Methods for treating pancreatitis
Provided herein is a method for preventing, treating, ameliorating, or managing pancreatitis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an antibody or functional fragment thereof that binds to CA19-9.
1. A method for treating, ameliorating, or managing pancreatitis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an antibody or functional fragment thereof that binds to Sialyl-Lewis a (anti-sLe a ), wherein said anti-sLe a antibody or functional fragment comprises:
(i) a variable heavy chain (VH) domain comprising three VH complementarity defining regions (CDRs) present in the amino acid sequence of SEQ ID NO: 2; and a variable light chain (VL) domain comprising three VL CDRs present in the amino acid sequence of SEQ ID NO: 4;
(ii) a VH domain comprising three VH CDRs present in the amino acid sequence of SEQ ID NO: 6; and a VL domain comprising three VL CDRs present in the amino acid sequence of SEQ ID NO: 8;
(iii) a V5 domain comprising three V2 CDRs present in the amino acid sequence of SEQ ID NO: 10; and a VL domain comprising three VL CDRs present in the amino acid sequence of SEQ ID NO: 12;
(iv) a VH domain comprising three VH CDRs present in the amino acid sequence of SEQ ID NO: 14; and a VL domain comprising three VL CDRs present in the amino acid sequence of SEQ ID NO: 16: or
(v) a VH domain comprising three VH CDRs present in the amino acid sequence of an antibody produced by a hybridoma deposited under American Type Culture Collection (ATCC) Accession No. HB-8059; and a VL domain comprising three VL CDRs present in the amino acid sequence of an antibody produced by a hybridoma deposited under American Type Culture Collection (ATCC) Accession No. HB-8059.
2. The method of claim 1 , wherein the method further comprises:
determining a first severity of pancreatitis in said subject prior to administering said antibody or functional fragment thereof,
determining a second severity of pancreatitis in said subject after administering said antibody or functional fragment thereof, and
administering a second dose of the antibody or functional fragment thereof at the same or lower amount than the first dose if the second severity of pancreatitis in the subject is reduced in comparison to the first severity of pancreatitis in the subject, or administering a second dose of the antibody or functional fragment thereof at a higher amount than the first dose if the second severity of pancreatitis in the subject is not reduced compared to the first severity of pancreatitis.
3. The method of claim 1 , wherein said VH domain and said VL domain respectively comprise an amino acid sequence selected from the group consisting of residues 20-142 of SEQ ID NO: 2 and residues 20-130 of SEQ ID NO: 4; residues 20-142 of SEQ ID NO: 6 and residues 20-129 of SEQ ID NO: 8; residues 20-142 of SEQ ID NO: 10 and residues 20-130 of SEQ ID NO: 12; and residues 20-145 of SEQ ID NO: 14 and residues 23-130 of SEQ ID NO: 16.
4. The method of claim 2 , wherein said anti-sLe a antibody or functional fragment thereof comprises a heavy chain variable region consisting of the amino acid sequence of the heavy chain variable region of an antibody produced by a hybridoma deposited under American Type Culture Collection (ATCC) Accession No. HB-8059, and a light chain variable region consisting of the amino acid sequence of the light chain variable region of an antibody produced by a hybridoma deposited under ATCC Accession No. HB-8059.
5. The method of claim 2 , wherein said anti-sLe a antibody or functional fragment thereof comprises a heavy chain consisting of the amino acid sequence of the heavy chain of an antibody produced by a hybridoma deposited under ATCC. Accession No. HB-8059, and a light chain consisting of the amino acid sequence of the light chain of an antibody produced by a hybridoma deposited under ATCC. Accession No. HB-8059.
6. The method of claim 1 , wherein said anti-sLe a antibody functional fragment is selected from the group consisting of a Fab, a Fab′, a F(ab′)2, a scFV, a diabody, a triabody, and a minibody.
7. The method of claim 6 , wherein said anti-sLe a antibody functional fragment is a diabody.
8. The method of claim 7 , wherein said diabody comprises the amino acid sequence of SEQ ID NO: 18 or 20.
9. The method of claim 1 , wherein said anti-sLe a antibody or functional fragment thereof is a monoclonal antibody.
10. The method of claim 1 , wherein said anti-sLe a antibody or functional fragment thereof is an IgG or IgM isotype.
11. The method of claim 10 , wherein said IgG antibody is an IgG1, IgG2, IgG3, or IgG4 subclass.
12. The method of claim 1 , wherein the anti-sLe a antibody or functional fragment thereof is formulated as a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
13. The method of claim 1 , wherein the antibody or functional fragment thereof is administered by a parenteral route of administration.
14. The method of claim 13 , wherein the parenteral administration is selected from a group consisting of subcutaneous injection, intramuscular injection, and intravenous injection.
15. The method of claim 1 , wherein the antibody or functional fragment thereof is administered at a dose range from about 0.1 mg/kg/dose to about 10 mg/kg/dose.
16. The method of claim 1 , wherein the antibody or functional fragment thereof is administered weekly, bi-weekly, monthly, or bi-monthly.
17. The method of claim 16 , wherein the antibody or functional fragment thereof is administered for about one, two, three, four, five, or six months.
18. The method of claim 9 , wherein the anti-sLe a antibody or functional fragment thereof is a mouse, a chimeric, a humanized, or a fully human monoclonal antibody.
19. The method of claim 1 , wherein the pancreatitis is characterized by one or more markers.
20. The method of claim 2 , wherein the severity of the pancreatitis is determined by one or more markers.
21. The method of claim 2 , wherein the subject has elevated levels of one or more markers for pancreatitis.
22. The method of claim 2 , wherein the administering of the therapeutic agent results in reduced levels of one or more markers for pancreatitis in the subject.
23. The method of claim 19 , wherein the one or more markers are selected from a group consisting of a physiological marker, a histological marker, a serological marker, and a signaling marker.
24. The method of claim 23 , wherein the histological marker is selected from a group consisting of immune cell invasion, collagen deposition, fibrotic tissue, fat necrosis, interstitial edema, acinar and blood vessel destruction, interstitial hemorrhage, ductal dilation, acinar cell homogenization, and expression level of CA19-9.
25. The method of claim 19 , wherein the one or more markers comprise expression level of CA19-9.
26. The method of claim 25 , wherein the one or more markers are determined by immunohistochemistry.
27. The method of claim 23 , wherein the serological marker is selected from a group consisting of serum lipase level, serum amylase level, and serum C reactive protein level.
28. The method of claim 27 , wherein the serum lipase level is over 200 U/L.
29. The method of claim 27 , wherein the serum amylase level is over 200 U/L.
30. The method of claim 27 , wherein the serum amylase level is three times over the upper limit of normal serum amylase level of a control subject.
31. The method of claim 27 , wherein the serum lipase level is three times over the upper limit of normal serum lipase level of a control subject.
32. The method of claim 23 , wherein the physiological marker is selected from a group consisting of weight loss, malabsorption of food, pancreatic atrophy, pancreatic enlargement, pancreatic inflammation, and bile reflux.
33. A method for treating, ameliorating, or managing pancreatitis in a subject having elevated pancreatic sLe a , said method comprising administering to the subject a therapeutically effective amount of an antibody or functional fragment thereof that specifically binds to sLe a , wherein said anti-sLe a antibody or functional fragment comprises:
(i) a variable heavy chain (VH) domain comprising three VH complementarity defining regions (CDRs) present in the amino acid sequence of SEQ ID NO: 2; and a variable light chain (VL) domain comprising three VL CDRs present in the amino acid sequence of SEQ ID NO: 4;
(ii) a VH domain comprising three VH CDRs present in the amino acid sequence of SEQ ID NO: 6; and a VL domain comprising three VL CDRs present in the amino acid sequence of SEQ ID NO: 8;
(iii) a VH domain comprising three VH CDRs present in the amino acid sequence of SEQ ID NO: 10; and a VL domain comprising three VL CDRs present in the amino acid sequence of SEQ ID NO: 12;
(iv) a VH domain comprising three VH CDRs present in the amino acid sequence of SEQ ID NO: 14; and a VL domain comprising three VL CDRs present in the amino acid sequence of SEQ ID NO: 16: or
(v) a VH domain comprising three VH CDRs present in the amino acid sequence of an antibody produced by a hybridoma deposited under American Type Culture Collection (ATCC) Accession No. HB-8059; and a VL domain comprising three VL CDRs present in the amino acid sequence of an antibody produced by a hybridoma deposited under American Type Culture Collection (ATCC) Accession No. HB-8059.
34. The method of claim 33 , wherein the pancreatitis is a pancreatitis selected from a group consisting of chronic pancreatitis and acute pancreatitis.
35. The method of claim 34 , wherein the chronic pancreatitis is selected from a group consisting of mild chronic pancreatitis, moderate chronic pancreatitis, and severe chronic pancreatitis.
36. The method of claim 34 , wherein the acute pancreatitis is selected from a group consisting of mild acute pancreatitis, moderate acute pancreatitis, and severe acute pancreatitis.
37. The method of claim 34 , wherein the subject is a mammal.
38. The method of claim 37 , wherein the mammal is a human.