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US-12622969-B2 - Methods for treatment using anti-α4β7 antibody

US12622969B2US 12622969 B2US12622969 B2US 12622969B2US-12622969-B2

Abstract

Antibody formulations are described comprising a mixture of a non-reducing sugar, an anti-α4β7 antibody and at least one amino acid. The disclosed formulations have improved stability, reduced aggregate formation, and may retard degradation of the anti-α4β7 antibody therein or exhibit any combinations thereof. The present invention further provides a safe dosing regimen of these antibody formulations that is easy to follow, and which results in a therapeutically effective amount of the anti-α4β7 antibody in vivo.

Inventors

  • Catherine Scholz
  • Irving H. Fox

Assignees

  • TAKEDA PHARMACEUTICAL COMPANY LIMITED

Dates

Publication Date
20260512
Application Date
20250605

Claims (20)

  1. 1 . A method for treating human patients having inflammatory bowel disease (IBD) and for minimizing human antihuman antibody (HAHA) formation in the human patients, said method comprising administering to the human patients a humanized antibody having binding specificity for human α4β7 integrin according to a dosing regimen comprising: a. an induction phase comprising i. an initial dose of 300 mg of the humanized antibody as an intravenous infusion; ii. a second subsequent dose of 300 mg of the humanized antibody as an intravenous infusion at about two weeks after the initial dose; iii. a third subsequent dose of 300 mg of the humanized antibody as an intravenous infusion at about six weeks after the initial dose; and b. a maintenance phase comprising a fourth and subsequent doses of 300 mg of the humanized antibody as an intravenous infusion every four weeks or every eight weeks after the third subsequent dose of the humanized antibody; wherein the method induces a clinical response and clinical remission in the IBD of the human patients, wherein the IBD is Crohn's disease or ulcerative colitis, wherein at least 80% of the human patients are maintained as HAHA-negative for at least 6 weeks following the initial dose, and wherein the humanized antibody is an IgG1 isotype, and wherein the humanized antibody comprises a light chain variable region comprising a CDR1 as set forth in SEQ ID NO: 11; a CDR2 as set forth in SEQ ID NO: 12, and a CDR3 as set forth in SEQ ID NO: 13; and comprises a heavy chain variable region comprising a CDR1 as set forth in SEQ ID NO: 8; a CDR2 as set forth in SEQ ID NO: 9, and a CDR3 as set forth in SEQ ID NO: 10.
  2. 2 . The method of claim 1 , wherein the Crohn's disease is moderately to severely active Crohn's disease.
  3. 3 . The method of claim 2 , wherein the humanized antibody comprises a light chain variable region sequence that is 95% identical to amino acids 20 to 131 of SEQ ID NO: 4 or amino acids 21 to 132 of SEQ ID NO: 5, and comprises a heavy chain variable region sequence that is 95% identical to amino acids 20 to 140 of SEQ ID NO: 2; or wherein the humanized antibody comprises a light chain variable region comprising amino acids 20 to 131 of SEQ ID NO: 4 or 21 to 132 of SEQ ID NO: 5, and comprises a heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 2.
  4. 4 . The method of claim 2 , wherein the humanized antibody is administered to the human patients every eight weeks during the maintenance phase after the third subsequent dose.
  5. 5 . The method of claim 4 , wherein administration of the humanized antibody is increased to every four weeks if the human patients experience a return of one or more disease symptoms during the maintenance phase.
  6. 6 . The method of claim 1 , wherein clinical remission is achieved by week 52 following the initial dose.
  7. 7 . The method of claim 2 , wherein at least 90% of the human patients are maintained as HAHA-negative for at least 6 weeks following the initial dose.
  8. 8 . The method of claim 2 , wherein at least 90% of the human patients are maintained as HAHA-negative for at least 15 weeks following the initial dose.
  9. 9 . The method of claim 2 , wherein the ulcerative colitis is moderately to severely active ulcerative colitis.
  10. 10 . The method of claim 9 , wherein the humanized antibody comprises a light chain variable region sequence that is 95% identical to amino acids 20 to 131 of SEQ ID NO: 4 or amino acids 21 to 132 of SEQ ID NO: 5, and comprises a heavy chain variable region sequence that is 95% identical to amino acids 20 to 140 of SEQ ID NO: 2; or wherein the humanized antibody comprises a light chain variable region comprising amino acids 20 to 131 of SEQ ID NO: 4 or 21 to 132 of SEQ ID NO: 5, and comprises a heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 2.
  11. 11 . The method of claim 9 , wherein the humanized antibody is administered to the human patients every eight weeks during the maintenance phase after the third subsequent dose.
  12. 12 . The method of claim 11 , wherein administration of the humanized antibody is increased to every four weeks if the human patients experience a return of one or more disease symptoms during the maintenance phase.
  13. 13 . The method of claim 9 , wherein clinical remission is achieved by week 52 following the initial dose.
  14. 14 . The method of claim 9 , wherein at least 90% of the human patients are maintained as HAHA-negative for at least 6 weeks following the initial dose.
  15. 15 . The method of claim 9 , wherein at least 90% of the human patients are maintained as HAHA-negative for at least 15 weeks following the initial dose.
  16. 16 . A method for treating human patients having inflammatory bowel disease (IBD) and for minimizing human antihuman antibody (HAHA) formation in the human patients, said method comprising administering vedolizumab to the human patients according to a dosing regimen comprising: a) an induction phase comprising i. an initial dose of 300 mg of vedolizumab as an intravenous infusion; ii. a second subsequent dose of 300 mg of vedolizumab as an intravenous infusion at about two weeks after the initial dose; iii. a third subsequent dose of 300 mg of vedolizumab as an intravenous infusion at about six weeks after the initial dose; and b) a maintenance phase comprising a fourth and subsequent doses of 300 mg of vedolizumab as an intravenous infusion every four weeks or every eight weeks after the third subsequent dose of vedolizumab; wherein the method induces a clinical response and clinical remission in the IBD of the human patients, wherein the IBD is Crohn's disease or ulcerative colitis, and wherein at least 80% of the human patients are maintained as HAHA-negative for at least 6 weeks following the initial dose.
  17. 17 . The method of claim 16 , wherein the Crohn's disease is moderately to severely active Crohn's disease.
  18. 18 . The method of claim 17 , wherein vedolizumab is administered to the human patients every eight weeks during the maintenance phase after the third subsequent dose.
  19. 19 . The method of claim 18 , wherein administration of vedolizumab is increased to every four weeks if the human patients experience a return of one or more disease symptoms during the maintenance phase.
  20. 20 . The method of claim 17 , wherein clinical remission is achieved by week 52 following the initial dose.

Description

RELATED APPLICATIONS This application is a continuation of U.S. Non-Provisional Ser. No. 18/922,371 filed on Oct. 21, 2024, which is a continuation of U.S. Non-Provisional Ser. No. 18/778,906 filed on Jul. 19, 2024, which is a continuation of U.S. Non-Provisional Ser. No. 16/743,813 filed on Jan. 15, 2020, which is a continuation of U.S. Non-Provisional patent application Ser. No. 15/678,744 filed on Aug. 16, 2017, which is a continuation of U.S. Non-Provisional application Ser. No. 14/114,832 filed on Feb. 25, 2014, now U.S. Pat. No. 9,764,033 issued on Sep. 19, 2017, which is a National Stage Entry of International Application No. PCT/US2012/036072 filed on May 2, 2012, which claims the benefit of U.S. Provisional Application 61/585,859 filed on Jan. 12, 2012, U.S. Provisional Application 61/550,545 filed on Oct. 24, 2011, and U.S. Provisional Application 61/481,533 filed on May 2, 2011. The entire contents of the foregoing applications are hereby incorporated by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML file format via EFS-Web and is hereby incorporated by reference in its entirety. Said XML copy, created on Jun. 5, 2025, is named T103022_1010US_C14T1_SLxml and is 19,535 bytes in size. BACKGROUND OF THE INVENTION Advances in biotechnology have made it possible to produce a variety of proteins for pharmaceutical applications using recombinant DNA techniques. Because proteins are larger and more complex than traditional organic and inorganic drugs (i.e. possessing multiple functional groups in addition to complex three-dimensional structures), the formulation of such proteins poses special problems. For a protein to remain biologically active, a formulation must preserve the conformational integrity of at least a core sequence of the protein's amino acids, while at the same time protecting the protein's multiple functional groups from degradation. Proteins may suffer from a lack of stability, and monoclonal and polyclonal antibodies in particular may be relatively unstable (See e.g., Wang et al., J. Pharm Sci. 96:1-26 (2007)). A large number of formulation options are available, and not one approach or system is suitable for all proteins. Several factors to be considered have been reported (See e.g., Wang et al.). Numerous characteristics may affect a protein's stability. In fact, even in the case of purified antibodies, the antibody structures may be heterogeneous, which further complicates the formulation of such systems. Moreover, the excipients included in antibody formulations preferably minimize any potential immune response. In the case of antibodies, preservation of the conformational integrity is even more important. Degradation pathways for proteins can involve chemical instability (i.e., any process which involves modification of the protein by bond formation or cleavage resulting in a new chemical entity) or physical instability (i.e., changes in the higher order structure of the protein). Chemical instability is manifested in, for example, deamidation, isomerization, hydrolysis, oxidation, fragmentation, glycan beta elimination or disulfide exchange. Physical instability can result from denaturation, aggregation, precipitation or adsorption, for example. The four most common protein degradation pathways are protein fragmentation, aggregation, deamidation, and oxidation. Consequences of chemical or physical instability of therapeutic protein include a lowering of the effective administered dose, decreased safety of the therapy due to, for example irritation or immunological reactivity, and more frequent manufacturing due to short shelf life. Freeze-drying is a commonly employed technique for preserving proteins; freeze-drying serves to remove water from the protein preparation of interest. Freeze-drying, or lyophilization, is a process by which the material to be dried is first frozen and then the ice or frozen solvent is removed by sublimation under vacuum. Excipients can be included in the pre-lyophilized formulation to stabilize proteins during the lyophilization process and/or to improve the stability of the lyophilized protein formulation (Pikal M., Biopharm. 3(9) 26-30 (1990) and Arakawa et al. Pharm. Res. (3): 285-291 (1991)). Several publications have disclosed generally various methods of treating inflammatory bowel diseases, and provided dosing schemes for administration of agents designed to treat inflammatory bowel disease. For example, WO 96/24673 discloses mucosal vascular addressins and treatment of diseases associated with leukocyte recruitment to the gastrointestinal tract as a result of leukocyte binding to cells expressing MAdCAM. U.S. 2005/0095238 describes methods of treating a disease associated with leukocyte infiltration of mucosal tissue and administration to a human an effective amount of a human or humanized immunoglobulin or antigen binding fragment having binding specificity for α4β