Compositions and Methods for the Therapy and Diagnosis of Cytomegalovirus

• US 20090324613A1
• Filed: 03/10/2009
• Published: 12/31/2009
• Est. Priority Date: 03/10/2008
• Status: Active Grant

• Current Assignee: Theraclone Sciences, Inc.
• Original Assignee: Spaltudaq Corporation
• Inventors: Olsen, Ole
• Granted Patent: US 7,982,012 B2
• Time in Patent Office: Days
• US Class Current: 424/159.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/42 viral
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/089 Cytomegalovirus
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/045 Cytomegalovirus
• CPC Class Codes: G01N 33/56994 Herpetoviridae, e.g. cytomegalovirus, Epstein-Barr virus

Abstract

The present invention provides novel anti-cytomegalovirus antibodies and related compositions and methods. These antibodies may be used in the diagnosis, prevention, and treatment of cytomegalovirus infection.

Claims

1. An isolated anti-CMV antibody or fragment thereof, wherein said antibody comprises:

I;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of SNHGIH (SEQ ID NO;

     36);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISSDGDDDRYADSVKG (SEQ ID NO;

     37);

(iii) a V_H CDR3 region comprising the amino acid sequence of DGRCGEPKCYSGLPDY (SEQ ID NO;

     38); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGGYLA (SEQ ID NO;

     43);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASNRAT (SEQ ID NO;

     44);

(iii) a V_L CDR3 region comprising the amino acid sequence of LQRNTWPPLT (SEQ ID NO;

     45);

II;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of SNYGMH (SEQ ID NO;

     48);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISSDGSNEHYADSVKG (SEQ ID NO;

     49);

(iii) a V_H CDR3 region comprising the amino acid sequence of DGRCPDVNCYSGLIDY (SEQ ID NO;

     50); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGRYLA (SEQ ID NO;

     53);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASNRAT (SEQ ID NO;

     44);

(iii) a V_L CDR3 region comprising the amino acid sequence of QQRSNWPPLT (SEQ ID NO;

     54);

III;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of SSNGIH (SEQ ID NO;

     57);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISSDANDKQYADSVKG (SEQ ID NO;

     58);

(iii) a V_H CDR3 region comprising the amino acid sequence of DGTCSGGNCYSGLIDY (SEQ ID NO;

     59); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGGYLA (SEQ ID NO;

     43);

(ii) a V_L CDR2 region comprising the amino acid sequence of ASIRAT (SEQ ID NO;

     64);

(iii) a V_L CDR3 region comprising the amino acid sequence of HQRSNWPPLT (SEQ ID NO;

     65);

IV;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of SNHGIH (SEQ ID NO;

     36);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISKDGTNAHYADSVRG (SEQ ID NO;

     68);

(iii) a V_H CDR3 region comprising the amino acid sequence of EGRCIEENCYSGQIDY (SEQ ID NO;

     69); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGRYMA (SEQ ID NO;

     74);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASIRAT (SEQ ID NO;

     75);

(iii) a V_L CDR3 region comprising the amino acid sequence of QQRSSWPPLT (SEQ ID NO;

     76);

V;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of SNHGIH (SEQ ID NO;

     36);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISKDGTNAHYADSVRGR (SEQ ID NO;

     79);

(iii) a V_H CDR3 region comprising the amino acid sequence of EGRCIEEKCYSGQIDY (SEQ ID NO;

     80); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGRYMA (SEQ ID NO;

     74);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASIRAT (SEQ ID NO;

     75);

(iii) a V_L CDR3 region comprising the amino acid sequence of QQRSSWPPLT (SEQ ID NO;

     76);

VI;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of SDYGMH (SEQ ID NO;

     85);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISKDGTNTHYADSVRG (SEQ ID NO;

     86);

(iii) a V_H CDR3 region comprising the amino acid sequence of DGKCPDLKCYSGLIDY (SEQ ID NO;

     87);

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGGYLA (SEQ ID NO;

     43);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASKRAT (SEQ ID NO;

     92);

(iii) a V_L CDR3 region comprising the amino acid sequence of HQRSSWPPLT (SEQ ID NO;

     93);

VII;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of SXXGXH (SEQ ID NO;

     95), SXXGIH (SEQ ID NO;

     98), or SXYGMH (SEQ ID NO;

     101);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISXDXXXXXYADSVRG (SEQ ID NO;

     96) or VISXDGXNXHYADSVXG (SEQ ID NO;

     99);

(iii) a V_H CDR3 region comprising the amino acid sequence of DGXCSXXXCYSGLXDY (SEQ ID NO;

     100), EGRCIEEXCYSGQIDY (SEQ

ID NO;

     102), or DGXCPDXXCYSGLIDY (SEQ ID NO;

     103); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGXYXA (SEQ ID NO;

     111) or RASQSVGXYLA (SEQ ID NO;

     114);

(ii) a V_L CDR2 region comprising the amino acid sequence of XASXRAT (SEQ ID NO;

     112) or DASXRAT (SEQ ID NO;

     115);

(iii) a V_L CDR3 region comprising the amino acid sequence of XQRXXWPPLT (SEQ ID NO;

     113), HQRSXWPPLT (SEQ ID NO;

     116), or QQRSXWPPLT (SEQ ID NO;

     117).

4. The anti-CMV antibody of claim 1, wherein said antibody binds an epitope of the glycoprotein b (gB) envelope protein of the CMV virus.

5. The anti-CMV antibody of claim 4, wherein said epitope comprises the antigenic determinant 2 site 1 of gB, gp116.

6. A composition comprising the antibody of claim 1.

7. The composition of claim 6, further comprising an anti-viral treatment.

8. The composition of claim 7, wherein said anti-viral treatment is ganciclovir, foscarnet, cidofovir, valganciclovir, and intravenous immunoglobulin (IVIG).

9. The composition of claim 6, further comprising a second anti-CMV antibody.

10. The antibody of claim 1, wherein said antibody is operably-linked to a therapeutic agent or a detectable label.

11. A method for the treatment or prevention of a CMV infection in a subject, comprising administering to the subject the composition of claim 6.

12. The method of claim 11, wherein the method further comprises administering an anti-viral treatment.

13. The method of claim 11, wherein said anti-viral treatment is ganciclovir, foscarnet, cidofovir, valganciclovir, and intravenous immunoglobulin (IVIG).

14. The method of claim 11, wherein said antibody is administered prior to or after exposure to CMV.

15. The method of claim 11, wherein said antibody is administered at a dose sufficient to neutralize CMV infection.

16. A method for determining the presence of a CMV infection in a patient, comprising the steps of:

(a) contacting a biological sample obtained from the patient with the antibody according to claim 1;

(b) detecting an amount of the antibody that binds to the biological sample; and

(c) comparing the amount of antibody that binds to the biological sample to a control value, and therefrom determining the presence of the influenza virus in the patient.

17. A diagnostic kit comprising the antibody according to claim 1.

2. An isolated anti-CMV antibody or fragment thereof, wherein said antibody comprises:

I;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of GFTFSN (SEQ ID NO;

     39);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISSDGDDDR (SEQ ID NO;

     40);

(iii) a V_H CDR3 region comprising the amino acid sequence of DGRCGEPKCYSGLPDY (SEQ ID NO;

     38); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGGYLA (SEQ ID NO;

     43);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASNRAT (SEQ ID NO;

     44);

(iii) a V_L CDR3 region comprising the amino acid sequence of LQRNTWPPLT (SEQ ID NO;

     45);

II;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of GLTFSN (SEQ ID NO;

     118);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISSDGSNEH (SEQ ID NO;

     51);

(iii) a V_H CDR3 region comprising the amino acid sequence of DGRCPDVNCYSGLIDY (SEQ ID NO;

     50); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGRYLA (SEQ ID NO;

     53);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASNRAT (SEQ ID NO;

     44);

(iii) a V_L CDR3 region comprising the amino acid sequence of QQRSNWPPLT (SEQ ID NO;

     54);

III;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of GFTFSS (SEQ ID NO;

     60);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISSDANDKQ (SEQ ID NO;

     61);

(iii) a V_H CDR3 region comprising the amino acid sequence of DGTCSGGNCYSGLIDY (SEQ ID NO;

     59); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGGYLA (SEQ ID NO;

     43);

(ii) a V_L CDR2 region comprising the amino acid sequence of ASIRAT (SEQ ID NO;

     64);

(iii) a V_L CDR3 region comprising the amino acid sequence of HQRSNWPPLT (SEQ ID NO;

     65);

IV;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of KFIFSN (SEQ ID NO;

     70);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISKDGTNAH (SEQ ID NO;

     71);

(iii) a V_H CDR3 region comprising the amino acid sequence of EGRCIEENCYSGQIDY (SEQ ID NO;

     69); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGRYMA (SEQ ID NO;

     74);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASIRAT (SEQ ID NO;

     75);

(iii) a V_L CDR3 region comprising the amino acid sequence of QQRSSWPPLT (SEQ ID NO;

     76);

V;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of KFIFSN (SEQ ID NO;

     70);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISKDGTNAH (SEQ ID NO;

     71);

(iii) a V_H CDR3 region comprising the amino acid sequence of EGRCIEEKCYSGQIDY (SEQ ID NO;

     80); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGRYMA (SEQ ID NO;

     74);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASIRAT (SEQ ID NO;

     75);

(iii) a V_L CDR3 region comprising the amino acid sequence of QQRSSWPPLT (SEQ ID NO;

     76);

VI;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of GLTFSD (SEQ ID NO;

     88);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISKDGTNTH (SEQ ID NO;

     89);

(iii) a V_H CDR3 region comprising the amino acid sequence of DGKCPDLKCYSGLIDY (SEQ ID NO;

     87); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGGYLA (SEQ ID NO;

     43);

(ii) a V_L CDR2 region comprising the amino acid sequence of DASKRAT (SEQ ID NO;

     92);

(iii) a V_L CDR3 region comprising the amino acid sequence of HQRSSWPPLT (SEQ ID NO;

     93);

VII;

(a) a V_H region comprising

(i) a V_H CDR1 region comprising the amino acid sequence of XXXFSX (SEQ ID NO;

     104) or GXTFSX (SEQ ID NO;

     107);

(ii) a V_H CDR2 region comprising the amino acid sequence of VISXDXXXXX (SEQ ID NO;

     105) or VISKDGTNXH (SEQ NO;

     108);

(iii) a V_H CDR3 region comprising the amino acid sequence of XGXCXXXXCYSGXXDY (SEQ ID NO;

     106), DGXCXXXXCYSGLXDY (SEQ ID NO;

     109), or EGRCIEEXCYSGQIDY (SEQ ID NO;

     110); and

(b) a V_L region comprising

(i) a V_L CDR1 region comprising the amino acid sequence of RASQSVGXYXA (SEQ ID NO;

     111) or RASQSVGXYLA (SEQ ID NO;

     114);

(ii) a V_L CDR2 region comprising the amino acid sequence of XASXRAT (SEQ ID NO;

     112) or DASXRAT (SEQ ID NO;

     115);

(iii) a V_L CDR3 region comprising the amino acid sequence of XQRXXWPPLT (SEQ ID NO;

     113), HQRSXWPPLT (SEQ ID NO;

     116), or QQRSXWPPLT (SEQ ID NO;

     117).

3. An isolated anti-CMV antibody comprising:

a) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO;

35 and a light chain sequence comprising amino acid sequence SEQ ID NO;

42 or;

b) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO;

47 and a light chain sequence comprising amino acid sequence SEQ ID NO;

52 or;

c) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO;

56 and a light chain sequence comprising amino acid sequence SEQ ID NO;

63 or;

d) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO;

67 and a light chain sequence comprising amino acid sequence SEQ ID NO;

73 or;

e) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO;

78 and a light chain sequence comprising amino acid sequence SEQ ID NO;

82 or;

f) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO;

84 and a light chain sequence comprising amino acid sequence SEQ ID NO;

91.