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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4066-4071
A Phase II Study of BTI-322, a Monoclonal Anti-CD2 Antibody, for
Treatment of Steroid-Resistant Acute Graft-Versus-Host Disease
By
Donna Przepiorka,
Gordon L. Phillips,
Voravit Ratanatharathorn,
Michele Cottler-Fox,
Laurie H. Sehn,
Joseph H. Antin,
Donna LeBherz,
Michel Awwad,
James Hope, and
J. Bruce McClain
From The University of Texas M.D. Anderson Cancer Center, Houston;
the University of Kentucky Chandler Medical Center, Lexington; the
University of Michigan Medical Center, Ann Arbor; the University of
Maryland Greenebaum Cancer Center, Baltimore; Brigham and Women's
Hospital, Dana-Farber Cancer Institute, Boston, MA; BioTransplant, Inc,
Charlestown, MA; and MedImmune, Inc, Gaithersburg, MD.
 |
ABSTRACT |
BTI-322, a rat monoclonal IgG2b directed against the CD2 antigen on
T cells and natural killer (NK) cells, blocks primary and memory
alloantigen proliferative responses in vitro. We have evaluated the
pharmacokinetics and safety of BTI-322 during treatment of 20 transplant recipients with steroid-refractory acute graft-versus-host disease (GVHD). Treatment consisted of BTI-322 by intravenous (IV)
bolus or 30-minute infusion at approximately 0.1 mg/kg/d for 10 days in
addition to continuing high-dose steroids and tacrolimus or
cyclosporine. Pharmacokinetic sampling was performed in 10 patients;
the t1/2 ± SE was 9.1 ± 1.3 hours, the Cmax
was 2,549 ± 291 ng/mL, the Vd was 3.97 ± 0.95 L, and
the Vd/kg was 0.05 ± 0.01 L/kg. Ten patients experienced transient
dyspnea sometimes accompanied by nausea, vomiting, diarrhea, and
tachycardia shortly after the initial bolus dose of drug, but serious
drug-related adverse events were not seen during the remainder of the
infusions. At the end of treatment (day 11), there were six patients
with complete responses and five with a reduction in grade of GVHD for
a total response rate of 55% (95% confidence interval
[CI], 32% to 77%). Antibodies targeting CD2 may be
active in the treatment of acute GVHD, and evaluation of a humanized
form of BTI-322 is warranted.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
THE CD2 MOLECULE (T11,
LFA-2) is a 55-kD glycoprotein expressed on thymocytes,
mature T lymphocytes, and natural killer (NK) cells.1 It
was first identified due to its ability to act as a receptor for sheep
erythrocytes,2,3 but its natural ligand was subsequently
shown to be LFA-3, a widely-distributed adhesion molecule.4
CD2 acts as a costimulatory molecule for antigen-specific lymphocyte
activation.5 Stabilization of the cell-cell interaction via
the extracellular domain of CD2 on T cells and its ligand on
antigen-presenting cells is necessary for this costimulatory
function,6 but signaling through the cytoplasmic portion of
the molecule is required as well.7 Stimulation of CD2 alone
is not sufficient for T-cell activation; signaling through CD2 during
the afferent phase of the T-cell response only serves to enhance the
response of the T-cell receptor to antigen stimulation.8
During the efferent phase of the immune response, CD2 also plays a role
in adhesion between activated T cells or NK cells with target
cells,9,10 and signaling through CD2 on activated cytotoxic
cells stimulates exocytosis of cytotoxic granules.11,12 The
participation of CD2 in both the afferent and efferent phases of the
immune response makes it an attractive target in development of
immunosuppressive drugs.
The extracellular portion of the CD2 molecule can be divided into three
regions by epitope mapping.13 Monoclonal antibodies directed against CD2 inhibited adhesion and/or modulated T-cell activation, depending on the region of the cognate epitope. In vitro,
anti-CD2 blocking antibodies inhibited T-cell activation when added to
the mixed lymphocyte reaction5,9,14 and inhibited cell-mediated cytolysis when added to cytotoxicity
assays.4,9 In animal models, when administered in vivo,
such antibodies blunted contact sensitivity reactions, inhibited
development of both helper and cytotoxic responses to antigen, and
prolonged the survival of cardiac and pancreatic islet cell
allografts.14-17
BTI-322 (LO-CD2a) is an anti-human CD2 rat monoclonal IgG2b described
by Xia et al.18 The antibody recognized  90% of
E-rosette-forming peripheral blood lymphocytes and T-cell leukemias,
but it had no reactivity with B lymphocytes, B-cell leukemia cells, or
cells of myeloid origin. The amount of bound BTI-322 was greater on phytohemagglutinin (PHA)-activated lymphocytes than on resting lymphocytes, and it did not inhibit binding of OKT11, Leu5, or MP910,
suggesting that BTI-322 recognizes a partially cryptic epitope on CD2
that is expressed more highly after activation.18 BTI-322
itself is not mitogenic for human lymphocytes. In vitro, it inhibited
the proliferative response to tetanus toxoid, alloantigen, and
stimulation by OKT3, and the proliferative response to alloantigen was
blunted even when the antibody was added to the mixed lymphocyte reaction as late as day 4 of culture.18,19 The presence of BTI-322 in primary cultures led to hyporesponsiveness in secondary cultures, suggesting that anergy was induced during culture with BTI-322.20 In clinical studies, BTI-322 was shown to be
active for prevention or treatment of renal allograft
rejection.21,22 To further evaluate its immunosuppressive
activity, we have conducted a Phase II study of BTI-322 for treatment
of steroid-refractory acute graft-versus-host disease (GVHD) in
allogeneic marrow or blood stem cell transplant recipients.
| |
MATERIALS AND METHODS |
Patients.
Allogeneic marrow or blood stem cell recipients with steroid-refractory
acute GVHD from five participating transplant programs were enrolled in
the study. The protocol was reviewed and approved by the Institutional
Review Board at each center, and written informed consent was obtained
from each patient. Eligibility criteria included age 18 years,
evidence of hematopoietic recovery (absolute neutrophil count >0.5 × 109/L), and histologically documented persistent or
worsening GVHD of grade 2 after 3 to 10 sequential days of treatment
with methylprednisolone 2 mg/kg/d or its equivalent. Patients were
not eligible if they were more than 60 days posttransplant, had more
than one allogeneic transplant, were unlikely to survive more than 10 days, were pregnant or nursing, were human immunodeficiency virus
(HIV)-1 seropositive, had evidence of active malignancy, required
hemodialysis or use of a ventilator, had ascites detectable by physical
examination, or had a known hypersensitivity to mouse, rat, or rabbit
protein.
Treatment with BTI-322.
BTI-322 0.1 mg/kg rounded up to the nearest milligram was administered
intravenously (IV) daily for 10 consecutive days. This dose-schedule
was found to be safe and active in phase I/II studies for renal
allograft rejection.21,22 Dosing was based on actual body
weight. The dose was capped at 10 mg, the highest dose known to be safe
for humans. The drug was supplied in phosphate-buffered saline, and the
individual daily dose was diluted to a total volume of 50 mL in normal
saline (USP). The first dose of BTI-322 was administered
by rapid push over 5 minutes for the first nine patients and as a
30-minute infusion for the next 11 patients. The remainder of the doses
were administered as 30-minute infusions. Diphenhydramine 50 mg IV or
orally and acetaminophen 650 mg orally were required premedications for
the first dose only.
Safety monitoring.
Vital signs were recorded hourly through 4 hours from the start of each
infusion for the first three doses and thereafter only as needed.
Patients were monitored through 30 days after completion of therapy,
and adverse events were graded according to the National Cancer
Institute (NCI) Common Toxicity Criteria. Blood cell
counts and serum chemistries were performed before treatment and on
study days 2, 4, 6, 8, 10, 11, 20, 30, 45, and 100. Urinalyses were
performed before treatment and on study days 2, 4, 6, 8, and 10.
GVHD grading and response criteria.
GVHD was graded by the consensus criteria23 modified such
that poor performance status was not used to upstage an organ for
assignment of grade 4. Response was scored on study day 11. For the
overall assessment, a complete response (CR) was defined as stage 0 in
all organ systems, and a partial response (PR) was defined as a
decrease in at least one grade, but less than a CR and no worsening in
any organ system. For assessment of an organ system, a CR required
resolution of all manifestations of GVHD in that organ system, and a PR
required a decrease in stage in that organ system, but less than a CR.
CR and PR together constituted the total response rate.
Measurement of anti-BTI-322 activity.
Anti-BTI-322 by enzyme-linked immunosorbent assay (ELISA) activity was
evaluated before the first dose and at 11 and 45 days after the first
dose of BTI-322 (BioTransplant Inc, Charlestown, MA). For assessment of
anti-BTI-322 antibodies, 96-well plates (MaxiSorp Nunc Immuno Plates,
Nalge Nunc International, Rochester, NY) were coated with 50 µL
BTI-322 5 µg/mL, serial dilutions of patient or hyperimmune control
sera were loaded into the wells, and bound Ig was detected using
horseradish peroxidase-conjugated donkey anti-human IgG (Accurate
Scientific, Westbury, NY) or rabbit anti-human IgM (Dako, Carpenteria,
CA). Color development was achieved using o-phenylenediamine
dihydrochloride (Sigma, St Louis, MO), and absorbance was measured at
490 nm using a THERMOmax plate reader (Molecular Devices, Sunnyvale,
CA). Samples with antibody detected at 1:50 dilution were considered
positive.
For assessment of serum neutralizing activity, serial dilutions of
patient or hyperimmune control sera were spiked with BTI-322 40 ng/mL
and loaded into 96-well plates coated with 100 µL recombinant human
CD2 (sCD2; BioTransplant Inc) 2.5 µg/mL. Bound BTI-322 was detected
using horseradish peroxidase-conjugated rabbit antirat Ig (Dako).
Percent inhibition of binding was calculated as [(SB-C)/SB] × 100 where SB is the mean of the true absorbance of the spiked buffer
and C is the true absorbance of the serum dilution. Samples with
neutralizing activity detectable at 1:50 dilution were considered positive.
Pharmacokinetics.
Disposition parameters were determined in six patients with and four
patients without gut GVHD. Blood samples were collected before and at
1, 4, 8, 12, and 24 hours after the first and fourth doses of BTI-322.
Serum BTI-322 concentration was measured by ELISA (BioTransplant
Incorporated). A 96-well plate was coated with a murine monoclonal
antirat IgG2b (MARG2b, IMEX, Brussels, Belgium) and blocked with bovine
serum albumin. The plate was loaded with patient sera, and bound
BTI-322 was detected using horseradish peroxidase-conjugated mouse
antirat Ig (MARK-1 and MARK-3, IMEX) as described above. BTI-322
concentrations were determined by interpolation of sample absorbance
against a standard curve constructed using known graded concentrations
of BTI-322 in phosphate-buffered saline-Tween. PKAnalyst (MicroMath
Software, Salt Lake City, UT) was used to calculate the pharmacokinetic parameters, including volume of distribution (Vd), clearance (Cl), and
half-life (t1/2). The data were fitted to a
noncompartmental exponential model. Results for doses 1 and 4 were
calculated separately. Elimination function was estimated by least
squares. Vd was calculated using the concentration at time 0 extrapolated from the elimination function, and plasma Cl was
determined. The Vd was also normalized for patient weight.
Cmax, the maximal concentration, was the actual value
measured at 1-hour postdose.
Lymphocyte immunophenotyping.
Immunophenotyping was performed by flow cytometry using standard
techniques at Specialty Laboratories, Inc (Santa Monica, CA).
Peripheral blood samples were collected before and 4, 11, 20, 30, 45, and 100 days after the first dose of BTI-322. The absolute lymphocyte
count and the absolute numbers of lymphocytes expressing CD2 (OKT11),
CD3, CD3/CD4, CD3/CD8, CD16/CD56, and CD19/CD20 were determined for
each sample.
Statistical considerations.
The protocol was designed as an open-label phase II study. Treatment of
20 patients allowed detection of at least 15% activity with a beta
error of 5%. Analyses were descriptive in nature and no formal tests
of hypotheses were performed. Continuous variables were reported as
medians or means and standard errors (SE), and categorical data were
enumerated. Response rates were reported, and 95% confidence intervals
(CI) were calculated using the exact binomial distribution. Categorical
data were compared using Fisher's exact test.
| |
RESULTS |
Patient characteristics.
Twenty patients with steroid-resistant acute GVHD were enrolled in the
study. Patient characteristics are shown in
Table 1. Diagnoses included 8 chronic
myelogenous leukemia (5 in first chronic phase), 3 acute lymphoblastic
leukemia, 2 acute myelogenous leukemia, 1 myelodysplastic syndrome, 3 multiple myeloma, 2 malignant lymphoma, and 1 breast cancer. All
patients had received standard GVHD prophylaxis, and 7 (35%) had
T-cell-depleted transplants. For 5 patients, BTI-322 was the second
salvage therapy. At baseline, all patients had at least grade 2 GVHD,
and 15 (75%) had grades 3-4 GVHD.
Response to therapy.
Response to therapy was assessed on study day 11 (Table 2). Overall, 6 (30%; 95% CI, 12%
to 54%) patients had a CR and 5 (25%; 95% CI, 9% to 49%) had a PR
for a total response rate of 55% (95% CI, 32% to 77%). High
response rates were seen in skin (87%) and gut (54%), but liver GVHD
was unaffected by treatment with BTI-322. The total response rate was
significantly higher for patients with grade 2 GVHD (5 of 5 v 6 of 15, P = .04), but there was no difference in total response
when patients were categorized by transplant processing (7 of 13 with
T-cell depletion v 4 of 7 without T-cell depletion), or type of
donor (4 of 10 with an HLA-identical donor v 7 of 10 with an
alternative donor).
The total number of patients with grade 0 or 1 GVHD was near maximal by
study day 11, although GVHD resolved in a few additional patients after
study day 11 (Fig 1). Three of the six
patients who achieved a CR by study day 11 had a later recurrence of
acute GVHD. Five patients who completed the study day 100 assessment were in CR; the assessment was performed on day 99 for one patient who
then expired on day 100. Four patients developed chronic GVHD within
the study period.
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| Fig 1.
Distribution of grades of GVHD during and after treatment
with BTI-322. Height of bar represents the number of patients with
grade 0 ( ), grade 1 ( ), grade 2 ( ), or grade 3-4 ( ). Total
number of patients represents evaluable survivors at each evaluation
timepoint.
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Laboratory correlates.
The mean absolute lymphocyte count fell from 0.765 (±0.147) × 109/L pretreatment to 0.48 (±0.138) × 109/L on study day 11 and rose to
0.743 (± 0.220) × 109/L by study day 20. The
absolute CD2+ cell count fell rapidly after infusion of
BTI-322, remained low throughout the treatment period, and returned to
pretreatment levels by study day 20 (Fig
2). The decrease in CD2+ cells was not due to inhibition of
detection by blockade of CD2 by bound BTI-322, as a similar change in
T-cell subsets as measured by other antibodies (CD3, CD4, and CD8) was
observed (Fig 2). The absolute CD56+ cell count was
affected less, and the number of B cells was relatively unaltered by
treatment with BTI-322. There was no correlation between response to
therapy and the absolute CD2 count on study day 11.
Pharmacokinetics of BTI-322.
Pharmacokinetic studies were performed in 10 patients, 6 with and 4 without gut GVHD (Table 3). The presence of
gut GVHD did not appear to affect the pharmacokinetics of BTI-322.
Serum concentrations of BTI-322 increased rapidly after infusion, and the concentration curves essentially decreased in parallel after the
first and fourth doses (Fig 3). The
t1/2 was 9.1 hours with the first dose and 11.2 hours with
the fourth dose (P = not significant [NS]). The
mean Vd exceeded ideal plasma volume with the first dose and approached
ideal plasma volume with the fourth dose.
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| Fig 3.
Serum concentrations (mean ± SE) of BTI-322 after
infusion of the first (solid line) or fourth (dashed line) dose of
drug. Data are displayed for all 10 patients who had pharmacokinetic
sampling.
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Safety evaluation.
One patient received only four doses of BTI-322; treatment was
discontinued because of progressive GVHD. The remainder of the patients
received all 10 doses according to the treatment schedule. A total of
930 adverse events were reported; 156 were considered severe or
life-threatening (Table 4). No patient
manifested a posttransplant lymphoproliferative disorder through study
day 100.
Eleven (55%) patients had an adverse event related to BTI-322. Of the
total 930 adverse events, there were 44 (5%) considered related to
BTI-322. Twenty-two (2.4%) adverse events related to BTI-322 were
mild, 19 (2.0%) were moderate, three (0.3%) were severe, and none was
life-threatening. Eighty-nine percent of the adverse events related to
BTI-322 occurred with the first dose in 10 patients. These patients
experienced dyspnea sometimes accompanied by nausea, vomiting,
diarrhea, hypertension, and tachycardia after infusion of the first
dose of BTI-322; four had chills, and two had fever. The intensity of
the reaction was less with 30-minute infusion than with bolus dosing.
The reaction was transient and did not preclude subsequent dosing. A
typical cytokine release syndrome was not seen.
One patient developed graft failure. This patient had an absolute
neutrophil count of 0.7 × 109/L before treatment with
BTI-322 and >1.0 × 109/L after completion of
therapy. However, the absolute neutrophil count had been persistently
<0.5 × 109/L when the patient died of progressive
GVHD and sepsis on study day 38. The only other hematologic abnormality
noted in the study patients was lymphopenia (see above).
There were no abnormalities in serum chemistries that could be ascribed
to BTI-322 treatment. No IgG or IgM anti-BTI-322 antibodies were found
in the 26 samples tested after therapy. Neutralizing activity of
undetermined nature was detected in one patient's pretreatment sample.
This patient died on study day 19 of progressive liver GVHD and sepsis.
Neutralizing activity was not found in any of the posttreatment
samples.
Causes of death.
Four patients were alive on study day 100 for a survival rate of 20%
(95% CI, 6% to 44%). Sixteen patients died; 7 had persistent or
recurrent GVHD, 3 had GVHD with infection, and 6 died with infection
after resolution of GVHD.
| |
DISCUSSION |
Although antithymocyte globulin (ATG) is widely accepted as primary
treatment of steroid-refractory acute GVHD, overall response rates are
only 29% to 54%,24-26 and new strategies are required. Use of BTI-322, a monoclonal antibody directed against CD2, for treatment of GVHD was an attractive therapeutic approach, as in vitro
experiments demonstrated that anti-CD2 antibodies blocked both primary
and memory alloantigen responses and may also inhibit activated
cytotoxic cells. In preliminary clinical studies using anti-CD2
monoclonal antibodies 9.6, 35.1, or B-E2 alone or in combination with
other antibodies, improvement in GVHD was reported for 11 (48%) of 23 patients.27,28 We have treated 20 patients with BTI-322 for
steroid-refractory GVHD. The complete response rate was 30%, and the
overall response rate was 55%. These results confirm that targeting
CD2 is a viable treatment strategy for patients with GVHD.
Treatment with BTI-322 was most successful in patients with skin or gut
GVHD. None of the five patients with hepatic GVHD achieved a CR by day
11 in this study. With most therapies for GVHD, it is common to see no
or minimal response in hepatic GVHD. If the bile ducts are injured
severely, it may not be possible to see a reduction in serum bilirubin
in the short-term.
Determining the means by which BTI-322 induces remission of GVHD might
help design treatment schedules with a greater response rate. Ayroldi
et al29 reported that CD2 engagement reduces
anti-CD3-induced apoptosis of T lymphocytes. If blockade of CD2
engagement released the apoptotic mechanism, the prolonged
hyporesponsiveness seen after treatment with anti-CD2 might be due to
clonal deletion. This does not appear to be the mechanism of action of
anti-CD2 antibodies in vivo, however, because the hyporesponsive state is of limited duration,15-17 and recurrence of GVHD was
seen in this study after completion of therapy with BTI-322.
In our patients, there was a rapid and marked loss of CD2+
and CD56+ cells from the peripheral blood after treatment
with BTI-322, and all T-cell subsets were involved. Because trafficking
of lymphocytes may depend in part on the adhesive property of
CD2,30 downregulation of CD2 expression on lymphocytes may
impede return of these cells to the intravascular space and to target
organs for GVHD. The rapid return of CD2+ and
CD3+ cells to pretreatment numbers after cessation of
therapy with BTI-322 is consistent with this hypothesis. Further
evidence is derived from rodent models in which treatment with anti-CD2
antibodies led to downregulation of expression of CD2 without altering
expression of CD3, and normal numbers of CD3+ cells were
seen in lymphoid organs.15-17
An alternative mechanism for the hyporesponsiveness induced by anti-CD2
is blockade of the CD2-transduced costimulatory signal required for
T-cell activation. In vitro, CD2 antibodies can inhibit both primary
and memory alloantigen responses,5,9,14 but it is
noteworthy that anergy is induced only with the primary response.20 Consequently, although the GVH reaction could
be blunted by treatment with BTI-322, a long- lasting state of
tolerance may not be induced if alloreactivity involved memory T cells
directed against cross-reactive epitopes on target tissues. Longer or
repeated courses of therapy with BTI-322 may be required for successful treatment of GVHD.
Administration of mitogenic T-cell antibodies such as OKT3 frequently
results in high fever, chills, bronchospasm, and hypotension due to
release of cytokines. BTI-322 is not mitogenic and, in fact, inhibits
cytokine production in lymphocytes stimulated through the T-cell
receptor,19 so a classic "first dose reaction" was not expected for our patients. However, rapid infusion of BTI-322 was
associated with transient dyspnea, gastrointestinal reactions, hypertension, and tachycardia that were self-limiting, and this response was abrogated by slow infusion of the drug. This was not a
reaction unique to the marrow transplant patients, as it was also
reported to occur in the renal allograft recipients treated with
BTI-322.21,22 Similar reactions reported with other rodent monoclonal antilymphocyte antibodies have been attributed to histamine release.31 Overall, treatment with BTI-322 was otherwise
well-tolerated.
The immunosuppression induced by anti-CD2 antibodies may be sufficient
to abrogate antitumor immunity,16 and this raises a concern
when using BTI-322 in patients with malignancies. However, neither
relapse nor posttransplant lymphoproliferative disorders (PTLPD) were
noted in our patients, albeit the follow-up is short. An increased risk
of PTLPD was also not seen in renal transplant recipients who received
BTI-322.21 Infections were the major complication seen in
our patients. Given the severity of GVHD and the use of multiple
immunosuppressive drugs, it is difficult to determine if BTI-322
altered the risk of infection.
Acute GVHD of the gut is frequently manifested as a protein-losing
enteropathy, and the protein-losing state may alter the clearance of
therapeutic antibodies. However, pharmacokinetic studies in our
patients demonstrated that GVHD of the gut did not significantly alter
clearance of BTI-322, so dose modification is not required for patients
with gut GVHD. The half-life of BTI-322 in our patients was 9 to 11 hours, which suggests that immunosuppressive concentrations of antibody
(>500 ng/mL in vitro) could be maintained with daily or
every-other-day dosing. Incorporating the epitope binding regions of
the rodent antibody onto a human background generally results in a
therapeutic antibody with a much longer half-life than for the rodent
form. Our results show that BTI-322 has activity in the treatment of
GVHD with little toxicity. Pursuit of a humanized form of the antibody,
which could be administered on a more convenient dosing schedule, is
therefore warranted.
| |
ACKNOWLEDGMENT |
We are grateful to Dr D. Latinne (IMEX, Brussels, Belgium), who
generously provided the murine antirat antibodies for the immunoassays.
| |
FOOTNOTES |
Submitted May 21, 1998;
accepted July 29, 1998.
Supported in part by grants from MedImmune, Inc and by Grant No.
CA16672 from the National Institutes of Health.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Donna Przepiorka, MD, PhD, Baylor College
of Medicine, Center for Cell and Gene Therapy, 6621 Fannin St,
MC3-3320, Houston, TX 77030; e-mail: donnap{at}bcm.tmc.edu.
| |
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Abstract
Introduction
