Neutralizing monoclonal anti-VP1 antibodies to BK virus

1 . An isolated anti-VP1 antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) having three complementarity determining regions (CDRs) of HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) having three CDRs of LCDR1, LCDR2, and LCDR3, wherein:

(a) HCDR1 comprises SEQ ID NO: 113,

HCDR2 comprises SEQ ID NO: 114,

HCDR3 comprises SEQ ID NO: 115,

LCDR1 comprises SEQ ID NO: 116,

LCDR2 comprises SEQ ID NO: 117, and

LCDR3 comprises SEQ ID NO: 118;

(b) HCDR1 comprises SEQ ID NO: 97,

HCDR2 comprises SEQ ID NO: 98,

HCDR3 comprises SEQ ID NO: 99, 131, or 139,

LCDR1 comprises SEQ ID NO: 100,

LCDR2 comprises SEQ ID NO: 101, and

LCDR3 comprises SEQ ID NO: 102;

(c) HCDR1 comprises SEQ ID NO: 1,

HCDR2 comprises SEQ ID NO: 2,

HCDR3 comprises SEQ ID NO: 3,

LCDR1 comprises SEQ ID NO: 4,

LCDR2 comprises SEQ ID NO: 5, and

LCDR3 comprises SEQ ID NO: 6;

(d) HCDR1 comprises SEQ ID NO: 9,

HCDR2 comprises SEQ ID NO: 10,

HCDR3 comprises SEQ ID NO: 11,

LCDR1 comprises SEQ ID NO: 12,

LCDR2 comprises SEQ ID NO: 13, and

LCDR3 comprises SEQ ID NO: 14;

(e) HCDR1 comprises SEQ ID NO: 17,

HCDR2 comprises SEQ ID NO: 18,

HCDR3 comprises SEQ ID NO: 19,

LCDR1 comprises SEQ ID NO: 20,

LCDR2 comprises SEQ ID NO: 21, and

LCDR3 comprises SEQ ID NO: 22;

(f) HCDR1 comprises SEQ ID NO: 25,

HCDR2 comprises SEQ ID NO: 26,

HCDR3 comprises SEQ ID NO: 27,

LCDR1 comprises SEQ ID NO: 28,

LCDR2 comprises SEQ ID NO: 29, and

LCDR3 comprises SEQ ID NO: 30;

(g) HCDR1 comprises SEQ ID NO: 33,

HCDR2 comprises SEQ ID NO: 34,

HCDR3 comprises SEQ ID NO: 35,

LCDR1 comprises SEQ ID NO: 36,

LCDR2 comprises SEQ ID NO: 37, and

LCDR3 comprises SEQ ID NO: 38;

(h) HCDR1 comprises SEQ ID NO: 41,

HCDR2 comprises SEQ ID NO: 42,

HCDR3 comprises SEQ ID NO: 43,

LCDR1 comprises SEQ ID NO: 44,

LCDR2 comprises SEQ ID NO: 45, and

LCDR3 comprises SEQ ID NO: 46;

(i) HCDR1 comprises SEQ ID NO: 49,

HCDR2 comprises SEQ ID NO: 50,

HCDR3 comprises SEQ ID NO: 51,

LCDR1 comprises SEQ ID NO: 52,

LCDR2 comprises SEQ ID NO: 53, and

LCDR3 comprises SEQ ID NO: 54;

(j) HCDR1 comprises SEQ ID NO: 65,

HCDR2 comprises SEQ ID NO: 66,

HCDR3 comprises SEQ ID NO: 67,

LCDR1 comprises SEQ ID NO: 68,

LCDR2 comprises SEQ ID NO: 69, and

LCDR3 comprises SEQ ID NO: 70;

(k) HCDR1 comprises SEQ ID NO: 73,

HCDR2 comprises SEQ ID NO: 74,

HCDR3 comprises SEQ ID NO: 75,

LCDR1 comprises SEQ ID NO: 76,

LCDR2 comprises SEQ ID NO: 77, and

LCDR3 comprises SEQ ID NO: 78;

(l) HCDR1 comprises SEQ ID NO: 81,

HCDR2 comprises SEQ ID NO: 82,

HCDR3 comprises SEQ ID NO: 83,

LCDR1 comprises SEQ ID NO: 84,

LCDR2 comprises SEQ ID NO: 85, and

LCDR3 comprises SEQ ID NO: 86;

(m) HCDR1 comprises SEQ ID NO: 89,

HCDR2 comprises SEQ ID NO: 90,

HCDR3 comprises SEQ ID NO: 91,

LCDR1 comprises SEQ ID NO: 92,

LCDR2 comprises SEQ ID NO: 93, and

LCDR3 comprises SEQ ID NO: 94;

(n) HCDR1 comprises SEQ ID NO: 105,

HCDR2 comprises SEQ ID NO: 106,

HCDR3 comprises SEQ ID NO: 107,

LCDR1 comprises SEQ ID NO: 108,

LCDR2 comprises SEQ ID NO: 109, and

LCDR3 comprises SEQ ID NO: 110;

(o) HCDR1 comprises SEQ ID NO: 121,

HCDR2 comprises SEQ ID NO: 122,

HCDR3 comprises SEQ ID NO: 123,

LCDR1 comprises SEQ ID NO: 124,

LCDR2 comprises SEQ ID NO: 125, and

LCDR3 comprises SEQ ID NO: 126;

(p) HCDR1 comprises SEQ ID NO: 145,

HCDR2 comprises SEQ ID NO: 146,

HCDR3 comprises SEQ ID NO: 147,

LCDR1 comprises SEQ ID NO: 148,

LCDR2 comprises SEQ ID NO: 149, and

LCDR3 comprises SEQ ID NO: 150;

(q) HCDR1 comprises SEQ ID NO: 153,

HCDR2 comprises SEQ ID NO: 154,

HCDR3 comprises SEQ ID NO: 155,

LCDR1 comprises SEQ ID NO: 156,

LCDR2 comprises SEQ ID NO: 157, and

LCDR3 comprises SEQ ID NO: 158;

(r) HCDR1 comprises SEQ ID NO: 161,

HCDR2 comprises SEQ ID NO: 162,

HCDR3 comprises SEQ ID NO: 163,

LCDR1 comprises SEQ ID NO: 164,

LCDR2 comprises SEQ ID NO: 165, and

LCDR3 comprises SEQ ID NO: 166;

(s) HCDR1 comprises SEQ ID NO: 169,

HCDR2 comprises SEQ ID NO: 170,

HCDR3 comprises SEQ ID NO: 171,

LCDR1 comprises SEQ ID NO: 172,

LCDR2 comprises SEQ ID NO: 173, and

LCDR3 comprises SEQ ID NO: 174; or

(t) HCDR1 comprises SEQ ID NO: 177,

HCDR2 comprises SEQ ID NO: 178,

HCDR3 comprises SEQ ID NO: 179,

LCDR1 comprises SEQ ID NO: 180,

LCDR2 comprises SEQ ID NO: 181, and

LCDR3 comprises SEQ ID NO: 182.

2 . The isolated antibody or antigen binding fragment thereof of claim 1 , wherein:

(a) the VH comprises at least 90% sequence identity to any one of SEQ ID NO: 7, 15, 23, 31, 39, 47, 55, 23, 71, 79, 87, 95, 103, 111, 119, 127, 135, 143, 151, 159, 167, 175, or 183; and

(b) the VL comprises at least 90% sequence identity to any one of SEQ ID NO: 8, 16, 24, 32, 40, 48, 56, 24, 72, 80, 88, 96, 104, 112, 120, 128, 136, 144, 152, 160,168, 176, or 184.

3 . The isolated antibody or antigen binding fragment thereof of claim 2 , wherein,

(a) VH comprises SEQ ID NO: 119, and VL comprises SEQ ID NO: 120;

(b) VH comprises SEQ ID NO: 103, and VL comprises SEQ ID NO: 104;

(c) VH comprises SEQ ID NO: 135, and VL comprises SEQ ID NO: 136;

(d) VH comprises SEQ ID NO: 143, and VL comprises SEQ ID NO: 144;

(e) VH comprises SEQ ID NO: 7, and VL comprises SEQ ID NO: 8;

(f) VH comprises SEQ ID NO: 15, and VL comprises SEQ ID NO: 16;

(g) VH comprises SEQ ID NO: 31, and VL comprises SEQ ID NO: 32;

(h) VH comprises SEQ ID NO: 39, and VL comprises SEQ ID NO: 40;

(i) VH comprises SEQ ID NO: 47, and VL comprises SEQ ID NO: 48;

(j) VH comprises SEQ ID NO: 55, and VL comprises SEQ ID NO: 56;

(k) VH comprises SEQ ID NO: 23, and VL comprises SEQ ID NO: 24;

(l) VH comprises SEQ ID NO: 71, and VL comprises SEQ ID NO: 72;

(m) VH comprises SEQ ID NO: 79, and VL comprises SEQ ID NO: 80;

(n) VH comprises SEQ ID NO: 87, and VL comprises SEQ ID NO: 88;

(o) VH comprises SEQ ID NO: 95, and VL comprises SEQ ID NO: 96;

(p) VH comprises SEQ ID NO: 111, and VL comprises SEQ ID NO: 112;

(q) VH comprises SEQ ID NO: 127, and VL comprises SEQ ID NO: 128;

(r) VH comprises SEQ ID NO: 151, and VL comprises SEQ ID NO: 152;

(s) VH comprises SEQ ID NO: 159, and VL comprises SEQ ID NO: 160;

(t) VH comprises SEQ ID NO: 167, and VL comprises SEQ ID NO: 168;

(u) VH comprises SEQ ID NO: 175, and VL comprises SEQ ID NO: 176; or

(v) VH comprises SEQ ID NO: 183, and VL comprises SEQ ID NO: 184.

4 . The antibody or antigen binding fragment thereof of claim 1 , wherein the VH of the antibody or antigen binding fragment thereof comprises heavy chain framework regions HFR1, HFR2, HFR3, HFR4, and wherein the VL of the antibody or antigen binding fragment thereof comprises light chain framework regions LFR1, LFR2, LFR3, LFR4, wherein:

(a) the HFR1 region comprises the amino acid sequence of any one of SEQ ID NOs: 185, 193, 197, 205, 213, 226, 234, 241, 250, or 269;

(b) the HFR2 region comprises the amino acid sequence of any one of SEQ ID NOs: 186, 194, 198, 206, 214, 223, 227, 232, 242, or 253;

(c) the HFR3 region comprises the amino acid sequence of any one of SEQ ID NOs: 187, 195, 199, 207, 215, 219, 224, 228, 233, 235, 243, 251, 254, 258, 259, 262, 265, 267, or 270;

(d) the HFR4 region comprises the amino acid sequence of any one of SEQ ID NOs: 188, 200, 208, 220, 229, 236, 244, or 271;

(e) the LFR1 region comprises the amino acid sequence of any one of SEQ ID NOs: 189, 201, 209, 237, 245, 255, or 260;

(f) the LFR2 region comprises the amino acid sequence of any one of SEQ ID NOs: 190, 202, 210, 216, 221, 225, 230, 238, 246, 261, 263, or 272;

(g) the LFR3 region comprises the amino acid sequence of any one of SEQ ID NOs: 191, 196, 203, 211, 217, 222, 230, 239, 247, 249, 252, 256, 264, 266, 268, or 273; and

(h) the LFR4 region comprises the amino acid sequence of any one of SEQ ID NOs: 192, 204, 212, 218, 240, 248, or 257.

5 . The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof further comprises a heavy chain constant (CH) domain and a light chain constant (CL) domain, wherein:

(a) said CH domain is selected from the group consisting of lgG, IgGl, IgG2, IgG2a, IgG2b, IgG2c, IgG3, IgG4, IgA, IgAl, IgA2, IgD, IgM, and IgE constant domains, and comprises a sequence with at least 90% sequence identity to one of SEQ ID NOs: 274-290; and

(b) said CL domain is selected from the group consisting of lg kappa and Ig lambda constant domains, and comprises a sequence with at least 90% sequence identity to one of SEQ ID NOs: 291-301.

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

7 . The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof has reduced glycosylation, no glycosylation, or is hypofucosylated.

8 . A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of claim 1 and a pharmaceutically acceptable excipient.

9 . A method of neutralizing a BK virus infection in a subject in need thereof, the method comprising administering an effective amount of the antibody or antigen binding fragment thereof of claim 1 to the subject.

10 . The method of claim 9 , wherein the subject is diagnosed with BK virus infection or BK viremia.

11 . A method of treating or reducing the likelihood of a BK virus or JC virus associated disorder, the method comprising administering to a subject in need thereof an effective amount of the antibody or antigen binding fragment thereof of claim 1 , wherein the BK virus or JC virus associated disorder is selected from the group consisting of transplant rejection, graft-versus-host disease (GvHD), nephropathy, BKVAN, hemorrhagic cystitis (HC), Progressive Multifocal Leukoencephalopathy (PML), granule cell neuronopathy (GCN), interstitial kidney disease, ureteral stenosis, vasculitis, colitis, retinitis, meningitis, immune reconstitution inflammatory syndrome (IRIS).

12 . The method of claim 11 , wherein the antibody or antigen binding fragment thereof is administered via injection or infusion.

13 . The method of claim 11 , the method further comprising administering an additional therapeutic agent, wherein the therapeutic agent is an immunosuppressive agent.

14 . The method of claim 13 , wherein the immunosuppressive agent is a monophosphate dehydrogenase inhibitor, a purine synthesis inhibitor, a calcineurin inhibitor, or an mTOR inhibitor.

15 . The method of claim 13 , wherein the immunosuppressive agent is mycophenolate mofetil (MMF), mycophenolate sodium, azathioprine, tacrolimus, sirolimus, or cyclosporine.

16 . The method of claim 11 , wherein the therapeutic agent is an additional anti-VP1 antibody.

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

18 . A vector comprising the nucleic acid of claim 17 .

19 . An isolated host cell comprising the vector of claim 18 .

20 . A method of reducing the risk of transplant rejection in a transplant recipient receiving a donor organ, comprising

(i) determining serotype of BK virus present in the donor organ,

(ii) selecting an antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof neutralizes the serotype of BK virus present in the donor organ, and

(iii) administering the selected antibody or antigen binding fragment thereof to the transplant recipient via injection or infusion.