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Efalizumab Mechanism of Action and Dose Determination

Efalizumab Mechanism of Action and Dose Determination. Charles Johnson, MB, ChB Senior Director Head of Specialty Biotherapeutics Genentech, Inc. Efalizumab Characteristics. Heavy chain Light chain Heavy chain CDR Light chain CDR Carbohydrates.

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Efalizumab Mechanism of Action and Dose Determination

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  1. Efalizumab Mechanism of Action and Dose Determination Charles Johnson, MB, ChB Senior DirectorHead of Specialty Biotherapeutics Genentech, Inc.

  2. Efalizumab Characteristics Heavy chain Light chain Heavy chain CDR Light chain CDR Carbohydrates • Humanized mAb IgG1 kappa human framework containing murine antibody complementarity-determining regions (CDRs) (MW 150kd) • Specifically designed to bind to the CD11a chain of leukocyte function antigen-1 (LFA-1), which is an integrin expressed on all leukocytes • Blocks interaction between LFA-1 on T-cell and intracellular adhesion molecule (ICAM) on APC, endothelium and keratinocytes Concept from: Werther WA, et al. J Immunol. 1996;157:4986-4995.

  3. Efalizumab Blocks Activation of T-cells in Dermis and Epidermis Activated APC T-cell Immunologic Synapse CD11a LFA-1 ICAM • Cytokine production • Keratinocyte hyperproliferation • Inflammatory response Antigen-Peptide CD3 MHC T-cellActivation Signals TCR CD4/CD8 LFA-3 CD2 CD40 CD40L Costimulatory Signals B7 CD28 Costimulatory Molecules LFA-1 ICAM T-cell Activation, Proliferation, and Cytokine Production Concept based on : Krueger JG. J Am Acad Dermatol. 2002;46:1-23.

  4. Selectivity of Raptiva for T-cell Functions • LFA-1/ICAM interactions are important forT-cells • Activation of T-cell by antigen presenting cells • Trafficking of T-cell to dermis • Interaction of T-cells with keratinocytes • LFA-1 is the predominant integrin expressedon T-cells • Other immune effector cells (NK cells, PMNs,monocytes) predominantly express alternateintegrins

  5. Reversal of Histologic Changes in Psoriasis Lesions by Efalizumab Patient in ACD2142g Pre NL Lesional Week 2 Week 4 Week 8 H&E CD3(T-cells) K16 Courtesy of Dr. James Krueger, Rockefeller University

  6. Efalizumab Pharmacodynamics • Efalizumab binds to CD11a on leukocytes and • Saturates CD11a • Down modulates/reduces expression of CD11a • Saturation and down-modulation was rapid after IV and SC doses; full effect seen after 24-48 hrs • Full PD effect maintained between weekly Phase III doses

  7. Serum efalizumab Efalizumab dosing 100 10 Serum efalizumab (µg/mL) 1 0.1 Efalizumab Pharmacokinetic and Pharmacodynamic Profiles Following 1 mg/kg/wk for 12 Weeks Unbound CD11a 120 100 80 Unbound CD11a (% of baseline) 60 40 20 0 0 4 8 12 16 20 24 Time (Week)

  8. Rationale for 1 mg/kg SC as the Optimal Dose • At 0.6 mg/kg IV, CD11a was maximally down modulated and saturated • Dosed subcutaneously efalizumab is ~50% bioavailable • 1 mg/kg SC was selected to produce maximal effects on leukocyte CD11a • Both 1 and 2 mg/kg were assessed in Phase III studies • CD11a was maximally down modulated and saturated at both doses • Both doses were efficacious • There was no apparent advantage in the 2 mg dose group compared to 1 mg

  9. Summary • Monoclonal antibody with selective immunosuppressive effect targeted to CD11a • Inhibits T-cell activation and trafficking • By sub-cutaneous injection at weekly intervals (1 mg/kg) efalizumab completely down-modulates and blocks CD11a on T-cells • Effect is reversible

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