Methods of preventing and treating RSV infections and related conditions

• US 20060115485A1
• Filed: 10/31/2005
• Published: 06/01/2006
• Est. Priority Date: 10/29/2004
• Status: Abandoned Application

• Current Assignee: Medimmune LLC (Astrazeneca PLC)
• Original Assignee: Medimmune Incorporated (Astrazeneca PLC)
• Inventors: Wu, Herren, Losonsky, Genevieve, Dall'Acqua, William, Connor, Edward M., Young, James F.
• Application Number:
  US11/263,230
• Publication Number:
  US 20060115485A1
• Time in Patent Office: Days
• US Class Current: 424/159.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/543 intranasal
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07K 16/1027 Paramyxoviridae, e.g. respiratory syncytial virus
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/72 : Increased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention provides methods for preventing, managing, treating and/or ameliorating a Respiratory Syncytial Virus (RSV) infection (e.g., acute RSV disease, or a RSV upper respiratory tract infection (URI) and/or lower respiratory tract infection (LRI)), otitis media (preferably, stemming from, caused by or associated with a RSV infection, such as a RSV URI and/or LRI), and/or a symptom or respiratory condition relating thereto (e.g., asthma, wheezing, and/or reactive airway disease (RAD)) in a subject, comprising administering to said human an effective amount of one or more antibodies that immunospecifically bind to one or more RSV antigens with a high affinity and/or high avidity. In some embodiments, one or more antibodies comprise a modified IgG constant domain, or FcRn-binding fragment thereof resulting in longer in vivo serum half-life. In particular embodiments the methods of the invention comprising administering to subject an effective amount of one or more modified antibodies that immunospecifically bind to one or more RSV antigens with an association rate (k_on) of at least 2×10⁵ M⁻¹s⁻¹ and a dissociation rate (k_off) of less than 5×10⁻⁴ s⁻¹.

Claims

1. A method of preventing the progression of a RSV infection from the upper respiratory tract to the lower respiratory tract, the method comprising administering to a patient an effective amount of an antibody that immunospecifically binds to a RSV F antigen, said antibody comprising:

(a) a heavy chain comprising;

(1) a heavy chain variable (VH) domain having the amino acid sequence SEQ ID NO;

48,

(2) a VH chain having the amino acid sequence SEQ ID NO;

254;

(3) a VH CDR1 having the amino acid sequence SEQ ID NO;

10;

(4) a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19;

(5) a VH CDR3 having the amino acid sequence SEQ ID NO;

20;

(6) a VH CDR1 having the amino acid sequence SEQ ID NO;

10 and a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19;

(7) a VH CDR1 having the amino acid sequence SEQ ID NO;

10 and a VH CDR3 having the amino acid sequence SEQ ID NO;

20;

(8) a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19 and a VH CDR3 having the amino acid sequence SEQ ID NO;

20;

or

(9) a VH CDR1 having the amino acid sequence SEQ ID NO;

10, a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19, and a VH CDR3 having the amino acid sequence SEQ ID NO;

20; and

/or

(b) a light chain comprising;

(1) a light chain variable (VL) domain having the amino acid sequence SEQ ID NO;

11,

(2) a VL chain having the amino acid sequence SEQ ID NO;

255;

(3) a VL CDR1 having the amino acid sequence SEQ ID NO;

39;

(4) a VL CDR1 having the amino acid sequence SEQ ID NO;

39 and a VL CDR2 sequence having the amino acid sequence SEQ ID NO;

5;

(5) a VL CDR1 having the amino acid sequence SEQ ID NO;

39 and a VL CDR3 having the amino acid sequence SEQ ID NO;

6;

or

(6) a VL CDR1 having the amino acid sequence SEQ ID NO;

39, a VL CDR2 sequence having the amino acid sequence SEQ ID NO;

5, and a VL CDR3 having the amino acid sequence SEQ ID NO;

6.

4. The method of claim 1, 2 or 3 wherein antibody comprises an IgG constant domain.

5. The method of claim 4, wherein the IgG constant domain is a human IgG1 constant domain.

6. The method of claim 5, wherein the IgG1 constant domain comprises a tyrosine at position 252, a threonine at position 254 is a threonine, and a glutamic acid at position 256, numbered according to the EU Index as in Kabat et al. (1991). Sequences of proteins of immunological interest. (U.S. Department of Health and Human Services, Washington, D.C.) 5^th ed.

7. The method of claim 6, wherein the in vivo half-life of the antibody is extended by about two-fold, about three-fold, about four-fold, about five-fold, about six-fold, about seven-fold, about eight-fold, about nine-fold, or about ten fold as compared to the same antibody comprising an IgG1 constant domain without a tyrosine at position 252, a threonine at position 254 is a threonine, and a glutamic acid at position 256.

8. The method of claim 1, 2 or 3, wherein the antibody comprises a VH chain having the amino acid sequence SEQ ID NO:

254 and a VL chain having the amino acid sequence SEQ ID NO;

255.

9. The method of claim 8, wherein the VH chain constant domain comprises a tyrosine at position 252, a threonine at position 254 is a threonine, and a glutamic acid at position 256, numbered according to the EU Index as in Kabat et al.

10. The method of claim 1, 2, or 3, wherein the antibody has reduced or no cross-reactivity with a human tissue sample as compared to a second antibody.

11. The method of claim 10, wherein the second antibody is an A4B4 antibody or wherein the second antibody is a human IgG1 monoclonal antibody directed against an antigen other than RSV.

12. The method of claim 11, wherein the tissue sample is skin or lung.

13. The method of claim 1, 2 or 3, wherein the antibody has an association rate (k_on) of at least about 2×

10⁵ M<sup>−

1</sup>s<sup>−

1</sup>.

14. The method of claim 13, wherein the k_on is at least about 4×

10⁵ M<sup>−

1</sup>s<sup>−

1</sup>.

15. The method of claim 13, wherein the k_on is at least about 5×

10⁵ M<sup>−

1</sup>s<sup>−

1</sup>.

16. The method of claim 13, wherein the k_on is at least about 7.5×

10⁵ s<sup>−

1</sup>.

17. The method of claim 1, 2 or 3, wherein the antibody has a dissociation rate (k_off) of less than about 5×

10<sup>−

4</sup> s<sup>−

1</sup>.

18. The method of claim 1, 2 or 3, wherein the antibody has a dissociation constant (K_d) of less than about 1000 pM.

19. The method of claim 18, wherein the K_d is about 50 pM.

20. The method of claim 1, 2 or 3, wherein the antibody has an association constant of (K_a) of at least about 10⁹ M⁻

1.

21. The method of claim 20, wherein the K_a is at least about 10¹⁰ M⁻

1.

22. The method of claim 19, wherein the K_a is at least about 10¹¹ M⁻

1.

23. The method of claim 1, 2 or 3, wherein the effective amount is selected from the group consisting of about 30 mg/kg, about 25 mg/kg, about 20 mg/kg, about 15 mg/kg, about 10 mg/kg, about 5 mg/kg, about 3 mg/kg, about 1.5 mg/kg, about 1 mg/kg, about 0.75 mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about 0.05 mg/kg, and 0.025 mg/kg.

24. The method of claim 6, wherein the effective amount is selected from the group consisting of about 30 mg/kg, about 25 mg/kg, about 20 mg/kg, about 15 mg/kg, about 10 mg/kg, about 5 mg/kg, about 3 mg/kg, about 1.5 mg/kg, about 1 mg/kg, about 0.75 mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about 0.05 mg/kg, and 0.025 mg/kg.

25. The method of claim 1, 2 or 3, wherein the patient is a human patient.

26. The method of claim 6, wherein the patient is a human patient.

27. The method of claim 25, wherein the human is human who has had a bone marrow transplant, an elderly human, or a human who has cystic fibrosis, bronchopulmonary dysplasia, congenital heart disease, congenital immunodeficiency or acquired immunodeficiency.

28. The method of claim 26, wherein the human is human who has had a bone marrow transplant, an elderly human, or a human who has cystic fibrosis, bronchopulmonary dysplasia, congenital heart disease, congenital immunodeficiency or acquired immunodeficiency.

29. The method of claim 25, wherein the human is a human infant or a human infant born prematurely.

30. The method of claim 26, wherein the human is a human infant or a human infant born prematurely.

31. The method of claim 1, 2 or 3, wherein the antibody is administered to the patient by intranasal delivery, intramuscular delivery, intradermal delivery, intraperitoneal delivery, intravenous delivery, subcutaneous delivery, oral delivery, pulmonary delivery or combinations thereof.

32. The method of claim 6, wherein the antibody is administered to the patient intranasal delivery, intramuscular delivery, intradermal delivery, intraperitoneal delivery, intravenous delivery, subcutaneous delivery, oral delivery, pulmonary delivery or combinations thereof.

33. The method of claim 1, 2 or 3, wherein the antibody is administered to the patient five times, four times, three times, two times or one time during a RSV season.

34. The method of claim 6, wherein the antibody is administered to the patient five times, four times, three times, two times or one time during a RSV season.

35. The method of claim 1, 2 or 3, wherein the antibody is administered to the patient three times, two times, or one time within three months, two months, or one month prior to a RSV season.

36. The method of claim 6, wherein the antibody is administered to the patient three times, two times, or one time within three months, two months, or one month prior to a RSV season.

37. The method of claim 1 or 2, wherein the antibody is administered to the patient by intranasal delivery, and wherein the effective amount is selected from the group consisting of about 15 mg/kg, about 10 mg/kg, about 5 mg/kg, about 3 mg/kg, about 1.5 mg/kg, about 1 mg/kg, about 0.75 mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about 0.05 mg/kg, and 0.025 mg/kg.

38. The method of claim 6, wherein the antibody is administered to the patient by intranasal delivery, and wherein the effective amount is selected from the group consisting of about 15 mg/kg, about 10 mg/kg, about 5 mg/kg, about 3 mg/kg, about 1.5 mg/kg, about 1 mg/kg, about 0.75 mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about 0.05 mg/kg, and 0.025 mg/kg.

39. The method of claim 37, wherein the antibody is administered 1, 2, 3, 4, 5 or 6 times per day.

40. The method of claim 38, wherein the antibody is administered 1, 2, 3, 4, 5 or 6 times per day.

41. The method of claim 39, wherein the antibody is administered 1, 2, 3, 4, 5 or 6 times per day for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or 14 days.

42. The method of claim 40, wherein the antibody is administered 1, 2, 3, 4, 5 or 6 times per day for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or 14 days.

2. A method of preventing, managing, treating and/or ameliorating an RSV upper respiratory tract infection or otitis media, or a symptom thereof, the method comprising administering to a patient an effective amount of an antibody that immunospecifically binds to a RSV F antigen, said antibody comprising:

(a) a heavy chain comprising;

(1) a heavy chain variable (VH) domain having the amino acid sequence SEQ ID NO;

48,

(2) a VH chain having the amino acid sequence SEQ ID NO;

254;

(3) a VH CDR1 having the amino acid sequence SEQ ID NO;

10;

(4) a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19;

(5) a VH CDR3 having the amino acid sequence SEQ ID NO;

20;

(6) a VH CDR1 having the amino acid sequence SEQ ID NO;

10 and a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19;

(7) a VH CDR1 having the amino acid sequence SEQ ID NO;

10 and a VH CDR3 having the amino acid sequence SEQ ID NO;

20;

(8) a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19 and a VH CDR3 having the amino acid sequence SEQ ID NO;

20;

or

(9) a VH CDR1 having the amino acid sequence SEQ ID NO;

10, a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19, and a VH CDR3 having the amino acid sequence SEQ ID NO;

20; and

/or

(b) a light chain comprising;

(1) a light chain variable (VL) domain having the amino acid sequence SEQ ID NO;

11,

(2) a VL chain having the amino acid sequence SEQ ID NO;

255;

(3) a VL CDR1 having the amino acid sequence SEQ ID NO;

39;

(4) a VL CDR1 having the amino acid sequence SEQ ID NO;

39 and a VL CDR2 sequence having the amino acid sequence SEQ ID NO;

5;

(5) a VL CDR1 having the amino acid sequence SEQ ID NO;

39 and a VL CDR3 having the amino acid sequence SEQ ID NO;

6;

or

(6) a VL CDR1 having the amino acid sequence SEQ ID NO;

39, a VL CDR2 sequence having the amino acid sequence SEQ ID NO;

5, and a VL CDR3 having the amino acid sequence SEQ ID NO;

6.

3. A method of preventing, managing, treating and/or ameliorating RSV disease or a symptom thereof, the method comprising administering to a patient an effective amount of an antibody that immunospecifically binds to a RSV F antigen, said antibody comprising:

(a) a heavy chain comprising;

(1) a heavy chain variable (VH) domain having the amino acid sequence SEQ ID NO;

48,

(2) a VH chain having the amino acid sequence SEQ ID NO;

254;

(3) a VH CDR1 having the amino acid sequence SEQ ID NO;

10;

(4) a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19;

(5) a VH CDR3 having the amino acid sequence SEQ ID NO;

20;

(6) a VH CDR1 having the amino acid sequence SEQ ID NO;

10 and a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19;

(7) a VH CDR1 having the amino acid sequence SEQ ID NO;

10 and a VH CDR3 having the amino acid sequence SEQ ID NO;

20;

(8) a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19 and a VH CDR3 having the amino acid sequence SEQ ID NO;

20;

or

(9) a VH CDR1 having the amino acid sequence SEQ ID NO;

10, a VH CDR2 sequence having the amino acid sequence SEQ ID NO;

19, and a VH CDR3 having the amino acid sequence SEQ ID NO;

20; and

/or

(b) a light chain comprising;

(1) a light chain variable (VL) domain having the amino acid sequence SEQ ID NO;

11,

(2) a VL chain having the amino acid sequence SEQ ID NO;

255;

(3) a VL CDR1 having the amino acid sequence SEQ ID NO;

39;

(4) a VL CDR1 having the amino acid sequence SEQ ID NO;

39 and a VL CDR2 sequence having the amino acid sequence SEQ ID NO;

5;

(5) a VL CDR1 having the amino acid sequence SEQ ID NO;

39 and a VL CDR3 having the amino acid sequence SEQ ID NO;

6;

or

(6) a VL CDR1 having the amino acid sequence SEQ ID NO;

39, a VL CDR2 sequence having the amino acid sequence SEQ ID NO;

5, and a VL CDR3 having the amino acid sequence SEQ ID NO;

6.