METHODS OF ADMINISTERING ANTI-TNFalpha ANTIBODIES

a technology of antitnfalpha and antibody, applied in the direction of drug composition, immunological disorders, metabolism disorders, etc., can solve the problems of short serum half life, inability to trigger certain human effectors, limited use in vivo, etc., to reduce the number of injection site reactions, less frequent, and increase patient compliance

Inactive Publication Date: 2012-07-12
ABBVIE BIOTECHNOLOGY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]The present invention provides methods for biweekly dosing regimens for the treatment of TNFα associated disorders, preferably via a subcutaneous route. Biweekly dosing has many advantages over weekly dosing including, but not limited to, a lower number of total injections, decreased number of injection site reactions (e.g., local pain ...

Problems solved by technology

While these mouse anti-hTNFα antibodies often displayed high affinity for hTNFα (e.g., Kd≦10−9M) and were able to neutralize hTNFα activity, their use in vivo may be limited by problems associated with administration of mouse antibodies to humans, such as short serum half life, an inability to trigger certain human effector functions and elicitation of an unwanted immune response against the mouse antibody in a human (the “human anti-mouse antibody” (HAMA) reaction).
However, because these chimeric and humanized antibodies still retain some murine sequences, they still may elicit an unwanted immune reaction, the human anti-chimeric antibody (HACA) reaction, especially when administered for prolonged periods, e.g., for chronic indicatio...

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Treatment with an Anti-TNFα Antibody

D2E7 Efficacy Following Subcutaneous Administration

[0125]In this study, twenty-four patients with active RA were treated with weekly doses of 0.5 mg / kg D2E7 (n=18) or placebo (n=6) by s.c. injection for three months. Patients participating in this study had a mean duration of disease of 10.1 years with a disease activity score (DAS) score of 4.87 and a mean of 3.4 DMARDs (disease modifying anti-rheumatic drugs) prior to study entry; again reflecting considerable disease activity. Responders continued open-label treatment with D2E7, while patients who failed to respond to the 0.5 mg / kg dose or who lost a DAS response on the 0.5 mg / kg dose were escalated to receive 1 mg / kg by s.c. injection after week twelve of the study.

[0126]The first patients enrolled received up to sixty injections and were, therefore, sixty weeks on the study drug. The efficacy with s.c. dosing was similar to i.v. injections. Up to 78% of patients reached a DAS and ACR2...

example 2

Total Body Dose of a Subcutaneously Administered Anti-TNFα Antibody

Weekly, Subcutaneous Administration of D2E7

[0130]This study enrolled two hundred eighty-four patients with RA and was designed to determine the optimal total body dose of subcutaneously administered D2E7. Patients were randomized to receive either 20, 40, or 80 mg D2E7 or placebo weekly for twelve weeks, after which time placebo-treated patients were switched blindly to 40 mg D2E7 / week.

[0131]Approximately 49% of patients reached ACR20 at 20 mg, 55% of patients reached ACR20 at 40 mg, and 54% of patients reached ACR20 at 80 mg, while only 10% of patients receiving placebo reached ACR20 (set forth in FIG. 1A). Approximately 23% of patients reached ACR50 at 20 mg, 27% of patients reached ACR50 at 40 mg, and 20% of patients reached ACR50 at 80 mg, and only 2% of patients receiving placebo reached ACR50. These data illustrate that subcutaneous D2E7, particularly at a dose of 40 mg / week, generates a good response.

example 3

Biweekly, Subcutaneous Administration of an Anti-TNFα Antibody Biweekly, Subcutaneous Administration of D2E7

[0132]The clinical effects, safety, immunogenicity, and tolerance of RA patients with partial responses to MTX following every other week subcutaneous (s.c.) injections of placebo or D2E7 at several dose levels for up to twenty-four weeks in conjunction with continued MTX treatment was investigated.

Study Design

[0133]A placebo-controlled, double-blind, randomized, multi-center study in patients with RA, who had insufficient efficacy or tolerability to MTX was performed. During the course of the trial, patients were continued on a stable dose of MTX with dose ranges specified in the inclusion criteria described below.

[0134]This study consisted of two portions: 1) a “wash-out period” of four weeks prior to the administration of the first dose medication, during which time DMARDs (except for MTX) were withdrawn; and 2) a “placebo controlled period” during which time patients were ...

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Abstract

Methods of treating disorders in which TFNα activity is detrimental via biweekly, subcutaneous administration of human antibodies, preferably recombinant human antibodies, that specifically bind to human tumor necrosis factor α (hTNFα) are disclosed. The antibody may be administered with or without methotrexate. These antibodies have high affinity for hTNFα (e.g., Kd=10−8 M or less), a slow off rate for hTNFα dissociation (e.g., Koff=10−3 sec−1 or less) and neutralize hTNFα activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Kits containing a pharmaceutical composition and instructions for dosing, and preloaded syringes containing pharmaceutical compositions are also encompassed by the invention.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 163,657, filed on Jun. 5, 2002, which claims the benefit of the filing date under 35 U.S.C. §119(e) to U.S. Provisional Application No. 60 / 296,961, filed on Jun. 8, 2001. The entire contents of each of the foregoing applications, including specification, any drawings, and sequence listing, are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Tumor necrosis factor α (TNFα) is a cytokine produced by numerous cell types, including monocytes and macrophages, that was originally identified based on its capacity to induce the necrosis of certain mouse tumors (see e.g., Old, L. (1985) Science 230:630-632). Subsequently, a factor termed cachectin, associated with cachexia, was shown to be the same molecule as TNFα. TNFα has been implicated in mediating shock (see e.g., Beutler, B. and Cerami, A. (1988) Annu. Rev. Biochem. 57:505-518; Beutler, B. and Cerami, A. (19...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P1/00A61P1/04A61K38/20A61M5/28A61K31/519A61K38/00A61P1/16A61P3/10A61P7/04A61P9/00A61P9/10A61P11/00A61P13/12A61P17/02A61P19/02A61P19/06A61P19/08A61P25/00A61P27/02A61P29/00A61P31/00A61P35/00A61P37/02A61P37/06A61P37/08C07K16/24
CPCA61K39/3955A61K2039/505A61K2039/54A61K2039/545A61K2300/00C07K16/241C07K2317/565C07K2317/76C07K2317/21C07K2317/56C07K2317/52A61K9/0019A61K39/395A61K45/06C07K16/00C07K16/24A61K31/00A61M5/28A61K38/00A61K31/519A61P1/00A61P1/04A61P1/16A61P11/00A61P13/00A61P13/12A61P17/00A61P17/02A61P19/00A61P19/02A61P19/06A61P19/08A61P19/10A61P25/00A61P27/00A61P27/02A61P29/00A61P29/02A61P3/00A61P31/00A61P31/04A61P31/12A61P31/14A61P31/20A61P35/00A61P37/00A61P37/02A61P37/06A61P37/08A61P41/00A61P43/00A61P7/00A61P7/04A61P9/00A61P9/10A61P3/10Y02A50/30
Inventor FISCHKOFF, STEVEN A.KEMPENI, JOACHIMWEISS, ROBERTA
Owner ABBVIE BIOTECHNOLOGY LTD
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