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Chapter: Pharmaceutical Biotechnology: Fundamentals and Applications - Monoclonal Antibodies in Anti inflammatory Therapy

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Abatacept - Arthritides - Monoclonal Antibodies in Anti inflammatory Therapy

Abatacept is indicated for use as monotherapy or in combination with DMARDs in patients with moderate to severe active rheumatoid arthritis who have had an inadequate response to DMARDs or TNF antagonists.

 Abatacept

 

Abatacept is indicated for use as monotherapy or in combination with DMARDs in patients with moderate to severe active rheumatoid arthritis who have had an inadequate response to DMARDs or TNF antagonists. Abatacept is a fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 and a modified Fc portion of IgG1. Abatacept comes lyophilized and is administered after reconstitution in water by IV infusion over 30 minutes. The dose is weight-based such that patients weighing less than 60 kg receive 500 mg, patients weighing between 60 and 100 kg receive 750 mg, and patients weighing greater than 100 kg receive 1 gram. The dosing regimen consists of the first and second dose given 2 weeks apart followed my monthly dosing thereafter.

 

The interaction of CD80 and CD86 with CD28 is the costimulatory signal for full activation of T-lymphocytes. Abatacept is a costimulation modula-tor that binds CD80 and CD86 and blocks the interaction with CD28 inhibiting T-cell (T-lymphocyte) activation. The affinity of abatacept for its ligand is greater than the natural ligand CD28. Abatacept does not fix complement due to the modifications to the Fc portion of the molecule (Hervey and Keam, 2006).

 

In vitro studies demonstrated abatacept decreases T-cell proliferation and inhibits the production of TNF-a, interferon-g (IFNγ), and IL-2 in one study and in IL-1b, IL-6 and matrix metalloproteinase-3 (MMP-3) in another. In the in vivo rat collagen-induced arthritis model, abatacept suppressed inflammation, decreased anti-collagen antibody production, and reduced antigen specific production of INFg.

 

The pharmacokinetics after multiple doses of abatacept in RA patients was dose proportional between 2 and 10 mg/kg with steady-state achieved at 60 days. Steady-state clearance (mean) was 0.22 mL/hr/kg with mean peak and trough concen-trations of 295 mg/mL and 24 mg/mL, respectively, with a half-life of 13.1 days (Hervey and Keam, 2006).

 

In clinical studies, abatacept treatment resulted in decreases of varying degrees in soluble interleukin-2 receptor (sIL-2r), IL6, MMP-3, C-reactive protein, TNF-a and rheumatoid factor. In a study of psoriasis patients, administration of abatacept reduced peak antibody titers associated with secondary immune responses (Abrams et al., 1999).

 

Anti-abatacept antibodies were detected in 1.7% (34/1993) patients overall. However, when assessed in discontinuing subjects in order to circumvent drug interference in the assay, 5.8% (9/154) had developed anti-abatacept antibodies. When anti-abatacept anti-body positive subjects were assessed for neutralizing ability, 6/9 (67%) evaluable patients were shown to possess neutralizing antibodies.

 

In placebo controlled studies, ACR20, ACR50, and ACR70 scores (above placebo) ranged from 22% to 33%, 10% to 30%, and 6% to 23% depending on theduration of treatment and patient population. In the year long Abatacept in Inadequate Responders to Methotrexate (AIM) trial, treatment with abatacept inhibited the progression of radiographic evidence of structural joint damage as measured by Genant-modified Total Sharp Score (package insert for Orencia, 2006).

 

Study Material, Lecturing Notes, Assignment, Reference, Wiki description explanation, brief detail


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