditions suitable for gene expression.

[0058] In one aspect A9, the present disclosure relates to a diagnostic composition comprising an antibody molecule or binding fragment thereof described herein.

[0059] Aspect B

[0060] In one aspect B1, the present disclosure relates to an anti-BK virus antibody molecule or anti-BK virus binding fragment thereof.

[0061] Structural properties

[0062] In some embodiments of aspect B1, the present disclosure relates to an anti-BK virus antibody molecule or anti-BK virus binding fragment thereof, wherein the antibody molecule or binding fragment comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or all CDRs collectively) from a heavy chain variable region (VH) and / or light chain variable region (VL) comprising the amino acid sequences set forth in Table 4, wherein one or more CDRs (or all CDRs collectively) can have one, two, three, four, five, six or more alterations, e.g., amino acid substitutions (e.g., conservative amino acid substitutions), insertions or deletions, relative to the amino acid sequences set forth in Table 4.

[0063] In some embodiments of aspect B1, the present disclosure relates to an anti-BK virus antibody molecule or anti-BK virus binding fragment thereof, comprising:

[0064] (i) a heavy chain variable region (VH) comprising one, two, or three of the following: the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, the heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 35 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, and the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions; and / or a light chain variable region (VL) comprising one, two, or three of the following: the light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, the light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, and the light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions; or

[0065] (ii) a heavy chain variable region (VH) comprising one, two, or three of: a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions; and / or a light chain variable region (VL) comprising one, two, or three of: a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions; or

[0066] (iii) a heavy chain variable region (VH) comprising one, two, or three of: the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, the heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, and the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions; and / or a light chain variable region (VL) comprising one, two, or three of: the light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, the light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions, and the light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 48 or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions, or deletions.

[0067] In some embodiments of aspect B1, the disclosure relates to an anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprising:

[0068] (i) a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions); and / or

[0069] a light chain variable region (VL) comprising the light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions); or

[0070] (ii) a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36, or a sequence with one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions); and / or

[0071] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions), a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions), and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions); and / or

[0072] In some embodiments of aspect B1, the disclosure relates to an anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprising:

[0073] (i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions), a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 35, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions), and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions); and / or

[0074] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions), a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions), and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions); or

[0075] (ii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions), a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions), and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36, or a sequence with one, two, three or four amino acid substitutions (e.g., conservative amino acid substitutions); and / or

[0076] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and / or

[0077] or

[0078] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and / or

[0079] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 48.

[0080] In some embodiments of aspect B1, the present disclosure relates to an anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprising:

[0081] (i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 35, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and / or

[0082] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37 or a sequence with one or two amino acid substitutions, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39 or a sequence with one, two, three, or four amino acid substitutions; or

[0083] (ii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44 or a sequence with one, two, or three amino acid substitutions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and / or

[0084] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37 or a sequence with one or two amino acid substitutions, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39 or a sequence with one, two, three, or four amino acid substitutions; or

[0085] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44 or a sequence with one, two, or three amino acid substitutions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and / or

[0086] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37 or a sequence with one or two amino acid substitutions, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 48 or a sequence with one, two, three, or four amino acid substitutions.

[0087] In some embodiments of aspect B1, the anti-BK virus antibody molecule or anti-BK virus binding fragment thereof comprises:

[0088] (i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 35, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0089] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39;

[0090] wherein one or two amino acids within a CDR have been inserted, deleted, or substituted;

[0091] or

[0092] (ii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0093] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39;

[0094] wherein one or two amino acids within a CDR have been inserted, deleted, or substituted;

[0095] or

[0096] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0097] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 35, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0098] wherein one or two amino acids within a CDR have been inserted, deleted, or substituted.

[0099] In some embodiments of aspect B1, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises:

[0100] (i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 35, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0101] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39; or

[0102] (ii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0103] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39; or

[0104] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0105] a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 48.

[0106] In some embodiments of aspect B1, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises: (i) a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 40, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 40; or (ii) a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 45, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 45; or (iii) a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 49, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 49.

[0107] In some embodiments of aspect B1, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises: (i) a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 41, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 41; or (ii) a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 50, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 50.

[0108] In some embodiments of aspect B1, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises:

[0109] (i) a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 40, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 40; and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 41, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 41; or

[0110] (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:45, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO:45; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO:41; or

[0111] (iii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:49, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO:49; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:50, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO:50.

[0112] In some embodiments of aspect B1, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises:

[0113] (i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:40, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:41; or

[0114] (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:45, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:41; or

[0115] (iii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:49, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:50.

[0116] Functional properties

[0117] In some embodiments of aspect B1, the anti-BK virus antibody molecule, or anti-BK virus binding fragment thereof, comprises one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) of the following properties:

[0118] (i) for example when the antibody molecule or binding fragment thereof is tested as a bivalent molecule, e.g. as described in Example 2 using an ELISA, the antibody molecule or binding fragment thereof binds to BK virus serotype I VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM or 0.02 nM;

[0119] (ii) for example when the antibody molecule or binding fragment thereof is tested as a bivalent molecule, e.g. as described in Example 2 using an ELISA, the antibody molecule or binding fragment thereof binds to BK virus serotype II VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM or 0.02 nM;

[0120] (iii) for example when the antibody molecule or binding fragment thereof is tested as a bivalent molecule, e.g. as described in Example 2 using an ELISA, the antibody molecule or binding fragment thereof binds to BK virus serotype III VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM or 0.02 nM;

[0121] (iv) for example when the antibody molecule or binding fragment thereof is tested as a bivalent molecule using ELISA, for example as described in Example 2, the antibody molecule or binding fragment thereof binds to BK virus serotype IV VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, or 0.02 nM;

[0122] (v) does not bind to JC virus VP1; for example, as described in Example 6;

[0123] (vi) neutralizes BK virus serotype I;

[0124] (vii) neutralizes BK virus serotype II;

[0125] (viii) neutralizes BK virus serotype III;

[0126] (ix) neutralizes BK virus serotype IV.

[0127] In one aspect B2, the present disclosure relates to an antibody molecule or binding fragment thereof that competes for binding to BK virus serotype I VP1, BK virus serotype II VP1, BK virus serotype III VP1, and / or BK virus serotype IV VP1 with an antibody molecule or binding fragment thereof described herein. In some embodiments of aspect B2, the present disclosure relates to an antibody molecule or binding fragment thereof that competes for binding to BK virus serotype I VP1, BK virus serotype II VP1, BK virus serotype III VP1, and / or BK virus serotype IV VP1 with an antibody molecule or binding fragment thereof comprising:

[0128] (i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 35, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0129] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0130] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0131] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0132] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0133] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0134] In some embodiments of aspect B2, the present disclosure relates to an antibody molecule or binding fragment thereof that competes for binding to a BK virus serotype I VP1, a BK virus serotype II VP1, a BK virus serotype III VP1, and / or a BK virus serotype IV VP1 with an antibody molecule or binding fragment thereof comprising:

[0135] (i) a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 40 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 41; or

[0136] (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 45 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 41 ; or

[0137] (iii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 50.

[0138] In one aspect B3, the present disclosure relates to a pharmaceutical composition comprising an antibody molecule or binding fragment thereof described herein and a pharmaceutically acceptable carrier, excipient or stabilizer.

[0139] In one aspect B4, the present disclosure relates to an anti-BK virus antibody molecule or binding fragment thereof described herein, or a pharmaceutical composition comprising an anti-BK virus antibody molecule or binding fragment thereof described herein, for use in the treatment or prevention of a BK virus infection and / or a BK virus associated disorder. In some embodiments of aspect B4, the BK virus associated disorder is selected from the group consisting of nephropathy, BK virus associated nephropathy (BKVAN), hemorrhagic cystitis (HC).

[0140] In one aspect B5, the present disclosure relates to a nucleic acid encoding an antibody heavy chain variable region and / or a light chain variable region of an antibody molecule or binding fragment thereof described herein.

[0141] In one aspect B6, the present disclosure relates to an expression vector comprising a nucleic acid described herein.

[0142] In one aspect B7, the present disclosure relates to a host cell comprising a nucleic acid described herein or an expression vector described herein.

[0143] In one aspect B8, the present disclosure relates to a method of producing an antibody molecule, the method comprising culturing a host cell described herein under conditions suitable for gene expression.

[0144] In one aspect B9, the present disclosure relates to a diagnostic composition comprising an antibody molecule or binding fragment thereof described herein. BRIEF DESCRIPTION OF DRAWINGS

[0145] Figure 1 Binding of anti-BK virus antibodies to BKV-VP1 serotypes I-IV in ELISA. These data were used to determine EC50 values by a three parameter analysis in GraphPad Prism software E

[0146] Figure 2 ​Quantitative assessment of antibody-mediated neutralization of BKV strains (serotypes la, lb, II, III and IV). 293TT cells were used as targets for BK pseudovirus infection expressing luciferase formed by serotypes la, lb, II, III and IV VP1. Anti-BK virus antibodies were used at the indicated concentrations.

[0147] Figure 3 Long-term viral neutralization of wild-type BKV by anti-BK virus antibodies on human primary renal tubular epithelial cells. Residual viral load after long-term co-incubation of cells, BK virus and anti-BK virus antibodies at the indicated concentrations is shown. Antibody concentrations correspond to EC 95 (1.500), EC50 (0.15) and EC5 (0.015). P8D11 is labeled as "BM2" in this figure.

[0148] Figure 4 Binding of anti-BK virus antibodies to conformational epitopes.

[0149] Figure 5 Evaluation of binding strength of antibodies 319C07 and 336F07 to VP1-mutants and JCV- in comparison to antibody P8D11 in ELISA. EC50 values for various mutant forms of VP1 and JC-VP1 in comparison to wild-type VP1 were determined. VP1 mutants are indicated in standard format, where the numbers refer to the position in the VP1-STI sequence where the amino acid to the left of the number is changed to the amino acid to the right of the number.

[0150] This figure shows the binding of antibodies 319C07, 336F07, isotype control antibody 24C03 and antibody P8D11 to selected BKV-VP1 mutants and JCV-VP1 and CMV-gH pentamer as an unrelated antigen.

[0151] This table shows the data for all tested BKV-VP1 mutants and JCV-VP1. "+" is used to indicate that no difference in binding affinity was observed between the original sequence and the mutant sequence. "red" indicates reduced binding, "-" indicates that no binding was observed.

[0152] Figure 6 Inhibition of BKV spread on HRPTECs by anti-BK virus antibodies (P8D11 is labeled as "BM2" in this figure).

[0153] Figure 7 ADCC activity of anti-BKV antibodies on infected and uninfected HRPTECs.

[0154] Figure 8 CDC activity of anti-BKV antibodies on infected and uninfected HRPTECs in the presence of human serum. DETAILED DESCRIPTION

[0156] The application as described by way of example below can be suitably carried out without any single or multiple element, single or multiple limitation not specifically recited herein.

[0157] The application will be described with respect to particular embodiments and with reference to certain drawings but the application is not limited thereto but only by the claims.

[0158] When the term "comprising" is used in the present description and claims, it is not to exclude other elements. For the purposes of the present application, the term "consisting of is a preferred embodiment of the term "comprising". If a group is defined to comprise at least an element, it is also to be understood to disclose a group consisting of only that element.

[0159] The indefinite articles "a" or "an", as used herein in the disclosure and in the claims, are to be construed as covering both the singular and the plural, unless otherwise expressly specified. In the context of the present application, the term "about" or "approximately" denotes an interval of accuracy that will be appreciated by those skilled in the art to still ensure the technical effect intended by the feature in question. The term denotes a deviation of ± 20 %, preferably ± 10 %, more preferably ± 5 % from the indicated numerical values.

[0160] Technical terms are used in their commonly understood sense. If a specific meaning is conveyed by certain terms, the definition of the term will be given in the context of the use of the term below.

[0161] Certain aspects of the present disclosure are based, at least in part, on the identification of the following anti-BK virus antibody molecules or binding fragments thereof:

[0162] - bind to and neutralize BK virus serotype I; and / or

[0163] - bind to and neutralize BK virus serotype II; and / or

[0164] - bind to and neutralize BK virus serotype III; and / or

[0165] - bind to and neutralize BK virus serotype IV; and / or

[0166] - do not bind to JC virus VP1.

[0167] In preferred embodiments, the anti-BK virus antibody molecules or binding fragments thereof neutralize BK virus serotypes I, II, III and IV.

[0168] In another preferred embodiment, the anti-BK virus antibody molecule or binding fragment thereof does not bind to JC virus VP1. Enhanced specificity is manifested by not binding to the closely related JC virus VP1. Enhanced specificity is considered to be better safety due to lower risk of off-target effects.

[0169] As noted above, the present disclosure contemplates anti-BK virus antibody molecules or binding fragments thereof. Full-length antibodies include constant and variable regions. Constant regions are not necessarily present in an antigen-binding fragment of an antibody.

[0170] Accordingly, binding fragments can include portions of intact full-length antibodies, such as antigen-binding or variable regions of intact antibodies. Examples of antibody fragments include Fab, F(ab')2, Id, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); multispecific antibody fragments such as bispecific, trispecific, and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies); minibodies; chelating recombinant antibodies; tribodies or bibodies; intrabodies; nanobodies; small modular immunopharmaceuticals (SMIPs), binding domain immunoglobulin fusion proteins; camelized antibodies; VHH containing antibodies; and any other polypeptide formed from antibody fragments. It is known to those skilled in the art that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0171] Disclosed herein are polypeptides having a specified sequence or a sequence that is substantially identical or similar thereto, e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the specified sequence.

[0172] Determination of percent identity between two sequences is preferably accomplished using the mathematical algorithm of Karlin and Altschul (1993) Proc. Natl. Acad. Sci USA 90:5873-5877. Such an algorithm is incorporated into the BLASTp (Protein BLAST) program of Altschul et al. (1990) J. Mol. Biol. 215:403-410 available at NCBI (https: / / blast.ncbi.nlm.nih.gov / ). Determination of percent identity can be performed using the standard parameters of the BLASTp program. For general parameters, the "Max Target Sequences" box can be set to 100, the "Short queries" box can be checked, the "Expect threshold" box can be set to 10, the "Word size" box can be set to "3" and the "Max matches in a query range" can be set to "0". For scoring parameters, the "Matrix" box can be set to "BLOSUM62", the "Gap costs" box can be set to "Existence: 11 Extension: 1", the "Compositions adjust" box can be set to "Conditional compositional score matrix adjustment". For filter and masking parameters, the "Low complexity regions" box can be unchecked, the "Masking

[0173] According to the present disclosure, a "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0174] As mentioned, the present disclosure also relates, in some embodiments, to nucleic acids encoding the antibody molecule or binding fragment thereof, vectors comprising such nucleic acids, and host cells comprising such nucleic acids or vectors.

[0175] The antibody molecule or binding fragment thereof can be encoded by a single nucleic acid (e.g., a single nucleic acid comprising nucleotide sequences encoding the light and heavy polypeptides of the antibody), or by two or more separate nucleic acids, wherein each nucleic acid encodes a different portion of the antibody molecule or antibody fragment. The nucleic acid can be DNA, cDNA, RNA, etc.

[0176] The nucleic acids described herein can be inserted into a vector. A "vector" is any molecule or composition having the ability to carry nucleic acid sequences into a suitable cell in which the encoded polypeptide can be synthesized.

[0177] The present disclosure further provides, in some aspects, host cells (e.g., isolated or purified cells) comprising the nucleic acids or vectors of the application. The host cell can be any type of cell that can be transformed with the nucleic acids or vectors of the application to produce the polypeptides encoded thereby.

[0178] Anti-BK virus antibody molecules or anti-BK virus binding fragments thereof can be formulated in a composition, particularly a pharmaceutical composition. Such compositions comprise a therapeutically effective amount of the antibody or binding fragment thereof in admixture with a pharmaceutically acceptable carrier, excipient, or stabilizer.

[0179] Further, the anti-BK virus antibody molecules or anti-BK virus binding fragments thereof and pharmaceutical compositions described herein can be administered in methods of treating or preventing BK virus infection and / or BK virus-associated disorders.

[0180] Preferred embodiments of aspects B1-B9 of the application relate to:

[0181] 1. An anti-BK virus antibody molecule or anti-BK virus binding fragment thereof, comprising:

[0182] (i) a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34 or a sequence with one or two amino acid substitutions, the heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 35 or a sequence with one or two amino acid substitutions, and the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36 or a sequence with one or two amino acid substitutions; and

[0183] a light chain variable region (VL) comprising the light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 37 or a sequence with one or two amino acid substitutions, the light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 38 or a sequence with one or two amino acid substitutions, and the light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 39 or a sequence with one or two amino acid substitutions; or

[0184] (ii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34 or a sequence with one or two amino acid substitutions, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44 or a sequence with one or two amino acid substitutions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36 or a sequence with one or two amino acid substitutions; and

[0185] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34 or a sequence with one or two amino acid substitutions, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44 or a sequence with one or two amino acid substitutions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36 or a sequence with one or two amino acid substitutions; and

[0186] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34 or a sequence with one or two amino acid substitutions, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44 or a sequence with one or two amino acid substitutions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36 or a sequence with one or two amino acid substitutions; and

[0187] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34 or a sequence with one or two amino acid substitutions, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44 or a sequence with one or two amino acid substitutions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36 or a sequence with one or two amino acid substitutions; and

[0188] 2. The antibody molecule or binding fragment of item 1, comprising:

[0189] (i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 35, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0190] a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0191] (ii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0192] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0193] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0194] (iii) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 34, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 44, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 36; and

[0195] 3. The antibody molecule or binding fragment thereof of item 1 or 2, comprising:

[0196] (i) a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 40, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 40, and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 41, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 41; or

[0197] (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 45, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 41; or

[0198] (iii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 49, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 50, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 50.

[0199] 4. The antibody molecule or binding fragment thereof of any one of items 1-3, comprising:

[0200] (i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 40, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 41; or

[0201] (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 45, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 41; or

[0202] (iii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 50.

[0203] 5. The antibody molecule or binding fragment thereof of any one of items 1-4,

[0204] comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) of the following properties:

[0205] (i) for example when tested as a bivalent molecule using ELISA, for example as described in Example 2, the antibody molecule or binding fragment thereof binds to BK virus serotype I VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, or 0.02 nM;

[0206] (ii) for example when tested as a bivalent molecule using ELISA, for example as described in Example 2, the antibody molecule or binding fragment thereof binds to BK virus serotype II VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, or 0.02 nM;

[0207] (iii) for example when tested as a bivalent molecule using ELISA, for example as described in Example 2, the antibody molecule or binding fragment thereof binds to BK virus serotype III VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, or 0.02 nM;

[0208] (iv) binds to a BK virus serotype IV VP1 with an EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, or 0.02 nM, e.g. when the antibody molecule or binding fragment thereof is tested as a bivalent molecule using an ELISA, e.g. as described in Example 2;

[0209] (v) does not bind to a JC virus VP1 ;

[0210] (vi) neutralizes a BK virus serotype I;

[0211] (vii) neutralizes a BK virus serotype II;

[0212] (viii) neutralizes a BK virus serotype III;

[0213] (ix) neutralizes a BK virus serotype IV.

[0214] 6. An antibody molecule or binding fragment thereof which competes for binding to a BK virus serotype I VP1, a BK virus serotype II VP1, a BK virus serotype III VP1 and / or a BK virus serotype IV VP1 with the antibody molecule or binding fragment thereof of any one of items 1 to 5.

[0215] 7. A pharmaceutical composition comprising the antibody molecule or binding fragment thereof of any one of items 1 to 6 and a pharmaceutically acceptable carrier, excipient or stabilizer.

[0216] 8. An antibody molecule or binding fragment thereof according to any one of items 1 to 6 or a pharmaceutical composition according to item 7 for use in the treatment or prevention of a BK virus infection and / or a BK virus associated disorder.

[0217] 9. A nucleic acid encoding an antibody heavy chain variable region and / or a light chain variable region of the antibody molecule or binding fragment thereof of any one of items 1 to 6.

[0218] 10. An expression vector comprising the nucleic acid of item 9.

[0219] 11. A host cell comprising the nucleic acid of item 9 or the expression vector of item 10.

[0220] 12. A method of producing an antibody molecule, the method comprising culturing the host cell of item 11 under conditions suitable for genetic expression.

[0221] 13. A diagnostic composition comprising the antibody molecule or binding fragment thereof of any one of items 1-6. Examples

[0222] Introduction

[0223] The amino acid sequences of the VP1 protein constructs used in the following examples are summarized in Table 1 below.

[0224] Table 1 - Amino acid sequences of VP1 protein constructs

[0225]

[0226]

[0227]

[0228] Comparative antibody

[0229] P8D11 as described for other antibodies (WO 2017 / 046676). The VH and VL of P8D11 described in WO 2017 / 046676 were fused to the same constant domains of IgG as described below. The amino acid sequences of the comparative antibody P8D11 are summarized in Table 2 below.

[0230] The negative control 24C3 is an anti-tetanus toxoid antibody derived from a healthy human. The variable fragments were fused to the same constant domains of IgG as described below.

[0231] Table 2 - Amino acid sequences of the comparative antibody P8D11 (WO 2017 / 046676)

[0232]

[0233] Antibody discovery

[0234] Example 1

[0235] An antibody library expression library was prepared using peripheral blood memory B cells from a healthy human donor or a kidney transplant recipient by cloning the immunoglobulin light and heavy chain variable regions into expression cassettes providing human immunoglobulin constant heavy chain regions combined with a transmembrane domain derived from human CD8 to allow antibody display in mammalian cells. After transduction of the library in HEK 293T cells, the antibody library was screened by antigen-specific sorting using the fluorescently labeled VP1-pentamer of BK virus.

[0236] This sorting resulted in HEK cell clones expressing BK virus specific antibodies, which were further propagated to scale up antibody production for downstream analysis of antibody properties, such as additional binding assays in ELISA or BK virus neutralization. The neutralization capacity of the antibodies was tested using a BK pseudovirus (BK-PsV) carrying a luciferase expression reporter plasmid and wild type BKV. BK virus specific antibodies with high affinity and virus neutralization capacity were then subcloned into expression vectors for soluble antibody expression and expressed after transient transfection in HEK 293F or CHO cells. Antibodies were then purified on protein G or protein A for characterization in various assays. The amino acid sequences associated with the identified antibody 319C07 are summarized in Table 3 below. In addition, variants were made and the corresponding amino acid sequences are also summarized in Table 3 below. The amino acid sequences associated with the identified antibody 336F07 are summarized in Table 4 below. In addition, variants were made and the corresponding amino acid sequences are also summarized in Table 4 below.

[0237] Table 3 - Amino acid sequences of anti-BK virus antibodies 319C07 and 319C07-varl.

[0238]

[0239]

[0240]

[0241] Table 4 - Amino acid sequences of anti-BK virus antibodies 336F07, 336F07-varl and 336F07-var4.

[0242]

[0243]

[0244]

[0245] Assays

[0246] Example 2 - Binding to VP1-pentamer in ELISA

[0247] Materials and Methods

[0248] Anti-BK virus antibodies were analyzed for binding to BKV-VP1 pentamer by ELISA. Briefly, 96-well assay plates, half-area high-binding plates (Corning Inc. #3690) were coated overnight at 4°C with 30 μΙ / well of 1 μg / ml BKV-VP1 pentamers. Subsequently, plates were blocked using 5% skimmed milk powder (Rapilait, Migros #7610200017598) diluted in PBS. Antibodies were serially diluted in PBS containing 0.5% skimmed milk powder and added to the antigen-coated plates for 1.5 hours. Plates were then washed with PBS 0.05% Tween20 (AppliChem, A4974) and incubated with enzyme-labeled secondary antibody (HRP-conjugated goat anti-human IgG, Jackson-Immuno #109-035-098) diluted 1 :10,000 in PBS containing 0.5% skimmed milk powder for 45 minutes. Plates were washed 3 times with PBS containing 0.05% Tween 20. The reaction was developed using 30 μΙ / well TMB liquid substrate (Sigma-Aldrich, #T0440) and stopped with 15 μΙ / well H2SO4. Absorbance was detected at 450 nm (Tecan, CMINFINITE MONO200). Data were fitted and apparent EC50 ELISA values (EC50 E ) were determined by a three-parameter analysis in GraphPad Prism (GraphPad Software).

[0249] Results

[0250] Antibody 319C07 showed strong selective binding to all BKV-VP1 serotypes Figure 1 with EC50 E values as follows. Antibody 319C07 showed higher affinity to serotypes I, II and IV and comparable affinity to BKV-VP1-serotype III compared to the comparative antibody P8D11.

[0251]

[0252] Antibody 336F07 also showed strong selective binding to all BKV-VP1 serotypes Figure 1 with EC50 E values as follows. Antibody 336F07 showed higher affinity to all four serotypes compared to the comparative antibody P8D11.

[0253]

[0254] Example 3 - Neutralization of BKV by anti-BK virus antibodies

[0255] Materials and methods

[0256] BK pseudoviruses (BK-PsV) carrying the NanoLuc reporter were produced as described (Pastrana et al., J Virol, 2013 Sep;87(18):10105-13). Five different genotypes were produced: BKV-Ia (BK-D; JF894228), BKV-Ib2 (PittVR2; DQ989796), BKV-II (Q85238; CAA79596), BKV-III (Q0PDA6; BAF03017) and BKV-IVc2 (A-66H; AB369093). VP1 was purified on agarose gel beads as described (Bucket et al., J Virol, 2008 Jun;82(11):5190-7 and Bucket et al., Curr Protoc Cell Biol, 2007 Dec;Chapter 26;26.21). Infectious virus titers were determined on 293TT cells. Different dilutions of BK-PsV were tested in 96-well plates with and without inhibitors. The dilution chosen for further assays produced a high luminescence signal in non-inhibited cells.

[0257] 20,000 cells (293TT) were seeded in 96-well plates using DMEM containing 9% FBS, HEPES and penicillin / streptomycin. After 5 hours of incubation, different concentrations of antibodies and a fixed amount of BK pseudovirus were added to each well and the plates were incubated at 37°C, 5% CO2. After 3 days of incubation, the NanoGlo TM The luciferase activity in the supernatant was measured using the NanoGlo

[0258] Forty μΐ of cell culture or virus-cell-antibody-co-culture-supernatant were transferred to white-bottom 96-well plates, 40 μΐ of NanoGlo TM substrate were added and incubated for 2 minutes before the luciferase activity was determined using a luminescence reader (BioTek Synergy). Data were plotted on signal versus antibody concentration curves. IC50 values were determined by GraphPad Prism using nonlinear regression (curve fit) and the formula “log(inhibitor) versus normalized response (variable slope)” (GraphPad software).

[0259] Results

[0260] 319C07 and variant 319C07-var1 showed strong inhibitory effects on BK pseudoviruses of all serotypes. The performance of 319C07 was significantly better than P8D11 Figure 2 , with IC50 values as follows.

[0261]

[0262] Antibody 336F07 and variants 336F07-var1 and 336F07-var4 also showed strong inhibition against all serotypes of BK pseudovirus. The performance of 336F07 was significantly better than that of P8D11 ( Figure 2 , IC50 values ​​are as follows).

[0263]

[0264] Example 4 - Long-term virus neutralization by anti-BK virus antibodies

[0265] Materials and Methods

[0266] To address the issue of long-term virus neutralization by anti-BK virus antibodies in vitro, human primary renal proximal tubular epithelial cells (HPRTEC), wild-type BK virus strain I ( VR-837 TM ) and repeated co-culture cycles of anti-BK virus antibodies. At the beginning of the study, three different concentrations of anti-BK virus antibodies corresponding to their EC95, EC50, and EC5 viral inhibition potencies were added to the cell-virus co-culture for one week. After this period, the virus was harvested from the cells and the remaining supernatant through three freeze-thaw cycles. 10 μl of this viral extract was then added to newly inoculated HRPTEC cells in the presence of various concentrations of antibody. Two weeks after inoculation, the viral load was quantified again and viral extracts were generated for the next infection cycle. This procedure was repeated three times, resulting in a total of eight weeks of co-culture.

[0267] The assay was performed in triplicate in 96-well flat-bottom cell culture plates. Quantification of viral load in culture supernatants was performed by harvesting 15 μl of culture medium, which was then heat-inactivated at 95°C for 10 minutes and used for viral load analysis using primers 5′-GGATGGGCAGCCTATGTATG-3′ (SEQ ID NO: 53) and 5′-TCATATCTGGGTCCCCTGGA-3′ (SEQ ID NO: 54) and TaqMan TM qPCR of probe FAM-AGGGTGTTTGATGGCACAGA-TAMRA (SEQ ID NO: 55). PCR was performed using PerfeCta qPCR ToughMix (Quantabio, #95140) under the following conditions: 95°C for 8 minutes and 40 cycles of 95°C for 10 seconds and 60°C for 60 seconds.

[0268] result

[0269] Compared to P8D11, antibody 319C07 showed more complete virus neutralization. This became most apparent when observing the final neutralization cycle after 8 weeks of infection, when virus could no longer be detected at concentrations corresponding to EC95 and EC50, while P8D11 showed measurable viral loads at both EC95 and EC50. Figure 3 , P8D11 is marked as “BM2” in the figure).

[0270] Antibody 336F07 also showed more complete virus neutralization compared to P8D11. This became most apparent when looking at the last neutralization cycle after 8 weeks of infection ( Figure 3 , P8D11 is marked as “BM2” in the figure).

[0271] Example 5 - Anti-BK virus antibodies bind to conformational epitopes

[0272] Materials and Methods

[0273] To determine whether anti-BK virus antibodies bind to conformational epitopes, dot blotting was performed on native and denatured VP1. BKV-VP1 pentamers of serotypes I, II, III, and IV were spotted onto nitrocellulose membranes in their native form or after chemical and heat denaturation using Tris buffer containing SDS and β-mercaptoethanol at 85°C for 5 minutes. Both membranes were incubated with anti-BK virus antibodies, and their binding was revealed using an HRP-conjugated secondary antibody against human Fc. Detection was performed using a colorimetric substrate (Sigma Fast DAB).

[0274] result

[0275] Antibodies 319C07 and 336F07 showed selective binding to conformational epitopes ( Figure 4 Since there was no staining of denatured antigen, binding to linear epitopes could be excluded. Denatured and non-denatured VP1 were detected using a commercially available control antibody (Ab53977, Abcam, rabbit IgG) known to recognize linear epitopes.

[0276] Example 6 - Binding to BKV-VP1-pentamer mutants and JCV-VP1 pentamer in ELISA

[0277] Materials and Methods

[0278] The wild-type VP1 sequence of serotype Ib was used as a basis for introducing mutations at different positions. Similarly, VP1 of JC virus was used. Binding of anti-BK virus antibodies to wild-type and variant VP1 pentamers was analyzed by ELISA. In brief, Assay plates 96-well, half-area high-binding plates (Corning Inc. #3690) were coated overnight at 4°C with 30 μl / well of 1 μg / ml of BKV-VP1 pentamer variant. After 16 hours, non-specific binding was blocked using 5% skimmed milk powder (Rapilait, Migros #7610200017598) diluted in PBS. Antibodies were serially diluted from 67 nM to 0.02 nM in PBS containing 0.5% skimmed milk powder and incubated on the antigen-coated plates for 1.5 hours. Plates were then washed three times with PBS 0.05% Tween20 (AppliChem, A4974) and then incubated with secondary antibody (HRP-conjugated goat anti-human IgG, Jackson-Immuno #109-035-098) diluted 1 :10,000 in PBS containing 0.5% skimmed milk powder for 45 minutes. The HRP activity of the bound secondary antibody was revealed using 30 μl / well of TMB liquid substrate (Sigma-Aldrich, #T0440). The reaction was stopped after 2.5 minutes by adding 15 μl / well of 1 M H2SO4. The absorbance was detected at 450 nm (Tecan, CL INFINITE MONO200). Data were plotted and EC50values were determined by a three-parameter analysis in GraphPad Prism (GraphPad Software) and called EC50ELISA (EC50E).

[0279] Results

[0280] Antibody 319C07 was tested for binding to BKV VP1 mutant forms compared to VP1 of the closely related JC polyomavirus and wild-type VP1 compared to antibody P8D11. Antibody 319C07 did not bind at all to VP1 of JC virus, whereas antibody P8D11 showed weak but significant binding. 319C07 showed slightly reduced binding if the amino acid at position N62, D175 or S275 was mutated to alanine. Changing the amino acid K172 to alanine did not reduce binding. On the other hand, P8D11 showed reduced binding to VP1-I-K172A mutant, whereas binding was not affected by N62A, D175A or S275A mutants. 319C07 showed here a clearly different pattern compared to antibody P8D11, indicating different amino acid interactions with VP1 compared to P8D11 Figure 5 ).

[0281] Antibody 336F07 was tested for binding to BKV VP1 mutant forms compared to the closely related JC polyomavirus VP1 and wild type VP1 compared to antibody P8D11. Antibody 336F07 did not bind at all to the VP1 of JC virus, whereas antibody P8D11 showed weak but significant binding. If the amino acid at position N62 or E73 was mutated, 336F07 showed slightly reduced binding affinity. Changing the amino acid K172 to alanine did not reduce binding. On the other hand, P8D11 showed reduced binding to the VP1-I-K172A mutant, whereas binding was not affected by the N62A or E73Q mutants. 336F07 shows a clearly different pattern here compared to antibody P8D11, indicating different amino acid interactions with VP1 compared to P8D11 Figure 5

[0282] Example 7 - Inhibition of virus spread from infected HRPTEC cells

[0283] Materials and Methods

[0284] Primary human renal proximal tubular epithelial cells (HRPTEC) were infected with BKV (strain 33-1, 45024 TM ) 5 days later, cells were gently scraped with a cell scraper and washed extensively with PBS to remove all cell-free virus. Cells were then added to the wells containing HRPTEC grown adherently and various dilutions of BKV neutralizing antibodies. Eight days after seeding of the cells, 10 μΐ of supernatant was removed from each well and viral load was determined using quantitative PCR using primers 5'-GGATGGGCAGCCTATGTATG-3' (SEQ ID NO: 53), 5'-TCATATCTGGGTCCCCTGGA-3' (SEQ ID NO: 54) and probe FAM-5'-AGGGTGTTTGATGGCACAGA-3'-TAMRA (SEQ ID NO: 55) as described (Martelli et al., Viruses, 2018 Aug 30; 10(9):466).

[0285] Results

[0286] Antibody 319C07 showed about 100-fold advantage over P8D11 in inhibiting the spread of BKV in HRPTEC; antibody 336F07 also showed a significant advantage over P8D11 in inhibiting the spread of BKV in HRPTEC Figure 6 , P8D11 is labeled "BM2" in this figure.

[0287] Example 8 - Antibody dependent cellular cytotoxicity (ADCC)​

[0288] Materials and Methods

[0289] Using wild-type BK virus strain I ( VR-837 TM HPRT-expressing cells seeded in flat-bottom 96-well plates (infected or uninfected) were used as target cells. Engineered Jurkat cells were used as effector cells using components of the ADCCReporter Bioassay G7015 from Promega. In this assay, Fc-γRIIIa signaling from effector cells was quantified via luminescence readout as a surrogate marker for ADCC activity.

[0290] Serial dilutions of anti-BKV or control antibodies were added to HPRTC cultures along with effector cells and incubated for 6 h before development and measurement of bioluminescence as described by the assay kit manufacturer.

[0291] result

[0292] 319C07 and 336F07 showed comparable ADCC activity against infected HPRTEC, which was comparable to the ADCC activity of P8D11. No ADCC was observed on HPRTEC not infected with 319C07 and 336F07 or P8D11. Figure 7 ).

[0293] Example 9 - Complement-dependent toxicity

[0294] Materials and Methods

[0295] Using wild-type BK virus strain I ( VR-837 TM HPRT-expressing cells seeded in flat-bottom 96-well plates infected or uninfected with BKV were used as target cells. Cells were incubated overnight with serial dilutions of anti-BKV antibody starting at 100 μg / ml and 20% human serum, and cell viability was quantified by determining the ratio of viable cells using an FSC / SSC standard in a cell counter.

[0296] result

[0297] 319C07 and 336F07 showed no CDC activity against infected HPRTEC at a concentration of 100 μg / ml, and the same observation was made with antibody P8D11 and a control antibody, Rituximab, directed against an irrelevant target on HPRTEC ( Figure 8 ). Sequence Listing <110> Memo Therapeutics AG University of Bern University of Zurich <120> Anti-BK virus antibody molecules <130> M11468WO <160> 55 <170> PatentIn version 3.5 <210> 1 <211> 270 <212> PRT <213> Human polyomavirus 1 <400> 1 Gly Gly Val Glu Val Leu Glu Val Lys Thr Gly Val Asp Ala Ile Thr 1 5 10 15 Glu Val Glu Cys Phe Leu Asn Pro Glu Met Gly Asp Pro Asp Glu Asn 20 25 30 Leu Arg Gly Phe Ser Leu Lys Leu Ser Ala Glu Asn Asp Phe Ser Ser 35 40 45 Asp Ser Pro Glu Arg Lys Met Leu Pro Cys Tyr Ser Thr Ala Arg Ile 50 55 60 Pro Leu Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn Leu Leu Met 65 70 75 80 Trp Glu Ala Val Thr Val Gln Thr Glu Val Ile Gly Ile Thr Ser Met 85 90 95 Leu Asn Leu His Ala Gly Ser Gln Lys Val His Glu His Gly Gly Gly 100 105 110 Lys Pro Ile Gln Gly Ser Asn Phe His Phe Phe Ala Val Gly Gly Asp 115 120 125 Pro Leu Glu Met Gin Gly Val Leu Met Asn Tyr Arg Thr Lys Tyr Pro 130 135 140 Asp Gly Thr He Thr Pro Lys Asn Pro Thr Ala Gin Ser Gin Val Met 145 150 155 160 Asn Thr Asp His Lys Ala Tyr Leu Asp Lys Asn Asn Ala Tyr Pro Val 165 170 175 Glu Cys Trp Val Pro Asp Pro Ser Arg Asn Glu Asn Thr Arg Tyr Phe 180 185 190 Gly Thr Phe Thr Gly Gly Glu Asn Val Pro Pro Val Leu His Val Thr 195 200 205 Asn Thr Ala Thr Thr Val Leu Leu Asp Glu Gin Gly Val Gly Pro Leu 210 215 220 Cys Lys Ala Asp Ser Leu Tyr Val Ser Ala Ala Asp He Cys Gly Leu 225 230 235 240 Phe Thr Asn Ser Ser Gly Thr Gin Gin Trp Arg Gly Leu Ala Arg Tyr 245 250 255 Phe Lys He Arg Leu Arg Lys Arg Ser Val Lys Asn Pro Tyr 260 265 270 <210> 2 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> BK假病毒, VP1-Ia <400> 2 Met Ala Pro Thr Lys Arg Lys Gly Glu Cys Pro Gly Ala Ala Pro Lys 1 5 10 15 Lys Pro Lys Glu Pro Val Gln Val Pro Lys Leu Leu Ile Lys Gly Gly 20 25 30 Val Glu Val Leu Glu Val Lys Thr Gly Val Asp Ala Ile Thr Glu Val 35 40 45 Glu Cys Phe Leu Asn Pro Glu Met Gly Asp Pro Asp Glu Asn Leu Arg 50 55 60 Gly Phe Ser Leu Lys Leu Ser Ala Glu Asn Asp Phe Ser Ser Asp Ser 65 70 75 80 Pro Glu Arg Lys Met Leu Pro Cys Tyr Ser Thr Ala Arg Ile Pro Leu 85 90 95 Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn Leu Leu Met Trp Glu 100 105 110 Ala Val Thr Val Gln Thr Glu Val Ile Gly Ile Thr Ser Met Leu Asn 115 120 125 Leu His Ala Gly Ser Gln Lys Val His Glu His Gly Gly Gly Lys Pro 130 135 140 Ile Gin Gly Ser Asn Phe His Phe Phe Ala Val Gly Gly Asp Pro Leu 145 150 155 160 Glu Met Gin Gly Val Leu Met Asn Tyr Arg Thr Lys Tyr Pro Asp Gly 165 170 175 Thr He Thr Pro Lys Asn Pro Thr Ala Gin Ser Gin Val Met Asn Thr 180 185 190 Asp His Lys Ala Tyr Leu Asp Lys Asn Asn Ala Tyr Pro Val Glu Cys 195 200 205 Trp Val Pro Asp Pro Ser Arg Asn Glu Asn Thr Arg Tyr Phe Gly Thr 210 215 220 Phe Thr Gly Gly Glu Asn Val Pro Pro Val Leu His Val Thr Asn Thr 225 230 235 240 Ala Thr Thr Val Leu Leu Asp Glu Gin Gly Val Gly Pro Leu Cys Lys 245 250 255 Ala Asp Ser Leu Tyr Val Ser Ala Ala Asp He Cys Gly Leu Phe Thr 260 265 270 Asn Ser Ser Gly Thr Gin Gin Trp Arg Gly Leu Ala Arg Tyr Phe Lys 275 280 285 Ile Arg Leu Arg Lys Arg Ser Val Lys Asn Pro Tyr Pro He Ser Phe 290 295 300 Leu Leu Ser Asp Leu lie Asn Arg Arg Thr Gin Arg Val Asp Gly Gin 305 310 315 320 Pro Met Tyr Gly Met Glu Ser Gin Val Glu Glu Val Arg Val Phe Asp 325 330 335 Gly Thr Glu Arg Leu Pro Gly Asp Pro Asp Met lie Arg Tyr lie Asp 340 345 350 Lys Gin Gly Gin Leu Gin Thr Lys Met Leu 355 360 <210> 3 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> BK pseudovirus, VP1-Ib <400> 3 Met Ala Pro Thr Lys Arg Lys Gly Glu Cys Pro Gly Ala Ala Pro Lys 1 5 10 15 Lys Pro Lys Glu Pro Val Gin Val Pro Lys Leu Leu lie Lys Gly Gly 20 25 30 Val Glu Val Leu Glu Val Lys Thr Gly Leu Asp Ala lie Thr Glu Val 35 40 45 Glu Cys Phe Leu Asn Pro Glu Met Gly Asp Pro Asp Glu Asn Leu Arg 50 55 60 Gly Phe Ser Leu Lys Leu Ser Ala Glu Asn Asp Phe Ser Ser Asp Ser 65 70 75 80 Pro Asp Arg Lys Met Leu Pro Cys Tyr Ser Thr Ala Arg Ile Pro Leu 85 90 95 Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn Leu Leu Met Trp Glu 100 105 110 Ala Val Thr Val Gln Thr Glu Val Ile Gly Ile Thr Ser Met Leu Asn 115 120 125 Leu His Ala Gly Ser Gln Lys Val His Glu His Gly Gly Gly Lys Pro 130 135 140 Ile Gln Gly Ser Asn Phe His Phe Phe Ala Val Gly Gly Asp Pro Leu 145 150 155 160 Glu Met Gln Gly Val Leu Met Asn Tyr Arg Thr Lys Tyr Pro Glu Gly 165 170 175 Thr Ile Thr Pro Lys Asn Pro Thr Ala Gln Ser Gln Val Met Asn Thr 180 185 190 Asp His Lys Ala Tyr Leu Asp Lys Asn Asn Ala Tyr Pro Val Glu Cys 195 200 205 Trp Ile Pro Asp Pro Ser Arg Asn Glu Asn Thr Arg Tyr Phe Gly Thr 210 215 220 Phe Thr Gly Gly Glu Asn Val Pro Pro Val Leu His Val Thr Asn Thr 225 230 235 240 Ala Thr Thr Val Leu Leu Asp Glu Gln Gly Val Gly Pro Leu Cys Lys 245 250 255 Ala Asp Ser Leu Tyr Val Ser Ala Ala Asp Ile Cys Gly Leu Phe Thr 260 265 270 Asn Ser Ser Gly Thr Gln Gln Trp Arg Gly Leu Ala Arg Tyr Phe Lys 275 280 285 Ile Arg Leu Arg Lys Arg Ser Val Lys Asn Pro Tyr Pro Ile Ser Phe 290 295 300 Leu Leu Ser Asp Leu Ile Asn Arg Arg Thr Gln Arg Val Asp Gly Gln 305 310 315 320 Pro Met Tyr Gly Met Glu Ser Gln Val Glu Glu Val Arg Val Phe Asp 325 330 335 Gly Thr Glu Arg Leu Pro Gly Asp Pro Asp Met Ile Arg Tyr Ile Asp 340 345 350 Lys Gln Gly Gln Leu Gln Thr Lys Met Leu 355 360 <210> 4 <211> 270 <212> PRT <213> 人多瘤病毒1 <400> 4 Gly Gly Val Glu Val Leu Glu Val Lys Thr Gly Val Asp Ala Ile Thr 1 5 10 15 Glu Val Glu Cys Phe Leu Asn Pro Glu Met Gly Asp Pro Asp Asp Asn 20 25 30 Leu Arg Gly Tyr Ser Leu Lys Leu Thr Ala Glu Asn Ala Phe Asp Ser 35 40 45 Asp Ser Pro Asp Lys Lys Met Leu Pro Cys Tyr Ser Thr Ala Arg Ile 50 55 60 Pro Leu Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn Leu Leu Met 65 70 75 80 Trp Glu Ala Val Thr Val Lys Thr Glu Val Ile Gly Ile Thr Ser Met 85 90 95 Leu Asn Leu His Ala Gly Ser Gln Lys Val His Glu Asn Gly Gly Gly 100 105 110 Lys Pro Val Gln Gly Ser Asn Phe His Phe Phe Ala Val Gly Gly Asp 115 120 125 Pro Leu Glu Met Gln Gly Val Leu Met Asn Tyr Arg Thr Lys Tyr Pro 130 135 140 Gln Gly Thr Ile Thr Pro Lys Asn Pro Thr Ala Gln Ser Gln Val Met 145 150 155 160 Asn Thr Asp His Lys Ala Tyr Leu Asp Lys Asn Asn Ala Tyr Pro Val 165 170 175 Glu Cys Trp lie Pro Asp Pro Ser Arg Asn Glu Asn Thr Arg Tyr Phe 180 185 190 Gly Thr Tyr Thr Gly Gly Glu Asn Val Pro Pro Val Leu His Val Thr 195 200 205 Asn Thr Ala Thr Thr Val Leu Leu Asp Glu Gin Gly Val Gly Pro Leu 210 215 220 Cys Lys Ala Asp Ser Leu Tyr Val Ser Ala Ala Asp lie Cys Gly Leu 225 230 235 240 Phe Thr Asn Ser Ser Gly Thr Gin Gin Trp Arg Gly Leu Ala Arg Tyr 245 250 255 Phe Lys lie Arg Leu Arg Lys Arg Ser Val Lys Asn Pro Tyr 260 265 270 <210> 5 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> BK pseudovirus, VP1-II <400> 5 Met Ala Pro Thr Lys Arg Lys Gly Glu Cys Pro Gly Ala Ala Pro Lys 1 5 10 15 Lys Pro Lys Glu Pro Val Gin Val Pro Lys Leu Leu lie Lys Gly Gly 20 25 30 Val Glu Val Leu Glu Val Lys Thr Gly Val Asp Ala Ile Thr Glu Val 35 40 45 Glu Cys Phe Leu Asn Pro Glu Met Gly Asp Pro Asp Asp Asn Leu Arg 50 55 60 Gly Tyr Ser Leu Lys Leu Thr Ala Glu Asn Ala Phe Asp Ser Asp Ser 65 70 75 80 Pro Asp Lys Lys Met Leu Pro Cys Tyr Ser Thr Ala Arg Ile Pro Leu 85 90 95 Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn Leu Leu Met Trp Glu 100 105 110 Ala Val Thr Val Lys Thr Glu Val Ile Gly Ile Thr Ser Met Leu Asn 115 120 125 Leu His Ala Gly Ser Gln Lys Val His Glu Asn Gly Gly Gly Lys Pro 130 135 140 Val Gln Gly Ser Asn Phe His Phe Phe Ala Val Gly Gly Asp Pro Leu 145 150 155 160 Glu Met Gln Gly Val Leu Met Asn Tyr Arg Thr Lys Tyr Pro Gln Gly 165 170 175 Thr Ile Thr Pro Lys Asn Pro Thr Ala Gln Ser Gln Val Met Asn Thr 180 185 190 Asp His Lys Ala Tyr Leu Asp Lys Asn Asn Ala Tyr Pro Val Glu Cys 195 200 205 Trp Ile Pro Asp Pro Ser Arg Asn Glu Asn Thr Arg Tyr Phe Gly Thr 210 215 220 Tyr Thr Gly Gly Glu Asn Val Pro Pro Val Leu His Val Thr Asn Thr 225 230 235 240 Ala Thr Thr Val Leu Leu Asp Glu Gln Gly Val Gly Pro Leu Cys Lys 245 250 255 Ala Asp Ser Leu Tyr Val Ser Ala Ala Asp Ile Cys Gly Leu Phe Thr 260 265 270 Asn Ser Ser Gly Thr Gln Gln Trp Arg Gly Leu Ala Arg Tyr Phe Lys 275 280 285 Ile Arg Leu Arg Lys Arg Ser Val Lys Asn Pro Tyr Pro Ile Ser Phe 290 295 300 Leu Leu Ser Asp Leu Ile Asn Arg Arg Thr Gln Arg Val Asp Gly Gln 305 310 315 320 Pro Met Tyr Gly Met Glu Ser Gln Val Glu Glu Val Arg Val Phe Asp 325 330 335 Gly Thr Glu Gln Leu Pro Gly Asp Pro Asp Met Ile Arg Tyr Ile Asp 340 345 350 Arg Gin Gly Gin Leu Gin Thr Lys Met Val 355 360 <210> 6 <211> 362 <212> PRT <213> Human polyomavirus 1 <400> 6 Met Ala Pro Thr Lys Arg Lys Gly Glu Cys Pro Gly Ala Ala Pro Lys 1 5 10 15 Lys Pro Lys Glu Pro Val Gin Val Pro Lys Leu Leu Ile Lys Gly Gly 20 25 30 Val Glu Val Leu Glu Val Lys Thr Gly Val Asp Ala Ile Thr Glu Val 35 40 45 Glu Cys Phe Leu Asn Pro Glu Met Gly Asp Pro Asp Asp Asn Leu Arg 50 55 60 Gly Tyr Ser Gin His Leu Ser Ala Glu Asn Ala Phe Glu Ser Asp Ser 65 70 75 80 Pro Asp Arg Lys Met Leu Pro Cys Tyr Ser Thr Ala Arg Ile Pro Leu 85 90 95 Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn Leu Leu Met Trp Glu 100 105 110 Ala Val Thr Val Lys Thr Glu Val Ile Gly Ile Thr Ser Met Leu Asn 115 120 125 Leu His Ala Gly Ser Gin Lys Val His Glu Asn Gly Gly Gly Lys Pro 130 135 140 Val Gin Gly Ser Asn Phe His Phe Phe Ala Val Gly Gly Asp Pro Leu 145 150 155 160 Glu Met Gin Gly Val Leu Met Asn Tyr Arg Thr Lys Tyr Pro Gin Gly 165 170 175 Thr He Thr Pro Lys Asn Pro Thr Ala Gin Ser Gin Val Met Asn Thr 180 185 190 Asp His Lys Ala Tyr Leu Asp Lys Asn Asn Ala Tyr Pro Val Glu Cys 195 200 205 Trp He Pro Asp Pro Ser Arg Asn Glu Asn Thr Arg Tyr Phe Gly Thr 210 215 220 Tyr Thr Gly Gly Glu Asn Val Pro Pro Val Leu His Val Thr Asn Thr 225 230 235 240 Ala Thr Thr Val Leu Leu Asp Glu Gin Gly Val Gly Pro Leu Cys Lys 245 250 255 Ala Asp Ser Leu Tyr Val Ser Ala Ala Asp He Cys Gly Leu Phe Thr 260 265 270 Asn Ser Ser Gly Thr Gin Gin Trp Arg Gly Leu Ala Arg Tyr Phe Lys 275 280 285 Ile Arg Leu Arg Lys Arg Ser Val Lys Asn Pro Tyr Pro Ile Ser Phe 290 295 300 Leu Leu Ser Asp Leu Ile Asn Arg Arg Thr Gln Lys Val Asp Gly Gln 305 310 315 320 Pro Met Tyr Gly Met Glu Ser Gln Val Glu Glu Val Arg Val Phe Asp 325 330 335 Gly Thr Glu Gln Leu Pro Gly Asp Pro Asp Met Ile Arg Tyr Ile Asp 340 345 350 Arg Gln Gly Gln Leu Gln Thr Lys Met Val 355 360 <210> 7 <211> 362 <212> PRT <213> artificial sequence <220> <223> BK pseudovirus, VP1-III <400> 7 Met Ala Pro Thr Lys Arg Lys Gly Glu Cys Pro Gly Ala Ala Pro Lys 1 5 10 15 Lys Pro Lys Glu Pro Val Gln Val Pro Lys Leu Leu Ile Lys Gly Gly 20 25 30 Val Glu Val Leu Glu Val Lys Thr Gly Val Asp Ala Ile Thr Glu Val 35 40 45 Glu Cys Phe Leu Asn Pro Glu Met Gly Asp Pro Asp Asp Asn Leu Arg 50 55 60 Gly Tyr Ser Gin His Leu Ser Ala Glu Asn Ala Phe Glu Ser Asp Ser 65 70 75 80 Pro Asp Arg Lys Met Leu Pro Cys Tyr Ser Thr Ala Arg Ile Pro Leu 85 90 95 Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn Leu Leu Met Trp Glu 100 105 110 Ala Val Thr Val Lys Thr Glu Val Ile Gly Ile Thr Ser Met Leu Asn 115 120 125 Leu His Ala Gly Ser Gin Lys Val His Glu Asn Gly Gly Gly Lys Pro 130 135 140 Val Gin Gly Ser Asn Phe His Phe Phe Ala Val Gly Gly Asp Pro Leu 145 150 155 160 Glu Met Gin Gly Val Leu Met Asn Tyr Arg Thr Lys Tyr Pro Gin Gly 165 170 175 Thr Ile Thr Pro Lys Asn Pro Thr Ala Gin Ser Gin Val Met Asn Thr 180 185 190 Asp His Lys Ala Tyr Leu Asp Lys Asn Asn Ala Tyr Pro Val Glu Cys 195 200 205 Trp Ile Pro Asp Pro Ser Arg Asn Glu Asn Thr Arg Tyr Phe Gly Thr 210 215 220 Tyr Thr Gly Gly Glu Asn Val Pro Pro Val Leu His Val Thr Asn Thr 225 230 235 240 Ala Thr Thr Val Leu Leu Asp Glu Gin Gly Val Gly Pro Leu Cys Lys 245 250 255 Ala Asp Ser Leu Tyr Val Ser Ala Ala Asp He Cys Gly Leu Phe Thr 260 265 270 Asn Ser Ser Gly Thr Gin Gin Trp Arg Gly Leu Ala Arg Tyr Phe Lys 275 280 285 He Arg Leu Arg Lys Arg Ser Val Lys Asn Pro Tyr Pro He Ser Phe 290 295 300 Leu Leu Ser Asp Leu He Asn Arg Arg Thr Gin Arg Val Asp Gly Gin 305 310 315 320 Pro Met Tyr Gly Met Glu Ser Gin Val Glu Glu Val Arg Val Phe Asp 325 330 335 Gly Thr Glu Gin Leu Pro Gly Asp Pro Asp Met He Arg Tyr He Asp 340 345 350 Arg Gin Gly Gin Leu Gin Thr Lys Met Val 355 360 <210> 8 <211> 270 <212> PRT <213> Human polyomavirus 1 <400> 8 Gly Gly Val Glu Val Leu Glu Val Lys Thr Gly Val Asp Ala Ile Thr 1 5 10 15 Glu Val Glu Cys Phe Leu Asn Pro Glu Met Gly Asp Pro Asp Asn Asp 20 25 30 Leu Arg Gly Tyr Ser Leu Arg Leu Thr Ala Glu Thr Ala Phe Asp Ser 35 40 45 Asp Ser Pro Asp Arg Lys Met Leu Pro Cys Tyr Ser Thr Ala Arg Ile 50 55 60 Pro Leu Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn Leu Leu Met 65 70 75 80 Trp Glu Ala Val Thr Val Lys Thr Glu Val Ile Gly Ile Thr Ser Met 85 90 95 Leu Asn Leu His Ala Gly Ser Gln Lys Val His Glu Asn Gly Gly Gly 100 105 110 Lys Pro Ile Gln Gly Ser Asn Phe His Phe Phe Ala Val Gly Gly Asp 115 120 125 Pro Leu Glu Met Gln Gly Val Leu Met Asn Tyr Arg Thr Lys Tyr Pro 130 135 140 Glu Gly Thr Val Thr Pro Lys Asn Pro Thr Ala Gln Ser Gln Val Met 145 150 155 160 Asn Thr Asp His Lys Ala Tyr Leu Asp Lys Asn Asn Ala Tyr Pro Val 165 170 175 Glu Cys Trp Ile Pro Asp Pro Ser Arg Asn Glu Asn Thr Arg Tyr Phe 180 185 190 Gly Thr Tyr Thr Gly Gly Glu Asn Val Pro Pro Val Leu His Val Thr 195 200 205 Asn Thr Ala Thr Thr Val Leu Leu Asp Glu Gln Gly Val Gly Pro Leu 210 215 220 Cys Lys Ala Asp Ser Leu Tyr Val Ser Ala Ala Asp Ile Cys Gly Leu 225 230 235 240 Phe Thr Asn Ser Ser Gly Thr Gln Gln Trp Arg Gly Leu Pro Arg Tyr 245 250 255 Phe Lys Ile Arg Met Arg Lys Arg Ser Val Lys Asn Pro Tyr 260 265 270 <210> 9 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> BK pseudovirus, VP1-IVc <400> 9 Met Ala Pro Thr Lys Arg Lys Gly Glu Cys Pro Gly Ala Ala Pro Lys 1 5 10 15 Lys Pro Lys Glu Pro Val Gin Val Pro Lys Leu Leu lie Lys Gly Gly 20 25 30 Val Glu Val Leu Glu Val Lys Thr Gly Val Asp Ala lie Thr Glu Val 35 40 45 Glu Cys Phe Leu Asn Pro Glu Met Gly Asp Pro Asp Asn Asp Leu Arg 50 55 60 Gly Tyr Ser Leu Arg Leu Thr Ala Glu Thr Ala Phe Asp Ser Asp Ser 65 70 75 80 Pro Asp Arg Lys Met Leu Pro Cys Tyr Ser Thr Ala Arg lie Pro Leu 85 90 95 Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn Leu Leu Met Trp Glu 100 105 110 Ala Val Thr Val Lys Thr Glu Val lie Gly lie Thr Ser Met Leu Asn 115 120 125 Leu His Ala Gly Ser Gin Lys Val His Glu Asn Gly Gly Gly Lys Pro 130 135 140 Ile Gin Gly Ser Asn Phe His Phe Phe Ala Val Gly Gly Asp Pro Leu 145 150 155 160 Glu Met Gin Gly Val Leu Met Asn Tyr Arg Thr Lys Tyr Pro Glu Gly 165 170 175 Thr Val Thr Pro Lys Asn Pro Thr Ala Gin Ser Gin Val Met Asn Thr 180 185 190 Asp His Lys Ala Tyr Leu Asp Lys Asn Asn Ala Tyr Pro Val Glu Cys 195 200 205 Trp He Pro Asp Pro Ser Lys Asn Glu Asn Thr Arg Tyr Phe Gly Thr 210 215 220 Tyr Thr Gly Gly Glu Asn Val Pro Pro Val Leu His Val Thr Asn Thr 225 230 235 240 Ala Thr Thr Val Leu Leu Asp Glu Gin Gly Val Gly Pro Leu Cys Lys 245 250 255 Ala Asp Ser Leu Tyr Val Ser Ala Ala Asp He Cys Gly Leu Phe Thr 260 265 270 Asn Ser Ser Gly Thr Gin Gin Trp Arg Gly Leu Pro Arg Tyr Phe Lys 275 280 285 He Arg Leu Arg Lys Arg Ser Val Lys Asn Pro Tyr Pro He Ser Phe 290 295 300 Leu Leu Ser Asp Leu He Asn Arg Arg Thr Gin Arg Val Asp Gly Gin 305 310 315 320 Pro Met Tyr Gly Met Glu Ser Gin Val Glu Glu Val Arg Val Phe Asp 325 330 335 Gly Thr Glu Gin Leu Pro Gly Asp Pro Asp Met lie Arg Tyr lie Asp 340 345 350 Arg Gin Gly Gin Leu Gin Thr Lys Met Val 355 360 <210> 10 <211> 270 <212> PRT <213> JC polyomavirus <400> 10 Gly Gly Val Glu Val Leu Glu Val Lys Thr Gly Val Asp Ser lie Thr 1 5 10 15 Glu Val Glu Cys Phe Leu Thr Pro Glu Met Gly Asp Pro Asp Glu His 20 25 30 Leu Arg Gly Phe Ser Lys Ser lie Ser lie Ser Asp Thr Phe Glu Ser 35 40 45 Asp Ser Pro Asn Arg Asp Met Leu Pro Cys Tyr Ser Val Ala Arg lie 50 55 60 Pro Leu Pro Asn Leu Asn Glu Asp Leu Thr Cys Gly Asn lie Leu Met 65 70 75 80 Trp Glu Ala Val Thr Leu Lys Thr Glu Val lie Gly Val Thr Ser Leu 85 90 95 Met Asn Val His Ser Asn Gly Gin Ala Thr His Asp Asn Gly Ala Gly 100 105 110 Lys Pro Val Gin Gly Thr Ser Phe His Phe Phe Ser Val Gly Gly Glu 115 120 125 Ala Leu Glu Leu Gin Gly Val Leu Phe Asn Tyr Arg Thr Lys Tyr Pro 130 135 140 Asp Gly Thr He Phe Pro Lys Asn Ala Thr Val Gin Ser Gin Val Met 145 150 155 160 Asn Thr Glu His Lys Ala Tyr Leu Asp Lys Asn Lys Ala Tyr Pro Val 165 170 175 Glu Cys Trp Val Pro Asp Pro Thr Arg Asn Glu Asn Thr Arg Tyr Phe 180 185 190 Gly Thr Leu Thr Gly Gly Glu Asn Val Pro Pro Val Leu His He Thr 195 200 205 Asn Thr Ala Thr Thr Val Leu Leu Asp Glu Phe Gly Val Gly Pro Leu 210 215 220 Cys Lys Gly Asp Asn Leu Tyr Leu Ser Ala Val Asp Val Cys Gly Met 225 230 235 240 Phe Thr Asn Arg Ser Gly Ser Gin Gin Trp Arg Gly Leu Ser Arg Tyr 245 250 255 Phe Lys Val Gin Leu Arg Lys Arg Arg Val Lys Asn Pro Tyr 260 265 270 <210> 11 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 1 of heavy chain <400> 11 Asn Tyr Trp Met Thr 1 5 <210> 12 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 2 of heavy chain <400> 12 Asn Ile Lys Lys Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Arg 1 5 10 15 Gly <210> 13 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 3 of heavy chain <400> 13 Val Arg Ser Gly Arg Tyr Phe Ala Leu Asp Asp 1 5 10 <210> 14 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 1 of light chain <400> 14 Gly Gly Asp Asn Ile Gly Ser Arg Pro Val His 1 5 10 <210> 15 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 2 of light chain <400> 15 Asp Asp Ser Asn Arg Pro Ser 1 5 <210> 16 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Complementarity-determining region 3 of light chain <400> 16 Gln Val Trp Ser Ser Ser Thr Asp His Pro 1 5 10 <210> 17 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Heavy chain variable region <400> 17 Gln Val Gln Leu Val Glu Ser Gly Gly Thr Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Tyr 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Lys Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Thr Val Arg Ser Gly Arg Tyr Phe Ala Leu Asp Asp Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 18 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region <400> 18 Gln Ser Val Leu Thr Gin Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asp Asn Ile Gly Ser Arg Pro Val 20 25 30 His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Ile Leu Val Val Tyr 35 40 45 Asp Asp Ser Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gin Val Trp Ser Ser Ser Thr Asp His 85 90 95 Pro Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 <210> 19 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> Full Length Heavy Chain <400> 19 Gln Val Gln Leu Val Glu Ser Gly Gly Thr Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Tyr 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Lys Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Thr Val Arg Ser Gly Arg Tyr Phe Ala Leu Asp Asp Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 20 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> Full Length Light Chain <400> 20 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asp Asn Ile Gly Ser Arg Pro Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Val Tyr 35 40 45 Asp Asp Ser Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Ser Ser Ser Thr Asp His 85 90 95 Pro Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly Gln Pro Lys Ala 100 105 110 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala 115 120 125 Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala 130 135 140 Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val 145 150 155 160 Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser 165 170 175 Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr 180 185 190 Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <210> 21 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 1 of heavy chain <400> 21 Ala Tyr Tyr Trp Thr 1 5 <210> 22 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 2 of heavy chain <400> 22 Glu Ile Asn His Arg Gly Tyr Thr Asn Tyr Asn Pro Ser Leu Arg Gly 1 5 10 15 <210> 23 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 1 of heavy chain <400> 23 Leu Arg Ser Thr Ser Gly Trp His Asp Tyr Phe Asp Tyr 1 5 10 <210> 24 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 1 of light chain <400> 24 Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 <210> 25 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 2 of light chain <400> 25 Gly Ala Ser Ser Arg Ala Thr 1 5 <210> 26 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 3 of light chain <400> 26 Leu Gln Tyr Gly Ser Ser Pro Leu Thr 1 5 <210> 27 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain variable region <400> 27 Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Tyr Arg Gly Ser Phe Ser Ala Tyr 20 25 30 Tyr Trp Thr Trp Phe Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn His Arg Gly Tyr Thr Asn Tyr Asn Pro Ser Leu Arg 50 55 60 Gly Arg Val Ser Ile Ser Val Asp Thr Ser Lys Lys Gln Phe Ser Leu 65 70 75 80 Lys Leu Arg Ser Val Asn Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Thr Leu Arg Ser Thr Ser Gly Trp His Asp Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 28 <211> 108 <212> PRT <213> Artificial sequence <220> <223> Light chain variable region <400> 28 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Ser 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gin Gin Thr Pro Gly Gin Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Gin Asp Phe Val Val Tyr Phe Cys Leu Gin Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 29 <211> 451 <212> PRT <213> Artificial Sequence <220> <223> Full Length Heavy Chain <400> 29 Gln Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Tyr Arg Gly Ser Phe Ser Ala Tyr 20 25 30 Tyr Trp Thr Trp Phe Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45 Gly Glu lie Asn His Arg Gly Tyr Thr Asn Tyr Asn Pro Ser Leu Arg 50 55 60 Gly Arg Val Ser lie Ser Val Asp Thr Ser Lys Lys Gin Phe Ser Leu 65 70 75 80 Lys Leu Arg Ser Val Asn Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Thr Leu Arg Ser Thr Ser Gly Trp His Asp Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro He 325 330 335 Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 30 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> Full Length Light Chain <400> 30 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Thr Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Val Val Tyr Phe Cys Leu Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 31 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region <400> 31 Glu Ile Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Phe Cys Leu Gin Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 32 <211> 451 <212> PRT <213> Artificial sequence <220> <223> Full length heavy chain <400> 32 Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Tyr Arg Gly Ser Phe Ser Ala Tyr 20 25 30 Tyr Trp Thr Trp Phe Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn His Arg Gly Tyr Thr Asn Tyr Asn Pro Ser Leu Arg 50 55 60 Gly Arg Val Ser Ile Ser Val Asp Thr Ser Lys Lys Gln Phe Ser Leu 65 70 75 80 Lys Leu Arg Ser Val Asn Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Thr Leu Arg Ser Thr Ser Gly Trp His Asp Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 33 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> Full Length Light Chain <400> 33 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Phe Cys Leu Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 34 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 1 of heavy chain <400> 34 Leu Tyr Ala Met Asn 1 5 <210> 35 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 2 of heavy chain <400> 35 Leu He Ser Gly Ser Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val Thr 1 5 10 15 Gly <210> 36 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 1 of heavy chain <400> 36 Thr Tyr Pro Thr Trp Gly Gly Val Val Ile Gly Ala Ile Asp Val 1 5 10 15 <210> 37 <211 > 11 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 2 of heavy chain <400> 37 Arg Ala Ser Gln Ser Ile Gln Arg Trp Leu Ala 1 5 10 <210> 38 <211 > 7 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 1 of light chain <400> 38 Asp Ala Ser Thr Leu Glu Ser 1 5 <210> 39 <211 > 9 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 2 of light chain <400> 39 Gln Gln Tyr Asn Gly His Ala Ser Thr 1 5 <210> 40 <211 > 124 <212> PRT <213> Artificial Sequence <220> <223> Variable region of heavy chain <400> 40 Glu Glu Pro Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Leu Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Ser Gly Ser Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Thr Gly Arg Phe Ser Ile Ser Arg Asp Asn Tyr Lys Asn Arg Val Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Ala Asp Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Ala Lys Thr Tyr Pro Thr Trp Gly Gly Val Val Ile Gly Ala Ile Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 41 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region <400> 41 Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gln Arg Trp 20 25 30 Leu Ala Trp His Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile 35 40 45 His Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Gly His Ala Ser 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 42 <211> 454 <212> PRT <213> Artificial Sequence <220> <223> Full Length Heavy Chain <400> 42 Glu Glu Pro Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Leu Tyr 20 25 30 Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu He Ser Gly Ser Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Thr Gly Arg Phe Ser He Ser Arg Asp Asn Tyr Lys Asn Arg Val Tyr 65 70 75 80 Leu Gin Met Asp Ser Leu Arg Ala Asp Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Ala Lys Thr Tyr Pro Thr Trp Gly Gly Val Val He Gly Ala He Asp 100 105 110 Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro He Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg Glu 340 345 350 Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <210> 43 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Full Length Light Chain <400> 43 Asp Ile Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gin Ser Ile Gin Arg Trp 20 25 30 Leu Ala Trp His Gin Gin Lys Pro Gly Arg Ala Pro Lys Val Leu Ile 35 40 45 His Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Gly His Ala Ser 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160 Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 44 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Complementarity-determining region 2 of heavy chain <400> 44 Leu Ile Ser Gly Ser Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 45 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Variable region of heavy chain <400> 45 Glu Glu Pro Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Leu Tyr 20 25 30 Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Ser Gly Ser Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ser lie Ser Arg Asp Asn Ser Lys Asn Arg Val Tyr 65 70 75 80 Leu Gin Met Ser Ser Leu Arg Ala Asp Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Ala Lys Thr Tyr Pro Thr Trp Gly Gly Val Val lie Gly Ala lie Asp 100 105 110 Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 46 <211> 454 <212> PRT <213> Artificial Sequence <220> <223> Full Length Heavy Chain <400> 46 Glu Glu Pro Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Leu Tyr 20 25 30 Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu lie Ser Gly Ser Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ser lie Ser Arg Asp Asn Ser Lys Asn Arg Val Tyr 65 70 75 80 Leu Gin Met Ser Ser Leu Arg Ala Asp Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Ala Lys Thr Tyr Pro Thr Trp Gly Gly Val Val Ile Gly Ala Ile Asp 100 105 110 Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <210> 47 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Full Length Light Chain <400> 47 Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gln Arg Trp 20 25 30 Leu Ala Trp His Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile 35 40 45 His Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Gly His Ala Ser 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 48 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Complementarity determining region 3 of light chain <400> 48 Gln Gln Tyr Ser Gly His Ala Ser Thr 1 5 <210> 49 <211> 124 <212> PRT <213> Artificial sequence <220> <223> Complementarity determining region 3 of light chain <400> 49 Glu Glu Pro Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Leu Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Ser Gly Ser Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Arg Val Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Thr Tyr Pro Thr Trp Gly Gly Val Val Ile Gly Ala Ile Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 50 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region <400> 50 Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gln Arg Trp 20 25 30 Leu Ala Trp His Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 His Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly His Ala Ser 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 51 <211> 454 <212> PRT <213> Artificial Sequence <220> <223> Full length heavy chain <400> 51 Glu Glu Pro Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Leu Tyr 20 25 30 Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu He Ser Gly Ser Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Arg Val Tyr 65 70 75 80 Leu Gin Met Ser Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Thr Tyr Pro Thr Trp Gly Gly Val Val He Gly Ala He Asp 100 105 110 Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <210> 52 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Full Length Light Chain <400> 52 Asp Ile Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gin Ser Ile Gin Arg Trp 20 25 30 Leu Ala Trp His Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 His Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Gly His Ala Ser 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160 Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 53 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> qPCR primer <400> 53 ggatgggcag cctatgtatg 20 <210> 54 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> qPCR primer <400> 54 tcatatctgg gtcccctgga 20 <210> 55 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> qPCR probe <400> 55 agggtgtttg atggcacaga 20

Claims

1. An anti-BK virus antibody molecule or an anti-BK virus binding fragment thereof, comprising: a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 21, a heavy chain complementary determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 22, and a heavy chain complementary determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 23; and A light chain variable region (VL) comprising a light chain complementary determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 24, a light chain complementary determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 25, and a light chain complementary determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO:

26.

2. The anti-BK virus antibody molecule or anti-BK virus binding fragment thereof according to claim 1, comprising: (i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 27, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 28, or an amino acid sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 28; or (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence that has at least about 85%, 90%, 95% or 99% sequence identity to SEQ ID NO: 27; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence that has at least about 85%, 90%, 95% or 99% sequence identity to SEQ ID NO:

31.

3. The anti-BK virus antibody molecule or anti-BK virus binding fragment thereof according to claim 1, comprising: (i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 28; or (ii) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

31.

4. A pharmaceutical composition comprising the anti-BK virus antibody molecule or the anti-BK virus binding fragment thereof according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier, excipient or stabilizer.

5. A nucleic acid encoding the antibody heavy chain variable region and light chain variable region of the anti-BK virus antibody molecule or anti-BK virus binding fragment thereof according to any one of claims 1 to 3. An expression vector comprising the nucleic acid according to claim 5 .

7. A host cell comprising the nucleic acid of claim 5 or the expression vector of claim 6.

8. A method for producing an antibody molecule, the method comprising culturing the host cell of claim 7 under conditions suitable for gene expression.

9. A diagnostic composition comprising the anti-BK virus antibody molecule or anti-BK virus binding fragment thereof according to any one of claims 1 to 3.

10. Use of the anti-BK virus antibody molecule or anti-BK virus binding fragment thereof according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for treating or preventing BK virus infection and / or BK virus-associated nephropathy (BKVAN).

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