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Treatment of autoimmune disorders with cd154 antibodies

a technology of cd154 and autoimmune disorders, applied in the field of autoimmune and inflammatory diseases, can solve the problems of inadequate therapeutic armamentarium, discontinued hu5c8 development, and large number of side effects

Inactive Publication Date: 2018-01-25
BIOGEN MA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a study that found low levels of anti-drug antibodies in patients with SLE did not impact the pharmacokinetics of a specific drug. The study observed a weak response to the drug across all doses, with the highest response in a group that received a higher dosage. This information may help to better understand the impact of these low levels of antibodies on drug development.

Problems solved by technology

However, despite this promising evidence of clinical effect, further development of hu5c8 was discontinued because of an increased incidence of treatment-emergent cardiovascular thrombotic events.
Corticosteroids are the cornerstone of treatment but are associated with an extensive number of side effects most frequently seen during long-term use.
This present therapeutic armamentarium is inadequate because of limited efficacy and / or adverse events profile.
Despite the high medical need for new effective therapies of SLE with an good safety profile the development of such therapies has proven to be particularly difficult and many therapeutic candidates have failed (Eisenberg, 2009).

Method used

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  • Treatment of autoimmune disorders with cd154 antibodies
  • Treatment of autoimmune disorders with cd154 antibodies
  • Treatment of autoimmune disorders with cd154 antibodies

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0095]Determination of Binding Affinity.

[0096]Biamolecular Interaction Analysis (BIA) was performed using a BIAcore 3000 instrument. Affinipure goat F(ab′)2 fragment specific for human IgG, F(ab′)2 fragment was immobilised on a CM5 Sensor Chip via amine coupling chemistry to a capture level of approximately 4000 response units (RUs). HBS-EP buffer (10 mM HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA, 0.005% (v / v)) Surfactant P20) was used as the running buffer with a flow rate of 10 μL / minute (min). A 10 μL injection of test CD154 antibody or Fab at 10 μg / mL was used for capture by the immobilised anti-human IgG-F(ab′)2. Human CD154 was titrated over the captured CD154 antibody or Fab at various concentrations (1 nM or below) at a flow rate of 3 μL / min. The surface was regenerated by 2×10 μL injections of 40 mM HCl, followed by a 5 μL injection of 5 mM NaOH at a flow rate of 10 μL / min.

example 2

[0097]Study SL0013:

[0098]A clinical study of two parts in which, during the first part, ascending single intravenous doses of CDP7657 were assessed for safety, tolerability and pharmacokinetic profiles at 0.004 mg / kg, 0.02 mg / kg, 0.1 mg / kg, 0.5 mg / kg and 1.7 mg / kg in 5 groups, each of 3 healthy male volunteers, followed by a dose of 5 mg / kg in two more groups of 3 healthy male volunteers and 3 healthy female volunteers. Following establishment of acceptable profiles, the second part of the study assessed single intravenous doses at 5 mg / kg, 15 mg / kg, 30 mg / kg and 60 mg / kg in 4 groups of 3 patient volunteers (who had an established diagnosis of systemic lupus erythematosus; SLE). In addition to further assessments of safety, tolerability and pharmacokinetics, the pharmacodynamic effects were also explored using various disease markers.

[0099]In performing this study, the basic characteristics of both the anti-CD154 antibody / antibody fragment and its PEG component were established.

example 3

[0100]Study SL0014:

[0101]A clinical study in which patients with an established diagnosis of SLE were randomised in a double-blind fashion to receive six intravenous doses of CDP7657 (n=16) or matching placebo (n=8) over a period of 10 weeks. The dosing regimen under test (in those receiving active drug) comprised a single loading dose of 30 mg / kg followed by a maintenance dose of 15 mg / kg every 2 weeks thereafter, for a total of 6 doses of CDP7657. In addition to assessing the safety, tolerability and pharmacokinetic profiles of CDP7657 versus placebo, the study explored the immunogenicity (both anti-CD154 and PEG components), effects on various disease markers and effects on clinical disease parameters during and for 18 weeks after treatment. In this way the safety, tolerability and ability of the dosing regimen to deliver disease-modifying effects were established.

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Abstract

The present invention relates to a method of treating an autoimmune or inflammatory disease or a neurodegenerative disease with an antibody to CD154.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the treatment of autoimmune and inflammatory diseases, in particular the treatment of systemic lupus erythematosus with an antibody or antibody fragment binding specifically to CD154.BACKGROUND OF THE INVENTION[0002]Autoimmune diseases classically comprise more than 80 chronic diseases that affect about 5%-8% of the general population. There has been considerable progress made in understanding the immune system during recent decades, resulting in a better appreciation of the role of costimulatory molecules such as CD40 and its ligand CD154. Furthermore, a role for such molecules in the pathogenesis of much commoner diseases such as atherosclerosis is also emerging, which could greatly expand the applicability of therapies targeting this molecule.[0003]CD154 is expressed on activated T lymphocytes and, through interactions with its receptor CD40, plays a pivotal role in regulating the interplay between T cells and other cel...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28
CPCC07K16/2875A61K2039/545C07K2317/76C07K2317/92C07K2317/35C07K2317/565C07K2317/55A61K2039/505A61K39/395A61P13/12A61P17/06A61P19/02A61P21/00A61P25/00A61P25/28A61P29/00A61P37/02A61P37/06A61P3/10
Inventor OLIVER, RUTHZAMACONA, MIREN
Owner BIOGEN MA INC
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