1. 1 C-MOA- Efalizumab Mechanism of Action and Dose Determination Charles Johnson, MB, ChB Senior Director Head of Specialty Biotherapeutics Genentech, Inc.

2. 2 C-MOA- 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 Concept from: Werther WA, et al. J Immunol. 1996;157:4986-4995. Blocks interaction between LFA-1 on T-cell and intracellular adhesion molecule (ICAM) on APC, endothelium and keratinocytes Efalizumab Characteristics Heavy chain Light chain Heavy chain CDR Light chain CDR Carbohydrates

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

4. 4 C-MOA- Selectivity of Raptiva for T-cell Functions LFA-1/ICAM interactions are important for T-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 expressed on T-cells Other immune effector cells (NK cells, PMNs, monocytes) predominantly express alternate integrins

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

6. 6 C-MOA- 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 Efalizumab Pharmacodynamics

7. 7 C-MOA- Efalizumab Pharmacokinetic and Pharmacodynamic Profiles Following 1 mg/kg/wk for 12 Weeks Unbound CD11a (% of baseline) 0 20 40 60 80 100 120 Time (Week) 04812162024 Serum efalizumab Serum efalizumab (µg/mL) 0.1 1 10 100 Efalizumab dosing

8. 8 C-MOA- 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. 9 C-MOA- 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