التفاصيل البيبلوغرافية
| العنوان: |
Antibodies against human interleukin-13 and uses therefor |
| Document Number: |
20060063228 |
| تاريخ النشر: |
March 23, 2006 |
| Appl. No: |
11/149309 |
| Application Filed: |
June 09, 2005 |
| مستخلص: |
This application relates to antibodies, e.g., humanized antibodies, and antigen-binding fragments thereof, that bind to interleukin-13 (IL-13), in particular, human IL-13, and their uses in regulating immune responses mediated by IL-13. The antibodies disclosed herein are useful in diagnosing, preventing, and/or treating a subject, e.g., a human patient, one or more IL-13-associated disorders, e.g., respiratory disorders (e.g., asthma); atopic disorders (e.g., allergic rhinitis); inflammatory and/or autoimmune conditions of the skin (e.g., atopic dermatitis), and gastrointestinal organs (e.g., inflammatory bowel diseases (IBD)), as well as fibrotic and cancerous disorders. |
| Inventors: |
Kasaian, Marion T. (Charlestown, MA, US); Tchistiakova, Lioudmila (Andover, MA, US); Veldman, Geertruida M. (Sudbury, MA, US); Marquette, Kimberly Ann (Somerville, MA, US); Tan, Xiang-Yang (Reading, MA, US); Donaldson, Debra D. (Medford, MA, US); Lin, Laura Long (Weston, MA, US); Shane, Tania (Newton, MA, US); Tam, Amy Sze Pui (Medford, MA, US); Feyfant, Eric (Lexington, MA, US); Wood, Nancy L. (Somerville, MA, US); Fitz, Lori J. (Somerville, MA, US); Widom, Angela M. (Acton, MA, US); Parris, Kevin D. (Auburndale, MA, US); Goldman, Samuel J. (Acton, MA, US); Saldanha, Jose W. (Enfield, GB) |
| Claim: |
1. An antibody, or antigen-binding fragment thereof, that binds to IL-13 with a KD of less than 10−7 M and has one or more of the following properties: (a) the heavy chain immunoglobulin variable region comprises a heavy chain CDR3 of mAb13.2 (SEQ ID NO:24), or a heavy chain CDR3 that differs by fewer than 3 amino acid substitutions from a corresponding heavy chain CDR3 of mAb13.2; (b) the light chain immunoglobulin variable region comprises a light chain CDR1 of mAb13.2 (SEQ ID NO:19), or a light chain CDR1 that differs by fewer than 3 amino acid substitutions from a corresponding light chain CDR1 of mAb13.2; (c) the heavy chain immunoglobulin variable region comprises a sequence encoded by a nucleic acid that hybridizes under high stringency conditions to the complement of a nucleic acid encoding a heavy chain variable domain of h13.2 (SEQ ID NO:15, 16, or 36); (d) the light chain immunoglobulin variable region comprises a sequence encoded by a nucleic acid that hybridizes under high stringency conditions to the complement of a nucleic acid encoding a light chain variable domain of h13.2 (SEQ ID NO:11, 12, or 35); (e) the heavy chain immunoglobulin variable region is at least 90% identical a heavy chain variable domain of h13.2 (SEQ ID NO:15, 16, or 36); (f) the light chain immunoglobulin variable region is at least 90% identical a light chain variable domain of h13.2 (SEQ ID NO:11, 12, or 35); (g) the antibody, or antigen-binding fragment thereof, competes with mAb13.2 for binding to human IL-13; (h) the antibody, or antigen-binding fragment thereof, contacts one or more amino acid residues from IL-13 selected from the group consisting of residues 68, 72, 88, 91, 92, 93, and 105 of SEQ ID NO:31; (i) the heavy chain variable region has the same canonical structure as mAb13.2; (j) the light chain variable region has the same canonical structure as mAb13.2; (k) the heavy chain variable region and/or the light chain variable region has FR1, FR2, and FR3 framework regions from VH segments encoded by germline genes DP-54 and DPK-9 respectively or a sequence at least 95% identical to VH segments encoded by germline genes DP-54 and DPK-9; (l) confers a post-injection protective effect against exposure to Ascaris antigen in a sheep model at least 6 weeks after injection. |
| Claim: |
2. The antibody, or antigen-binding fragment thereof, of claim 1 that is purified. |
| Claim: |
3. The antibody, or antigen-binding fragment thereof, of claim 1 that is a recombinant, full length IgG. |
| Claim: |
4. The antibody, or antigen-binding fragment thereof, of claim 1 that is a Fab or scFv. |
| Claim: |
5. The antibody, or antigen-binding fragment thereof, of claim 1 that comprises framework regions that are at least 90% identical to human germline framework regions. |
| Claim: |
6. The antibody, or antigen-binding fragment thereof, of claim 1 that comprises human framework regions, a human Fc region, or both. |
| Claim: |
7. The antibody, or antigen-binding fragment thereof, of claim 1, wherein the heavy chain variable region has the same canonical structure as mAb13.2 (as in (i)), and the heavy chain variable domain comprises at least four IL-13 contacting amino acid residues of mAb13. |
| Claim: |
8. The antibody, or antigen-binding fragment thereof, of claim 1 that binds to human IL-13 with a KD of between 90 and 120 pM. |
| Claim: |
9. The antibody, or antigen-binding fragment thereof, of claim 1 that binds to human IL-13 with a koff of less than 1×10−4 s−1. |
| Claim: |
10. The antibody, or antigen-binding fragment thereof, of claim 1 that binds to human IL-13 with a kon of between 5×104 and 8×105 M−1s−1. |
| Claim: |
11. The antibody, or antigen-binding fragment thereof, of claim 1 that reduces the ability of IL-13 to bind to IL-4Rα. |
| Claim: |
12. The antibody, or antigen-binding fragment thereof, of claim 1 that binds to IL-13 that is in an in vitro complex with IL-13Rα1. |
| Claim: |
13. An isolated, recombinant IgG antibody that comprises two immunoglobulin chains: a light chain that include SEQ ID NO:9, 10, 11, 12, or 35 and a heavy chain that includes SEQ ID NO:13, 14, 15, 16, or 36. |
| Claim: |
14. The isolated, recombinant IgG antibody of claim 13 wherein the heavy chain further includes SEQ ID NO:17 and the light chain further includes SEQ ID NO:18. |
| Claim: |
15. An antibody, or antigen-binding fragment thereof, that has one or more of the following properties: (a) it specifically binds to an epitope comprising residues 81-93 or 114-132 of human IL-13 (SEQ ID NO:31), or a conservatively substituted form thereof; (b) it specifically binds to an epitope of human IL-13 comprising one or more of the following amino acid residues: Glutamate at position 49, Asparagine at position 53, Glycine at position 69, Proline at position 72, Histidine at position 73, Lysine at position 74, and Arginine at position 86 of SEQ ID NO:32, or a conservative amino acid substitution thereof; (c) it binds to a complex of IL-13 and IL13Rα1; (d) it interferes with a binding interaction between IL-13 and IL-4Rα; (e) it interferes with a binding interaction between IL-13/IL-13Rα1 and IL-4Rα; and (f) it binds specifically to human IL-13 and competitively inhibits the binding of a second antibody to said human, wherein said second antibody is chosen from mAb13.2, ch13.2, h13.2v1, h13.2v2, or h13.2v3. |
| Claim: |
16. The antibody, or antigen-binding fragment thereof, of claim 15 having a constant region mutated to decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function. |
| Claim: |
17. The antibody, or antigen-binding fragment thereof, of claim 15, further comprising a human IgG1 constant region mutated at one or more residues 116 and 119 of SEQ ID NO:17. |
| Claim: |
18. The antibody, or antigen-binding fragment thereof, of claim 15, further comprising a human kappa light chain. |
| Claim: |
19. The antibody, or antigen-binding fragment thereof, of claim 15, further comprising at least one complementarity determining region comprising an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO:19, the amino acid sequence of SEQ ID NO:20, the amino acid sequence of SEQ ID NO:21, the amino acid sequence of SEQ ID NO:22, the amino acid sequence of SEQ ID NO:23, the amino acid sequence of SEQ ID NO:24. |
| Claim: |
20. The antibody, or antigen-binding fragment thereof, of claim 15, wherein the fragment is an scFv, Fab, or a F(ab′)2 fragment. |
| Claim: |
21. The antibody, or antigen-binding fragment thereof, of claim 15, further comprising a light chain comprising a human kappa constant region, or an active fragment thereof, and a heavy chain comprising a human IgG constant region, or an active fragment thereof. |
| Claim: |
22. The antibody, or antigen-binding fragment thereof, of claim 21, wherein the human kappa constant region of said light chain comprises the amino acid sequence of SEQ ID NO:18, or an active fragment thereof. |
| Claim: |
23. The antibody, or antigen-binding fragment thereof, of claim 21, wherein the human IgG constant region of said heavy chain is mutated to reduce FcR and complement binding. |
| Claim: |
24. The antibody, or antigen-binding fragment thereof, of claim 23, wherein the mutated human IgG constant region of said heavy chain comprises the amino acid sequence of SEQ ID NO:17, or an active fragment thereof. |
| Claim: |
25. A pharmaceutical composition comprising the antibody, or antigen-binding fragment thereof, of claim 1 or 15 and a pharmaceutically acceptable carrier. |
| Claim: |
26. The pharmaceutical composition of claim 25 that is adapted for subcutaneous, inhalatory, or topical administration. |
| Claim: |
27. A nucleic acid that comprises a sequence that: (i) encodes a polypeptide that comprises a heavy chain immunoglobulin variable region that: (a) comprises a heavy CDR3 of mAb13.2 (SEQ ID NO:24), or a CDR3 that differs by fewer than 3 amino acid substitutions from a corresponding CDR3 of mAb13.2; or (b) is at least 90% identical to a heavy chain variable domain of h13.2 (SEQ ID NO:15, 16, or 36); or (ii) hybridizes under high stringency conditions to the complement of a nucleic acid encoding a heavy chain variable domain of h13.2 (SEQ ID NO: 15, 16, or 36). |
| Claim: |
28. A nucleic acid that comprises a sequence that: (i) encodes a polypeptide that comprises a light chain immunoglobulin variable region that: (a) comprises a light chain CDR1 of mAb13.2 (SEQ ID NO:19), or a CDR1 that differs by fewer than 3 amino acid substitutions from a corresponding CDR1 of mAb13.2; or (b) is at least 90% identical to a light chain variable domain of h13.2 (SEQ ID NO:11, 12, or 35); or (ii) hybridizes under high stringency conditions to the complement of a nucleic acid encoding a heavy chain variable domain of h13.2 (SEQ ID NO:11, 12, or 35). |
| Claim: |
29. A host cell comprising a nucleic acid sequence that encodes the antibody, or antigen-binding fragment thereof, of claim 1 or 15. |
| Claim: |
30. A method of providing a recombinant antibody, the method comprising: providing a host cell a nucleic acid sequence that encodes the antibody, or antigen-binding fragment thereof, and maintaining the cell under conditions in which the antibody, or antigen-binding fragment thereof, is expressed. |
| Claim: |
31. The method of claim 30, further comprising isolating the protein from the host cell or media in which the host cell is maintained. |
| Claim: |
32. The method of claim 31, further comprising formulating the isolated protein as a pharmaceutical composition. |
| Claim: |
33. A method of treating an IL-13-associated disorder, the method comprising: administering, to a subject having or at risk for the disorder, an effective amount of the antibody, or antigen-binding fragment thereof, of claim 1. |
| Claim: |
34. The method of claim 33, wherein the IL-13 associated disorder is selected from the group consisting of: asthmatic disorders, atopic disorders, chronic obstructive pulmonary disease (COPD), conditions involving airway inflammation, eosinophilia, fibrosis and excess mucus production, inflammatory conditions, autoimmune conditions, tumors or cancers, viral infection, and suppression of expression of protective type 1 immune responses. |
| Claim: |
35. The method of claim 33, wherein the disorder is an asthmatic disorder or allergic rhinitis. |
| Claim: |
36. The method of claim 33, wherein the disorder is inflammatory bowel disease. |
| Claim: |
37. The method of claim 33, wherein the disorder is chronic obstructive pulmonary disease (COPD). |
| Claim: |
38. The method of claim 33, wherein the disorder is an atopic disorder. |
| Claim: |
39. The method of claim 33, wherein the protein is administered subcutaneously, by inhalation, or topically. |
| Claim: |
40. A method of treating an IL-13-associated disorder, comprising administering to a subject an antibody that binds to IL-13, wherein the antibody has one or more of the following properties: (i) confers a post-injection protective effect against exposure to Ascaris antigen in a sheep model at least 6 weeks after injection, or (ii) prevents binding of IL-13 to IL-4Rα, but does not prevent binding of IL-13 to IL-13Rα1. |
| Claim: |
41. A method of detecting the presence of IL-13 in a sample, the method comprising: (i) contacting the sample with an anti-IL-13 antibody or fragment thereof; and (ii) detecting formation of a complex between the anti-IL-13 antibody or fragment thereof and the sample, wherein formation of the complex in the sample is indicative of the presence of IL-13 in the sample. |
| Claim: |
42. The method of claim 41, wherein the sample is from a subject. |
| Claim: |
43. A method of treating a subject exhibiting a symptom of asthma selected from the group consisting of wheezing, shortness of breath, bronchoconstriction, airway hyperreactivity, decreased lung capacity, fibrosis, airway inflammation, and mucus production, said method comprising the step of administering to the patient an antibody according to claim 1 or 15, wherein the antibody binds to IL-13 and interferes with the formation of a functional IL-13 signaling complex. |
| Current U.S. Class: |
435069/100 |
| Current International Class: |
07; 07; 12; 12 |
| رقم الانضمام: |
edspap.20060063228 |
| قاعدة البيانات: |
USPTO Patent Applications |