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Psoriasis as a Model for T-Cell–Mediated Disease
Immunobiologic and Clinical Effects of Treatment With Multiple Doses of Efalizumab, an Anti–CD11a Antibody
Alice B. Gottlieb, MD, PhD;
James G. Krueger, MD, PhD;
Knut Wittkowski, DSc, PhD;
Russell Dedrick, PhD;
Patricia Ann Walicke, MD, PhD;
Marvin Garovoy, MD
Arch Dermatol. 2002;138:591-600.
ABSTRACT
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Background Leukocyte function–associated antigen 1 (LFA-1), consisting of
CD11a and CD18 subunits, plays an important role in T-cell activation and
leukocyte extravasation.
Objective To test whether blocking CD11a decreases immunobiologic and clinical
activity in psoriatic plaques.
Design Open-label, multicenter, dose escalation study.
Patients Thirty-nine patients with moderate-to-severe psoriasis.
Intervention Intravenous infusions of efalizumab, a humanized anti-CD11a monoclonal
antibody, for 7 weeks at doses of 0.1 mg/kg every other week or 0.1 mg/kg
weekly (category 1), 0.3 mg/kg weekly (category 2), and 0.3 increasing to
0.6 or 1.0 mg/kg weekly (category 3). Skin biopsies were performed on days
0, 28, and 56.
Main Outcome Measures Serum efalizumab levels, levels of total and unoccupied T-cell CD11a,
T cell counts, epidermal thickness, cutaneous intercellular adhesion molecule
1 (ICAM-1) and keratin 16 (K16) expression, Psoriasis Area and Severity Index
(PASI) scores.
Results Dose-response relationships were observed for pharmacokinetics and pharmacodynamic
measures. Category 1 failed to maintain detectable serum efalizumab or T cell
CD11a down-modulation between doses. Category 2 achieved both. Category 3
achieved both and additionally maintained sustained T-cell CD11a saturation
between doses. A dose-response relationship was also observed clinically and
histologically. The mean decrease in the PASI score was 47% in category 3,
45% in category 2, and 10% in category 1 (P<.001).
Epidermal and dermal T-cell counts, epidermal thickness, and ICAM-1 and K16
expression decreased in categories 2 and 3 but not in category 1. Circulating
lymphocyte counts increased in categories 2 and 3.
Conclusions At doses of 0.3 mg/kg or more per week, intravenous efalizumab produced
significant clinical and histologic improvement in psoriasis, which correlated
with sustained serum efalizumab levels and T-cell CD11a saturation and down-modulation.
INTRODUCTION
INTERCELLULAR ADHESION molecules (ICAMs) facilitate the binding of antigen-presenting
cells and keratinocytes1 to T cells and are
thought to provide costimulatory signals necessary for T-cell activation.2 Interactions among cellular adhesion molecules also
facilitate the continuous recirculation of T lymphocytes among lymph nodes,
tissues, and blood.3
Leukocyte function–associated antigen 1 (LFA-1) is a member of
the leukocyte  2-integrin family of adhesion molecules, characterized
by heterodimers with a common chain (CD18) and a unique  chain
(CD11a for LFA-1).2 Expression of LFA-1 is
restricted to leukocytes. A receptor for LFA-1, ICAM-1, can be expressed on
a variety of cells, including T lymphocytes, endothelial cells, and epidermal
keratinocytes.3 Expression of ICAM-1 is coordinated
with the progression of local immune responses, and its induction in inflammation
is an important means of regulating LFA-1/ICAM-1 interactions.4
Antibodies to LFA-1 or its ligands that interfere with the LFA-1/ICAM adhesion
mechanism attenuate a broad range of T-cell–mediated reactions in vitro
and in animal models.5-14
CD11a blockade is predicted to produce less global immune suppression compared
with CD18 blockade because T cells are relatively dependent on CD11a/CD18
(LFA-1) compared with other types of leukocytes.1
Psoriasis is an inflammatory disease characterized by hyperproliferation
of keratinocytes and accumulation of activated T cells in the epidermis and
dermis of psoriatic lesions.15-20
Evidence indicates that T cells play a key role in the pathogenesis of psoriasis.17-23
Up-regulation of ICAM-1 expression in psoriatic plaques1
may facilitate T-cell extravasation, adhesion to keratinocytes, and activation
of T lymphocytes through interaction with LFA-1.21, 24
Therefore, inhibition of the ICAM-1/LFA-1 adhesion interaction may decrease
clinical activity in psoriatic plaques.
In a previous open-label study,25 patients
with moderate-to-severe psoriasis received a single dose of intravenous efalizumab,
ranging from 0.03 to 10 mg/kg. Although this single dose produced only a transient
blockade of lymphocyte CD11a, the mean decrease in Psoriasis Area and Severity
Index (PASI) scores 28 days later was 33% in 15 of 31 responding patients.
Clinical response was accompanied by decreased numbers of epidermal CD3+ T cells, reduced CD11a levels on T cells, decreased keratinocyte and
blood vessel expression of ICAM-1, epidermal thinning, and improved but not
normalized keratinocyte differentiation. Adverse events were mild at doses
of 0.3 mg/kg or less and included chills, abdominal discomfort, headache,
and fever.
In the study reported herein, 39 patients with moderate-to-severe psoriasis
were treated with multiple, intravenous doses of efalizumab for 7 weeks. Dose-response
relationships were examined for pharmacokinetic, pharmacodynamic, and histologic
and clinical psoriasis measures.
PATIENTS, MATERIALS, AND METHODS
STUDY DRUG
Efalizumab (Xanelim; Genentech, Inc, or hu1124) is a humanized IgG1
version of the murine anti–human CD11a monoclonal antibody MHM24, generated
by grafting the MHM24 complementarity determining regions into consensus human
IgG1  heavy and light chain sequences.26
PATIENT POPULATION
The study population consisted of patients with stable, moderate-to-severe
plaque psoriasis (defined as >15% body surface area involvement and a PASI
score  15.0). Patients discontinued treatment with psoralen–UV-A
and all systemic antipsoriatic therapies for at least 28 days before study
drug administration. Prescription topical therapies and use of UV-B were discontinued
for at least 2 weeks before study drug administration.
TRIAL DESIGN
This was an open-label, multiple-dose, dose escalation, 8-center, phase
1/2 study. The study was conducted in accordance with the Declaration of Helsinki.
Subjects sequentially received the following dose levels in an ascending dose
escalation paradigm: 0.1 mg/kg every other week (group A); 0.1 mg/kg weekly
(group B); 0.3 mg/kg weekly (group C); 0.3, 0.4, then 0.6 mg/kg for the remaining
weeks (group D); and 0.3, 0.4, 0.6, then 1.0 mg/kg for the remaining weeks
(group E). The intrasubject dose escalation in groups D and E was performed
because the prior phase 1/2 study25 demonstrated
that initial doses of more than 0.3 mg/kg were accompanied by more frequent
infusion-related adverse events.
Subjects were seen at least weekly during the treatment phase and were
followed up for a minimum of 98 days (56 days after the last dose). Efficacy
was monitored weekly by the PASI.27 This study
was a phase 1/2 study and did not have a formal primary end point at a predetermined
time point. However, the main analysis of efficacy was performed 1 week after
the last dose (day 56). Biologic activity was also assessed by histologic
analysis of skin biopsy specimens obtained at baseline, day 28, and day 56
from the same area of plaque. Safety was assessed by adverse events, clinical
laboratory assessments (including blood chemical analysis, hematologic analysis,
and urinalysis), pretreatment and posttreatment physical examinations (including
vital signs), and human antihumanized antibody tests. Additional clinical
immunology test results were examined, specifically cutaneous cell-mediated
immune reaction to tetanus, mumps, or Candida antigens
and secondary humoral antibody response to tetanus toxoid.
HISTOLOGIC METHODS ON CRYOSTAT SKIN SECTIONS
Immunohistochemical analysis for CD11a was performed with biotinylated
efalizumab (hu1124) and clone 25.3 (Beckman Coulter, Inc, Miami, Fla), another
CD11a antibody that binds to a noncompeting epitope on CD11a. Determination
of epidermal thickness, numbers of epidermal CD3+ and CD11a+ T cells, and keratinocyte ICAM-1 and keratin 16 (K16) expression were
performed as previously described.17-19
The biopsy codes were not unmasked until after the histologic assessments
were completed.
OTHER LABORATORY METHODS
Plasma efalizumab levels were measured by enzyme-linked immunosorbent
assay (ELISA) as previously described.25, 28
Limit of detection was 25 ng/mL of efalizumab. Antibody to efalizumab (hu1124)
was determined using a double-antigen sandwich ELISA as previously described.28 The detection limit was approximately 5 ng/mL. Flow
cytometry of circulating T cells was performed using a FACScan flow cytometer
(Becton Dickinson and Co, San Jose, Calif). Lymphocytes were identified by
forward and side scatter characteristics. T cells were identified by binding
to CD1 and fluorescein isothiocyanate (FITC) anti-CD3. Reduction in cell surface
expression of CD11a (down-modulation) on circulating CD3+ T cells
was monitored with a FITC anti-CD11a (clone 25.3; Beckman Coulter, Inc), as
previously described.28 Saturation of efalizumab
(hu1124) on circulating T cells was determined by comparing the amount of
bound drug to the total amount that could bind at saturation. Blood cells
were washed to remove plasma components and unbound efalizumab (hu1124). The
washed blood cells were incubated for 30 minutes at room temperature in the
absence (bound) or presence (saturated) of 25 µg/mL of efalizumab (hu1124).
The FITC-labeled goat F(ab')2 anti-human IgG (Cappel; ICN
Pharmaceuticals Inc, Aurora, Ohio) was used to detect efalizumab (hu1124)
bound to the T-cell surface on flow cytometry. For each time point, the mean
fluorescence intensity of the bound test was subtracted from the mean fluorescence
intensity of the saturated test to generate a measure of available binding
sites for efalizumab.
STATISTICAL DESIGN AND ANALYSIS
This was an exploratory study to examine potential correlations between
pharmacokinetic variables and outcome measures. The study was not formally
powered. Descriptive statistics are based on observed data only. For comparisons
over time, baseline was defined as study day 0, which was the first day study
drug was administered to subjects. Percent change values from baseline were
used to evaluate the effects of efalizumab on lymphocyte counts and surface
efalizumab content and saturation. Statistical analyses of histologic samples
for changes in epidermal thickness and skin-infiltrating T cells were performed
using univariate (Friedman) and multivariate (Kruskal-Wallis) methods. Clinical
efficacy was evaluated by examining the change in PASI score from baseline
to days 28 and 56. The Wilcoxon rank sum and Kruskal-Wallis tests were used
to compare the efficacy between or among the categories. Safety was evaluated
by examining the incidence, severity, causality, and type of treatment-emergent
adverse events reported and examining the change in vital signs, physical
examination results, and laboratory test results throughout the study. The
study did not include an untreated control group. Post hoc analysis showed
that the 5 dose groups could be divided into 3 categories based on distinctive
pharmacokinetic and pharmacodynamic profiles. The lowest-dose category did
not have clinical or histologic efficacy and therefore was used as a comparator
in some analyses.
RESULTS
PATIENT DEMOGRAPHICS
A total of 39 subjects (age range, 26-73 years) were enrolled at 8 study
centers (Figure 1). The median baseline
PASI score was 23 (range, 15-42). One subject in group C discontinued treatment
after the first dose of efalizumab because of headache and fever. All of the
remaining subjects completed the treatment portion of the study, but 4 subjects
did not complete the follow-up period. Three withdrew because of worsening
psoriasis and 1 was lost to follow-up. Pharmacokinetic, hematologic, and clinical
results are reported using data available at each time point for the entire
cohort of 39 subjects. However, because of early discontinuations or damage
to some biopsy samples during transit, histologic analyses were conducted
only for 32 subjects. Therefore, only 32 patients constituted the fully evaluable
subgroup for comparisons among laboratory, histologic, and clinical outcomes.
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Figure 1. Enrollment of subjects in the
study.
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PHARMACOKINETICS OF EFALIZUMAB
Group geometric mean plasma concentrations are indicated by the dotted
line graphs in Figure 2A; concentrations
are indicated on the logarithmic y-axis. In dose groups A and B, trough levels
of efalizumab were below the limit of detection. However, in group C, efalizumab
was still detectable before the next dose, with trough levels between 0.1
and 0.5 µg/mL. Mean trough levels in groups D and E were comparable
in the 2 groups, ranging from 4.6 to 5.3 µg/mL in group D to 3.0 to
4.4 µg/mL in group E. As previously observed in patients receiving a
single intravenous dose of efalizumab,28 drug
clearance decreased with increasing dose, from 130 mL/kg per day in group
A to 7.75 mL/kg per day in group E.
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Figure 2. Plasma efalizumab (hu1124) levels
and down-modulation of T-cell CD11a (A) and available binding sites (eg, saturation)
(B). CD11a expression on circulating T cells was measured by flow cytometry
in blood samples collected just before infusion. Plasma efalizumab (hu1124)
levels were measured by enzyme-linked immunosorbent assay in samples collected
before and immediately after the 90-minute infusion. For plasma efalizumab
levels, considerable variation was observed among subjects (more than a 30-fold
difference in concentration at some time points). Therefore, the plasma efalizumab
levels in A are expressed as the geometric mean (antilog of the mean of log
[efalizumab]) (logarithmic y-axis; dotted lines). B, Group arithmetic means
for T-cell surface CD11a were used because less intersubject variation was
observed. These data are expressed as percentage of baseline value (linear
y-axis; solid lines). Error bars indicate SEMs. Dose groups A through E correspond
to those defined in Figure 1.
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PHARMACODYNAMICS OF EFALIZUMAB
CD11a on the surface of circulating CD3+ T cells was measured
by flow cytometry using an FITC-labeled monoclonal antibody (clone 25.3),
whose binding is not inhibited by efalizumab. Decreased binding of FITC 25.3,
therefore, reflects down-modulation of CD11a. Figure 2A shows mean surface CD11a expression compared with the
concurrent geometric mean plasma efalizumab concentration. Surface CD11a expression
recovered to pretreatment levels in group A before the next dose and partially
recovered to within 30% of baseline between infusions in group B. In contrast,
T-cell surface CD11a remained down-modulated by 70% to 80% throughout the
treatment in groups C, D, and E. Full recovery of CD11a expression occurred
approximately 7 to 10 days after efalizumab was cleared from the plasma. When
these data are compared with the pharmacokinetic results, it seems that down-modulation
is maintained only if plasma efalizumab remains at detectable levels throughout
the interval between infusions. The 0.3-mg/kg weekly dose (group C) was the
lowest dose that produced detectable efalizumab levels and maintained CD11a
down-modulation throughout the treatment period.
The amount of LFA-1 (CD11a/CD18 heterodimer) available for biological
function may depend both on the level of down-modulation (Figure 2A) and on the number of remaining CD11a molecules not occupied
in vivo (Figure 2B). The amount
of remaining, unbound surface CD11a (ie, still available for binding and biological
activation) was determined by comparing the amount of efalizumab bound to
lymphocytes harvested from treated patients to the maximum amount of efalizumab
that could be bound after further incubation in vitro with a saturating amount
of drug (25 µg/mL). Figure 2B
shows available CD11a relative to baseline on circulating CD3+
T cells during and after efalizumab treatment. In dose group A, available
CD11a returned completely to pretreatment levels between doses. In dose group
B (0.1 mg/kg weekly), available CD11a was decreased about 30%. In dose group
C (0.3 mg/kg weekly), CD11a availability was largely suppressed, but a small
amount of available binding sites remained, suggesting incomplete saturation
with efalizumab. In the 2 highest-dose groups (D and E), available CD11a decreased
to less than 5% of baseline levels, reflecting full down-modulation and high
levels of saturation throughout treatment.
The patterns of efalizumab pharmacokinetics, CD11a down-modulation,
and CD11a saturation divide the 5 dose groups into 3 categories. Category
1 (groups A and B) is defined by the failure to maintain detectable efalizumab
serum levels and T-cell surface CD11a down-modulation between doses. Category
2 (group C) is characterized by sustained presence of detectable efalizumab
and T-cell CD11a down-modulation, but failure to maintain CD11a saturation
between doses. Category 3 (groups D and E) is characterized by sustained T-cell
CD11a down-modulation and saturation between doses. These 3 dose categories
will be used in the assessments of histologic and clinical outcomes.
HISTOLOGIC AND IMMUNOHISTOLOGIC EFFECTS OF EFALIZUMAB
T-cell decreases in the epidermis and dermis of psoriatic lesions occurred
most consistently in subjects in categories 2 and 3 (Figure 3). For category 3 subjects, the median number of epidermal
T cells decreased 70% and dermal T cells decreased 66% between baseline and
day 56. The major portion of the decrease in both dermal and epidermal T-cell
counts occurred between day 0 and day 28. The decrements observed for category
3 subjects at day 56 compared with day 0 were statistically significant for
both dermal (P = .01) and epidermal (P = .047) T-cell counts. In category 2 subjects, only the decrement
in epidermal T cells (P = .005) was significant at
day 56. In contrast, changes in epidermal and dermal T-cell counts were not
significant for category 1 subjects at either day 28 or day 56.
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Figure 3. Changes in epidermal thickness
(A), epidermal T-cell counts (B), and dermal T-cell counts (C). Separate plots
are shown for category 1 ( 0.1 mg/kg weekly), category 2 (0.3 mg/kg weekly),
and category 3 (>0.3 mg/kg weekly). Cell counts are expressed as number of
cells per analysis field (1.2 x 1.0 mm). Results for individual subjects
are indicated by circles and dotted lines; group geometric means, by solid
lines. Intragroup comparisons were performed using the Friedman test and intergroup
comparisons using a modified Kruskal-Wallis test.
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Histologic examinations of psoriatic skin revealed dose-dependent patterns
of alteration in the availability of CD11a on cutaneous T cells (Table 1). Immunohistochemical analysis
was performed with biotinylated efalizumab, providing an overall indication
of CD11a availability on cutaneous T cells. Staining with biotinylated efalizumab
was not changed at days 28 and 56 in 90% to 100% of the subjects in category
1. In contrast, 50% of category 2 and 100% of category 3 subjects had noticeably
decreased staining on day 56. At day 28, 50% of category 2 subjects and 90%
of category 3 subjects demonstrated no detectable staining with biotinylated
efalizumab. The lower proportion of subjects negative for CD11a staining at
day 56 may be related to poorer antibody penetration into skin as vascular
abnormalities secondary to psoriasis resolve. When immunohistochemical analysis
was performed with monoclonal antibody 25.3, which binds to a noncompeting
epitope on CD11a, residual CD11a expression was detectable in all samples.
These observations are similar to those for circulating T cells and indicate
that CD11a can be both down-modulated and saturated with efalizumab on T cells
in psoriatic plaques. However, as observed for circulating T cells, saturation
of T-cell surface CD11a is not sustained as fully in category 2 as in category
3. Reductions in epidermal thickness across the 3 dose categories tended to
parallel reductions in cutaneous T-cell infiltration and CD11a availability
(Figure 3).
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Table 1. Histologic Evidence of Decreased CD11a, ICAM-1, and K16 Expression
in Psoriatic Plaques*
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Keratinocyte expression of ICAM-1 and K16 is indicative of cytokine-mediated
inflammation and aberrant maturation, respectively. There were no subjects
in category 1 who became negative for ICAM or K16 expression during efalizumab
treatment, and only 1 subject had a noticeable decrease in staining at day
56 (Table 1). In contrast, approximately
30% to 40% of subjects in categories 2 and 3 became negative for K16 at day
56. Additionally, K16 immunohistochemical staining was noticeably decreased
in 50% of category 2 and 70% of category 3 subjects at day 56. Comparable,
though somewhat less frequent, changes were observed in staining for ICAM.
These observations demonstrate that efalizumab can reverse histologic evidence
of inflammation and pathologic epidermal hyperplasia in psoriatic plaques.
RELATIONSHIPS AMONG HISTOLOGIC, PHARMACOKINETIC, AND PHARMACODYNAMIC
OBSERVATIONS
Overall, the data indicate that a relationship exists among plasma level
of efalizumab, CD11a saturation and down-modulation, and histologic improvements
(Table 2). Detectable plasma levels
were not maintained between doses in category 1 but were maintained in categories
2 and 3. Trough levels were below the concentration needed to fully inhibit
T-cell adhesion in in vitro assays for category 2 but not for category 3.
Although all dose levels produced transient CD11a saturation and down-modulation,
down-modulation was sustained only in categories 2 and 3, and CD11a saturation
was sustained only in category 3. Changes in histologic variables of T-cell
infiltration and epidermal thickness were not significant in category 1 but
were evident in categories 2 and 3. These changes seemed to be more robust
in category 3 subjects. Saturation of cutaneous T-cell CD11a was higher in
category 3. Thus, it seems that a dose that maintains CD11a down-modulation
is required for efficacy, and maintaining saturation of CD11a results in further
increases in histologic improvement.
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Table 2. Summary of Results*
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EFALIZUMAB ADMINISTRATION–INDUCED SIGNIFICANT DISEASE IMPROVEMENT
AS MEASURED BY PASI
During treatment with efalizumab, the PASI score changed little for
subjects in category 1 but decreased markedly for subjects in categories 2
and 3 (Figure 4). Changes in PASI
scores seemed to be dose dependent, with the largest change observed in category
3 (representative response illustrated in Figure 5). There were individual patients who, after discontinuing
therapy after 1 month and taking inadequate concentrations of efalizumab,
worsened during the period of observation. Patients in category 3 experienced
a mean decrease in PASI score from baseline of 47% at day 56 compared with
45% in category 2 and 10% in category 1 (P<.001).
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Figure 4. Summary of Psoriasis Area and
Severity Index (PASI) score by study day and analysis: category 1, (0.1 mg/kg
per week or biweekly); category 2, (0.3 mg/kg weekly); and category 3, >0.3
mg/kg weekly. Treatment concludes at day 42. Solid line indicates median PASI
score; open rectangles, range; and shading, 95% confidence intervals.
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Figure 5. Improvement in psoriatic lesions
at days 28 and 56 compared with day 0 in a patient treated with efalizumab
(hu1124) at 0.3 mg/kg. The Psoriasis Area and Severity Index scores were 19.2
on day 0, 13.4 on day 28, and 2.4 on day 56.
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SAFETY AND IMMUNOLOGIC EVALUATION
Safety information is provided for the entire cohort of 39 subjects
who had any exposure to efalizumab. Drug-related adverse events were mostly
mild or moderate in severity. The most common adverse events were fever (n
= 20), headache (n = 12), chills (n = 9), nausea (n = 9), asthenia (n = 6),
psoriasis (n = 8), and pharyngitis (n = 5). Fever and chills were reported
more frequently in subjects receiving 0.3 mg/kg weekly or more of efalizumab
than in subjects receiving 0.1 mg/kg weekly or less of efalizumab. The incidence
was 62% vs 20% for fever and 28% vs 10% for chills in the 2 groups. These
adverse events were particularly observed within 24 hours of the first dose
of efalizumab and decreased on subsequent doses. Eight patients experienced
return of psoriasis during the posttreatment, observation phase. One subject
experienced increased alkaline phosphatase levels that were severe and resolved
within 2 months. Seven additional subjects experienced elevated alanine aminotransferase
(serum glutamic-pyruvic transaminase) and aspartate aminotransferase (serum
glutamic-oxaloacetic transaminase) levels and elevated or decreased glucose
levels; however, none was considered clinically significant by the investigators.
No severe infections were noted in this study; the only noted malignancy was
a non–drug-related basal cell carcinoma (in a patient with a history
of PUVA therapy).
All but 2 subjects who were positive for tetanus antibody at screening
retained their tetanus antibody response after repeated exposure to efalizumab.
This indicates that an established IgG humoral antibody response persists
following multiple doses of efalizumab. Measurement of cell-mediated immunity
by administration of tetanus, mumps, and Candida
antigens by skin testing showed persistence of cell-mediated immunity in 32
(89%) of the 36 subjects tested after treatment. In addition, no subject developed
antibodies to efalizumab.
EFALIZUMAB INCREASES CIRCULATING LYMPHOCYTES
During efalizumab treatment, an increase in the number of circulating
lymphocytes was evident in categories 2 and 3 but not category 1 subjects
(Figure 6). The average number of
circulating lymphocytes increased by day 7 and remained elevated over pretreatment
levels by about 50% in category 2 and about 100% in category 3 for the duration
of treatment. Lymphocyte numbers returned to pretreatment levels after the
efalizumab was no longer in the plasma. Sustained increases in circulating
lymphocyte numbers occurred only at efalizumab dose levels sufficient to maintain
sustained decreases in CD11a availability. Absolute neutrophil counts were
unchanged.
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Figure 6. Mean lymphocyte counts in subjects
treated with efalizumab (hu1124). Lymphocyte counts are presented for subjects
in categories 1, 2, and 3. Error bars indicate SEM.
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COMMENT
The overall correlation between the effects of different dose levels
on CD11a availability and histologic or clinical outcomes supports the purported
mechanism that the therapeutic action of efalizumab is linked to its effects
on CD11a. In this study, 0.1-mg/kg doses of efalizumab (category 1) failed
to maintain saturation or down-modulation of CD11a on circulating T cells.
At doses of 0.3 mg/kg weekly (category 2), efalizumab was observed to maintain
down-modulation of CD11a but did not maintain complete saturation of CD11a
binding sites on circulating or plaque T cells. From preclinical in vitro
binding data, CD11a binding saturation of more than 99% requires a drug concentration
of about 5 µg/mL.26 In the present study,
doses of 0.3 mg/kg weekly maintained trough levels of 0.5 µg/mL or less
between doses. Not unexpectedly, binding site data for this dose group show
incomplete saturation of CD11a. In the higher-dose groups (>0.3 mg/kg weekly;
category 3), mean drug trough levels were 4 to 5 µg/mL between doses.
This level is much closer to the in vitro saturation level and was sufficient
to down-regulate and saturate CD11a on circulating and cutaneous T cells for
a sustained period. The clinical, histologic, and pharmacodynamic effects
observed in this study indicate that by reducing the availability of CD11a
on circulating and cutaneous T cells, efalizumab can attenuate the inflammatory
process and pathologic epidermal hyperplasia that are the hallmarks of psoriasis.
Administration of efalizumab does not result in a decrease in the number
of circulating lymphocytes. Rather, it is associated with a 2-fold increase
that persisted as long as efalizumab was detectable in the blood. Leukocyte
function–associated antigen 1 is an important adhesion molecule in normal
lymphocyte trafficking. The increase in circulating lymphocytes may reflect
decreased T-cell emigration into skin, demargination, or release from lymph
nodes or skin, as a result of CD11a blockade.
Other highly specific immunosuppressive therapies have been used in
recent studies.17, 29-31
CTLA4Ig is a fusion protein that binds to B7-1 and B7-2 molecules on the surface
of antigen-presenting cells and inhibits the CD28/B7-mediated costimulatory
signal for T-cell activation. Abrams et al23
reported that administration of CTLA4Ig improved psoriatic disease activity
as measured by the Physician's Global Assessment and improved histologic variables
such as CD3+ T-cell infiltration, K16 expression, and epidermal
thickening. More recently, single-dose intravenous infusions of an anti–CD80
(B7-1) monoclonal antibody showed clinical and histologic activity in moderate-to-severe
psoriasis.30 LFA-3-TIP is a fusion protein
that binds to CD2 on T cells and inhibits the CD2/LFA-3–mediated costimulatory
signal for T-cell activation. Phase 2 studies with LFA3-TIP in moderate-to-severe
psoriasis demonstrated clinical efficacy but, in contrast to efalizumab, which
does not deplete lymphocytes, LFA3-TIP depleted memory T cells.31
The mechanism of action may differ among CTLA4Ig, anti-CD80, LFA3-TIP, and
efalizumab. Although all of these targeted immunologic therapies are thought
to interfere with activation of T cells,23
efalizumab has the additional potential of interfering with T-cell extravasation
into skin.
With doses of 0.1 mg/kg, adverse events were infrequent. At doses of
0.3 mg/kg or greater, most adverse events noted in this study occurred with
the initial dose of efalizumab. The incidence of adverse events subsided with
subsequent doses, even when the amount of drug given was increased. This finding
suggests that continued exposure to efalizumab at levels high enough to maintain
CD11a down-modulation induced a conditioned state for adverse events and is
consistent with the disappearance of symptoms in subjects who maintained high
blood levels of efalizumab.
Overall, these results indicate that substantial disease improvement
resulted with administration of multiple doses of efalizumab in doses of at
least 0.3 mg/kg weekly, with tolerable adverse effects. This improvement was
associated with down-modulation of CD11a on circulating and plaque T cells,
decreased numbers of epidermal CD3+ T cells, and decreased keratinocyte
ICAM-1 and K16 expression.
AUTHOR INFORMATION
Accepted for publication July 6, 2001.
This work was supported in part by a Johnson & Johnson Corporate
Office of Science and Technology award through Johnson & Johnson's (New
Brunswick, NJ) Focused Giving Program (Dr Gottlieb); a general support grant
by Merck, Inc (Rahway, NJ), to The Clinical Research Center at University
of Medicine and Dentistry of New Jersey–Robert Wood Johnson (New Brunswick);
an endowment fund from Schering Inc to support the W. H. Conzen Chair in Clinical
Pharmacology (Dr Gottlieb); grant M01-RR00102 from the National Center for
Research Resources at the National Institutes of Health to the Rockefeller
University Hospital (Dr Krueger); and a National Institutes of Health (Bethesda,
Md) R01 grant AI39214 (Dr Krueger).
Partial support to all investigations and members of the HUPS249 study
was provided by XOMA (US) LLC and Genentech, Inc.
This work was presented in part at the annual meetings of the American
Academy of Dermatology and Society for Investigative Dermatology in 1999.
We thank members of the HUPS249 Study Group: Susan Bradshaw, MD, and
William Shapiro, MD, VRG of San Francisco, San Francisco, Calif; Ross Bright,
MD, Psoriasis Research Institute, Palo Alto, Calif; Scott D. Clark, MD, Longmont
Clinic, Longmont, Colo; Mark Ling, MD, PhD, Emory University School of Medicine,
Atlanta, Ga; Nicholas Lowe, MD, Clinical Research Specialists, Santa Monica,
Calif; Jon Ruckle MD, Northwest Kinetics, Tacoma, Wash; and Sun Sook Kim,
MS, Robert Bauer, PhD, and Mark White, XOMA (US), LLC, Berkeley, Calif.
Corresponding author and reprints: Alice B. Gottlieb, MD, PhD, University
of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical
School, Clinical Research Center, 1 Robert Wood Johnson Place, Room CN19,
New Brunswick, NJ 08903-0019 (e-mail: gottliab{at}UMDNJ.EDU).
From the Clinical Research Center, University of Medicine and Dentistry
of New Jersey–Robert Wood Johnson Medical School, New Brunswick (Dr
Gottlieb); Laboratory for Investigative Dermatology, The Rockefeller University,
New York, NY (Drs Krueger and Wittkowski); XOMA (US), LLC, Berkeley, Calif
(Drs Dedrick and Garovoy), and Genentech, Inc, South San Francisco, Calif
(Dr Walicke).
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