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

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Psoriasis: Efalizumab - Monoclonal Antibodies

Currently three biologic agents are approved for use in psoriasis: etanercept (Enbrel ), alefacept (Amevive , which binds T and NK cells via CD2), and efalizumab (Raptiva ), the latter of which is further elaborated below.



Currently three biologic agents are approved for use in psoriasis: etanercept (Enbrel ), alefacept (Amevive , which binds T and NK cells via CD2), and efalizumab (Raptiva ), the latter of which is further elaborated below.





Efalizumab is indicated for the treatment of adult patients (> 18 years of age) with moderate to severe plaque psoriasis. Efalizumab is a recombinant huma-nized IgG1 isotype monoclonal antibody, which comes lyophilized and upon reconstitution will deliver 1.25 mL of a 100 mg/mL solution or 125 mg. The pH of the reconstituted product is 6.2. As is typical for protein therapeutics, the amount of active ingredient is larger than what is deliverable. This is due to properties of protein therapeutics in that due to viscosity or binding to vial after reconstitution, some drug product can not be withdrawn into a syringe for administration. Efalizumab must be reconstituted prior to administration and is dispensed with a single-use pre-filled syringe containing 1.3 mL of diluent. Efalizumab can be self-administered in the home by the patient.



The approved dose of efalizumab is 1 mg/kg/ wk. This dose consistently resulted in the maximum effect on CD11a saturation and expression. In a comparison to the higher dose of 2 mg/kg/wk, there was no notable difference in the pharmacodynamics or efficacy profiles suggesting 1 mg/kg/wk is already at the top of the dose response curve. Efalizumab has not been tested in combination with other immuno-suppressive medications such as methotrexate and cyclosporine.


The specificity of efalizumab is against the CD11a subunit of leukocyte function antigen-1 (LFA-1). LFA-1 consists of CD11a and CD18 and is primarily found on leukocytes but is also reported on activated platelets. Efalizumab exerts an immunosup-pressive biologic effect by binding to CD11a thus interrupting the interaction of LFA-1 and its natural ligand intercellular adhesion molecule-1 (ICAM-1). In the absence of blockade by efalizumab, LFA-1/ICAM-1 binding stabilizes the immunological synapse necessary for an immune responses. The LFA-1/ ICAM-1 interaction is also involved in the demargina-tion of cells across the endothelium of blood vessels into tissues.


The effects of efalizumab have been extensively studied non-clinically in both in vitro and in vivo studies as well as in clinical trials. In vitro assaysassessing T-cell activation showed efalizumab is able to block activation. Among the different cell types with LFA-1, the immunosuppressant effects on T-cells (CD4 and CD8 cells) have been the most extensively studied although efalizumab is known to attenuate primary immune responses to neoantigens

Efalizumab pharmacokinetics have been well studied (Mortensen et al., 2005; Joshi et al., 2006). At the approved dose of 1 mg/kg, mean steady-state clearance was 24 mL/kg/day. Steady-state trough concentrations were approximately 9 mg/mL at the end of the approved 7-day dosing interval. Efalizumab is cleared through both receptor mediated and non-specific protein clearance mechanisms. The receptor-mediated clearance of efalizumab occurs through the binding of efalizumab to cell surface CD11a. The efalizumab-CD11a complex is then inter-nalized and degraded (Coffey et al., 2004).


The primary pharmacodynamic marker for efalizumab is CD11a, the cell surface marker it targets. The amount of cell surface CD11a (CD11a expression) and saturation of CD11a binding sites on the cell surface were measured in clinical and non-clinical studies. Data from phase I/II studies with intravenous IV and SC administration of efalizumab were used to identify the optimal dose for psoriasis (Joshi et al., 2006). Treatment with efalizumab has been shown to blunt the secondary humoral immune response.


At doses of 1 mg/kg/wk SC, efalizumab con-sistently decreased the amount of CD11a on the surface of lymphocytes to < 35% of baseline levels and saturated > 95% of remaining cell surface CD11a. The effects on CD11a were not dose dependent beyond 1 mg/kg/wk suggesting this dose was at the top of the dose response curve. The maximal effect on CD11a occurs at concentrations between 1 and 3 mg/ mL. The effects observed on CD11a were maintained throughout the dosing period but were reversible upon discontinuation.


In addition to CD11a expression and saturation, treatment related leukocytosis is a pharmacodynamic marker for efalizumab (Joshi et al., 2006). Consistent with the ability of efalizumab to inhibit LFA-1 mediated demargination, white blood cell counts increase during therapy with efalizumab. At the recommended dose of 1 mg/kg/wk, mean white blood cell counts increased 34% relative to baseline values. Among the leukocyte subsets, the increase in lymphocytes was the largest with a doubling of the baseline counts. Among the lymphocyte subsets tested, T-cells saw the greatest increase followed by B-cells then NK-cells. Similar to the effects on CD11a, the treatment related effects on absolute counts of circulating leukocytes and leukocyte subsets and lymphocyte subsets were reversible upon disconti-nuation of efalizumab

In subjects who were evaluated, 6.3% (67/1063) developed anti-efalizumab antibodies. These were predominantly low-titer antibodies to efalizumab or other protein components of the drug product. Comparison of the incidence of antibodies to efalizu-mab relative to the incidence of antibodies to other products should be interpreted with caution due to ranges of sensitivity and specificity of this assay format across products.


The measure of response used in the pivotal trials of efalizumab was the Psoriasis Area and Severity Index (PASI) during the study. The PASI is a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of the psoriatic changes. After treatment with efalizumab, between 17% and 37% of subjects treated had a 75% reduction from their baseline PASI score (PASI-75) (package insert for Raptiva, 2006).

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