Efalizumab Mechanism of Action and Dose Determination

1
Efalizumab Mechanism of Action and Dose
Determination

• Charles Johnson, MB, ChB
• Senior DirectorHead of Specialty Biotherapeutics
• Genentech, Inc.

2
Efalizumab Characteristics

• Humanized mAb IgG1 kappa human framework
  containing murine antibody complementarity-determi
  ning 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

Heavy chain Light chain Heavy chain CDR Light
chain CDR Carbohydrates

• 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.
19961574986-4995.
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. 2002461-23.
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
Week 8
Week 2
Lesional
Pre NL
Week 4
HE
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
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