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Abstract
This article focuses on the recent dramatic advances in the applications of monoclonal antibody therapy to hematopoietic and neoplastic disease. The increase in the understanding of the role of growth factors and their receptors in the pathogenesis of malignancy and other undesirable hematological events taken in conjunction with the ability to produce humanized chimeric monoclonal antibodies to these targets is providing a new perspective for the treatment of leukemia, lymphoma and breast cancer, autoimmune disease and for prevention of ischemic complications. Dr. Waldmann describes approaches targeting the Her2/neu and the II-2/IL-15 receptor systems. The Her2/neu receptor is overexpressed in select breast, ovarian, gastric and pancreatic neoplasms. The use of trastuzumab (Herceptin) in the treatment of patients with breast cancer whose tumors overexpress this receptor are reviewed. The IL-2 receptor (Tac) is expressed on select malignant cells (adult T cell leukemia, hairy cell leukemia) and activated T cells involved in autoimmune disease and organ rejection. Humanized anti-Tac alone (daclizumab, Zenapax) or armed with toxins or radionuclides have been used successfully in the treatment of leukemia. Dr. Levy updates the experience with rituximab targeting CD20 on B cell lymphomas and reviews the antibodies to CD3, CD22, CD33, CD52, HLA-DR ß chain and HLA-D currently in or proposed for clinical trials, including radiolabelled antibodies. In the last section, Dr. Coller reviews the therapeutic results achieved with abciximab (ReoPro), an antagonist of platelet receptor GPIIbIIIa for the prevention of restenosis in percutaneous coronary interventions and the treatment of unstable angina. The mechanism of action, pharmacology and safety and efficacy of abciximab are reviewed.
Introduction
Thomas A. Waldmann, M.D.*
The development of monoclonal antibody technology 25 years ago by Köhler and Milstein has provided enormous opportunities for ex vivo diagnosis in a range of disorders.1 However, in the area of immunotherapy of human disease monoclonal antibodies are just beginning to fulfill the promise inherent in their great specificity for recognizing and selectively binding to antigens on cells.2,3,4
Monoclonal antibodies (mAbs) have been applied clinically to the diagnosis and therapy of cancer and for the modulation of the immune response to produce immunosuppression for the treatment of autoimmune and graft-versus-host disease (GVHD) and for the prevention of allograft rejection. Furthermore, the role of monoclonal antibodies in the treatment of bacterial infections and to inhibit the accumulation of neutrophils and thus reduce tissue damage in bacterial meningitis and myocardial reperfusion injury has been under active study. Finally, monoclonal antibodies have been proposed for the therapy of myocardial infarctions and for the reversal of drug toxicity.
HER-2/neu: Target for Treatment of Epithelial
Malignancy
HER-2/neu, also known as c-erb B-2, is expressed on the breast,
ovarian, gastric and prostatic tumors of subsets of patients with these
disorders.5,6,7,8,9
HER-2/neu, the product of the proto-oncogene c-erb B-2 is a 185 kDa
transmembrane receptor with protein tyrosine kinase activity that is a member
of the epithelial growth factor (EGF) receptor family. This receptor is
modestly expressed in normal adult tissues; however, it is strongly associated
with the epithelial solid malignancies and is overexpressed in approximately
25-35% of human gastric, lung, prostatic and breast carcinomas.
HER-2/neu overexpression in breast carcinoma is inversely related to
estrogen receptor expression and is correlated with poor
prognosis.7
Trastuzumab (HerceptinTM), an IgG1 mAb that contains human
framework constant immunoglobulin regions associated with the complementarity
determining regions of the murine antibody (4D5) that binds to
HER-2/neu, was shown to enhance the antitumor activity of paclitaxel
and doxorubicin when studied in mice bearing HER-2/neu overexpressing
human breast cancer
xenografts.10 Two
clinical trials supported the efficacy of trastuzumab especially when used in
association with
chemotherapy.12,13,14
When studied as a single agent in a multicenter open-label single-arm clinical
trial, patients with the 2+ level of overexpression of HER-2 (based on a 0- 3+
scale) obtained a partial remission in 2% of cases, whereas in patients with
3+ levels of overexpression 2% of treated patients achieved a complete
remission and in an additional 15% a partial remission was reported. In a
randomized control trial patients with metastatic breast cancer who had not
been treated previously with chemotherapy for metastatic disease obtained
significantly greater responses [45% vs. 29% (p < 0.001)] and longer median
duration of response (9.1 months vs. 5.8 months) when they received
trastuzumab and chemotherapy (paclitaxel or cyclophosphamide plus doxorubicin)
as compared to those who received chemotherapy alone. On the basis of these
data, trastuzumab has received marketing clearance from the FDA for use in the
treatment of patients with HER-2 overexpressing breast
cancer.(11)
Toxicity, especially cardiac toxicity (including death), has been reported in
association with the use of trastuzumab, especially used in association with a
cardiotoxic regimen such as an anthracycline plus cyclophosphamide (28% of
patients on trastuzumab plus anthracycline and cyclophosphamide developed
cardiac toxicity compared to only 7% of patients on an anthracycline plus
cyclophosphamide without
trastuzumab).14
I. IL-2R and IL-15R: Targets for Immunotherapy of Leukemia/Lymphoma and Autoimmune Disease, and for the Prevention of Organ Allograft Rejection
Thomas A. Waldmann, M.D.
The expression of interleukin-2 (IL-2), the induction of its multisubunit receptor and the subsequent interplay of this ligand with its receptor are pivotal events in T cell activation. Our present understanding of the normal IL-2/IL-2R system and of disorders in this network in disease opens the possibility for more specific immune intervention. The clinical application of agents that inhibit IL-2 function by acting on the IL-2 receptor has provided a new perspective for the prevention of organ allograft rejection, for the treatment of select T cell-mediated autoimmune disorders, and for the therapy of leukemia and lymphoma.
IL-2 is a 15.5 kDa glycoprotein that exerts its effect on activated T
cells, natural killer (NK) cells and B cells by binding to a high-affinity
form of the IL-2R. This high-affinity IL-2R is composed of three distinct
membrane components: the 55 kDa IL-2R
chain (Tac, CD25), the 70-75 kDa
IL-2Rß chain (CD122), and the 64 kDa common gamma (
c)
chain (CD132).1
Cytokines such as IL-2 manifest considerable redundancy that is explained by
the sharing of common receptor subunits among members of the cytokine receptor
family. Most of these cytokines have their own "private" receptor,
but IL-2 also shares two of its receptor subunits. In particular, the
c chain is shared by IL-2, IL-4, IL-7, and IL-9, Recently
two groups including our own simultaneously reported the recognition of an
additional cytokine, IL-15, in this family that employs c
and can stimulate T cell
proliferation.2,3
In T and NK cells the IL-15 receptor includes IL-2Rß and
c subunits, which are shared with IL-2 as well as an
IL-15-specific receptor subunit, IL-15R. IL-2 and IL-15 share many
features: they are both members of the 4-helix bundle cytokine family, and
they both use IL-2Rß and c for their action in T cells.
Nevertheless, dramatic differences exist between these two cytokines in terms
of their cellular sites of synthesis and the levels of control of their
synthesis and secretion. IL-2 is produced by activated T cells, and its
expression is controlled at the levels of mRNA transcription and
stabilization, whereas the control of IL-15 expression is much more complex
with regulation at the levels of transcription, translation and intracellular
trafficking and translocation. As predicted from their sharing of receptor
subunits, IL-2 and IL-15 have certain redundant functions including their
action in innate immunity where they stimulate NK cell development, survival
and activation. In contrast, they have unique roles in many of the adaptive
immune responses of T cells where their functions are distinct. The unique
role of IL-2 is in the maintenance of peripheral tolerance by causing the
suicide of self-reactive T cells by a mechanism termed activation-induced cell
death (AICD).4 In
contrast, IL-15 inhibits IL-2-mediated AICD and has a predominant role in the
maintenance of immunological memory, especially the development and
persistence of memory-type CD8 cells directed toward foreign
pathogens.5
The private receptor for IL-2, the IL-2R, has become a target for
immune intervention. The scientific basis for this approach is that resting
normal cells do not express IL-2R, whereas it is expressed by a
proportion of the T cells involved in organ allograft rejection, by T
cell-mediated autoimmune disease, and by select leukemias and lymphomas. In
particular, IL-2R is constitutively expressed by the abnormal cells in
certain forms of lymphoid neoplasms including human T cell lymphotropic virus
I (HTLV-I)-induced adult T cell leukemia/lymphoma (ATL), cutaneous T cell
lymphoma (CTCL), B-cell hairy cell leukemia, and Hodgkin's
disease.1
To exploit this difference in IL-2R expression between normal cells
and leukemic T cells a series of approaches were developed including those
involving un-modified murine antibodies to IL-2R (anti-Tac), the
humanized form of this antibody (daclizumab, Zenapax), as well these
antibodies armed with toxins or - and ß-emitting radionuclides.
The original IL-2R studies focused on the treatment of
HTLV-I-associated ATL, an aggressive leukemia/lymphoma of mature lymphocytes
caused by the retrovirus HTLV-I. No chemotherapeutic regimen appears
successful in altering patient survival, and the patients have a median
survival duration of only 9
months.6 The
retrovirus HTLV-I encodes a 42-kDa protein termed tax that indirectly
stimulates the transcription of numerous host genes including those of IL-2
and IL-2R that are involved in T cell activation and potentially
HTLV-I-mediated leukemogenesis. The malignant ATL cells constitutively express
10,000-35,000 IL-2R chains identified by the anti-Tac mAb, whereas the
patient's normal resting cells do not. Furthermore, in approximately 10-20% of
patients with ATL there is evidence supporting an autocrine loop involving
IL-2 and IL-2R-dependent expansion of the leukemic cells. These observations
led us to perform therapeutic trials with the unmodified murine version of
anti-Tac mAb.7 Six
of 19 patients treated developed a partial (4) or complete (2) remission
lasting from one month to over 9 years as assessed by phenotypic analysis as
well as molecular genetic analysis of HTLV-I proviral integration and T cell
receptor gene rearrangements. On the basis of a murine model of ATL we have
developed, this action appears in part to be due to the prevention of the
interaction of IL-2 with its growth factor receptor leading to cytokine
deprivation-mediated apoptotic cell death. Activation-induced cell death also
is clearly a factor in this effective therapeutic response. Although murine
antibodies such as murine anti-Tac are of value in the therapy of human
disease, their effectiveness is limited because such rodent monoclonal
antibodies have a short in vivo survival in humans, induce an immune response
that neutralizes their therapeutic effect, and may be relatively ineffective
at recruiting host effector functions. To address this issue a humanized form
of anti-Tac (Hu-anti-Tac) was developed that retained the
complementarity-determining regions from the mouse but had virtually all of
the remainder of the molecule derived from human
IgG1
.8 The
humanized version of anti-Tac had improved pharmacokinetics (t1/2 survival of
20 days for the humanized as compared to 40 hours for the murine version), is
virtually nonimmunogenic in humans, and functions in antibody-dependent
cellular cytotoxicity with human mononuclear cells. Hu-anti-Tac has been used
in benign as well as malignant disorders. Following encouraging observations
in animal models and in phase I/II trials, Hoffmann-La Roche conducted two
double-blind placebo-controlled randomized trials that included 535 evaluated
patients to determine the value of Hu-anti-Tac (daclizumab, Zenapax) in
preventing renal allograft
rejection.9 In each
trial all patients received a standard immunosuppressive regimen. The parallel
treatment groups also received either an intravenous placebo or a dose of 1.0
mg/kg of daclizumab prior to transplant and on four subsequent occasions
separated by 2 weeks. No drug-specific adverse events or increased morbidity
were observed. Acute rejection episodes were reduced by 40% in patients
treated with daclizumab (p 
0.01). Ninety-eight percent of the patients
receiving triple immunotherapy and daclizumab retained their renal allograft
for 6 months whereas only 92% of the patients in the placebo controlled group
retained their grafts (p = 0.02). On the basis of these phase III trials the
FDA approved daclizumab for use in the prevention of acute kidney transplant
rejection. In addition to its use in the prevention of organ allograft
rejection, we have shown that daclizumab is of value in the therapy of T
cell-mediated autoimmune disorders. In particular, daclizumab provided
effective treatment for noninfectious intermediate and posterior uveitis in a
clinical trial.10
Furthermore, daclizumab therapy of patients with the neurological disease
HTLV-I-associated myelopathy (tropical spastic paraparesis) led to a reduction
in HTLV-I viral load, a decrease in the spontaneous T cell proliferation ex
vivo of the peripheral blood mononuclear cells of patients, and a
stabilization or amelioration of the neurological
disease.11
A limitation in the use of unmodified monoclonal antibodies in the
treatment of leukemia/lymphoma is that they are relatively ineffective as
cytocidal agents. This is true in late-stage HTLV-I-associated adult T cell
leukemia, a stage when the cells continue to express IL-2R but no
longer produce nor require IL-2 for their proliferation. This limited efficacy
of many unmodified mAbs in cancer therapy led to the alternative approach of
using agents such as anti-Tac as carriers of cytotoxic substances including
toxins or - and ß-emitting radionuclides. In one group of studies
Kreitman, Pastan and coworkers developed LMB2, a version of anti-Tac linked to
a truncated form of a Pseudomonas exotoxin (PE38) that has a deletion
of domain 1. Domain 1 is responsible for unwanted ubiquitous binding of the
toxin. A single chain toxin fusion protein, LMB2 (anti-Tac Fv-PE38) in which
the variable region (Fv) of anti-Tac was joined in peptide linkage to PE38,
has proved to be very effective in the treatment of IL-2R-expressing
hairy cell leukemia with all four treated patients undergoing a partial or
complete
remission.12 In an
alternative approach radiolabeled monoclonal antibodies were developed to
deliver a cytotoxic agent to target leukemic cells. One advantage in the use
of radiolabeled antibody conjugates is that with the appropriate choice of
radionuclide, radiolabeled monoclonal antibodies kill cells at distances of
several cell diameters. Therefore, a radiolabeled mAb such as anti-Tac binding
to an IL-2R-expressing cell may kill adjacent nonexpressing cells, thereby
overcoming the tumor cell antigenic heterogeneity that presents a problem for
most other monoclonal antibody-mediated approaches. In a clinical trial
involving 90Y-anti-Tac for the therapy of HTLV-I-associated ATL, in
16 evaluable patients seven partial and two complete remissions were
observed.13
Clinically meaningful (i.e. 
Grade 3) toxicity was limited to the
hematopoietic system. An important element in our present developmental
efforts with systemic radioimmunotherapy involves the use of -emitting
radionuclides to arm humanized anti-Tac or its fragments. Alpha-emitting
radionuclides that are under evaluation include 212Bi,
213Bi, and 211At.
Although IL-2R-directed therapy has met with considerable success in
selected leukemias, autoimmune disorders and allograft rejection, approaches
directed toward this receptor subunit have limitations. In particular,
antibodies to IL-2R do not inhibit the actions of IL-15, a cytokine
that does not bind to this subunit. Abnormalities of IL-15 expression have
been described in patients with rheumatoid arthritis, inflammatory bowel
disease, multiple sclerosis, chronic liver disease due to hepatitis C, T cell
alveolitis, and in diseases associated with the retroviruses HIV and
HTLV-I.14 Thus new
approaches directed toward IL-15, its receptor or its signaling pathway may be
of value in the therapy of these disorders. Our own IL-15-directed therapeutic
approach has focused on the cytokine receptor subunit and signaling pathways
shared among multiple cytokines including IL-15 in an effort to yield more
profound immunosuppression than can be achieved by the inhibition of the
action of a single cytokine such as IL-2. Our initial trials use Mikß1,
an antibody directed toward the ß subunit that is shared by IL-2 and
IL-15. The humanized version of this antibody inhibits the action of IL-15 on
T and NK cells and prolongs renal allograft survival in cynomologus monkeys.
In our current clinical trial we are evaluating Mikß1 in the therapy of
patients with T cell-type large granular lymphocytic leukemia associated with
granulocytopenia. The monoclonal large granular lymphocytosis involved in this
disease express IL-2/IL-15Rß and c, but not
IL-2R.
In summary, our expanding understanding of the IL-2/IL-2R as well as IL-15/IL-15R systems taken in conjunction with the ability to produce humanized antibodies directed toward the IL-2 and IL-15 receptors have provided a new perspective for the prevention of organ allograft rejection for the treatment of select autoimmune disorders and for the therapy of those leukemia/lymphomas that express the IL-2 receptor.
II. Monoclonal Antibodies for the Treatment of Lymphoma: Many Different Ways to Use a New Modality
Ronald Levy, M.D.*
Monoclonal antibodies are finally finding their way into the standard practice of hematology and oncology. With the approval by the FDA of rituximab for the treatment of relapsed low-grade lymphoma, a new and welcome modality has been added to the therapeutic armamentarium. Several other monoclonal antibodies are in late stages of clinical development and are likely to be available to the practicing hematologist/oncologist in the near future. In this section, the current states of naked monoclonal antibodies, antibody-drug conjugates and radiolabeled antibodies mainly for the treatment of non-Hodgkin's lymphoma (NHL) are reviewed.
Rituximab
Rituximab (Rituxan) is a chimeric human/mouse antibody directed against the
CD20 antigen, which is expressed on normal and malignant B-lymphocytes. In the
original phase I trial of this agent it was apparent that it had anti-tumor
activity1 with no
dose-limiting toxicity. In the pivotal trial that led to the FDA approval for
patients with recurrent low-grade lymphoma, the response rate of such patients
was approximately 50% PR + CR with a median duration of these responses of
approximately 13
months.2 Now that
this drug is in widespread use, a number of questions are being addressed:
The standard dosing schedule of 375 mg/m2 weekly x 4 has been investigated and compared to longer dosing regimens and repetitive dosing regimens. Because of the pharmacokinetics of this chimeric human/mouse antibody, detectable levels of the antibody are present as long as several months after the standard 4-week dose regimen. Therefore it is no surprise that extended numbers of doses have not led to substantial increases in response rates.3 The question of repetitive dosing cycles at more prolonged intervals is still open and under investigation.
It is clear that patients who initially respond to rituximab can be retreated successfully at the time of relapse. Approximately 40% of previously sensitive patients will respond a second or even a third time to this drug. It is not clear why the other 60% of patients who respond the first time fail to respond a second time. Interestingly, when they do occur, subsequent responses can last longer than initial responses.4
Although the original pivotal trial was limited to patients with non-bulky disease, subsequent studies have shown that the agent is almost as effective in patients with bulky disease.5
Numerous studies have been done combining this agent with a variety of chemotherapeutic regimens. It is clear that because of their non-overlapping toxicities, the monoclonal antibody can be safely combined with chemotherapy. There is even reason to believe that such combinations are at least additive in their anti-tumor effects. The antibody/chemotherapy study with the longest follow-up interspersed rituximab infusions before, during, and after the standard six cycles of CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone). This small series included predominantly patients with low-grade lymphoma, most of who were receiving their original lymphoma treatment. High rates of tumor response (95%) and long-term control of the disease (70% free from progression at 3 years) were observed.6 Other schedules, including administration of single infusions of rituximab immediately prior to each CHOP cycle, have also been reported in patients with intermediate-grade lymphoma.7
A number of different lymphoid malignancies have been tested for sensitivity to rituximab. Significant, but lower, single-agent response rates have been seen in diffuse large cell lymphoma, mantle cell lymphoma,8 chronic lymphocytic leukemia (CLL),9 Waldenström's macroglobulinemia,10 and post-transplant lymphoproliferative disease.11
The timing of the use of rituximab in the management of NHL is under investigation. Reports have appeared showing high rates of response when the drug is used as a single-agent, first-line therapy for the treatment of low-grade lymphoma.12,13 The reported series are small and the follow-up is short, but if these results are confirmed, the drug may eventually find a role as first-line therapy in an attempt to delay the time when chemotherapy will be needed for the management of low-grade lymphomas.
Mechanism of Action
The evidence to date suggests that the drug has its primary mechanism of
anti-tumor action by binding to the tumor cells and attracting killer cells
through an antibody-dependent cellular cytotoxicity mechanism (ADCC).
Experimental studies have shown that cells bearing an Fc receptor are
necessary for the acute anti-tumor effect of
rituximab.14 These
studies, conducted in special gene knock-out mouse models, point the way for
second generation antibody products, those with optimized Fc fragments that
may interact more effectively with Fc receptors. The longer term anti-tumor
effects of the drug and the longer durations of second remissions induced by
this drug are more difficult to understand by an ADCC mechanism. One
hypothesis involves a potential active immune response by the host against his
own tumor to account for these later effects, but there is as yet no evidence
for or against this hypothesis.
Tables 1 and 2 describe trials that are currently active or are about to be activated by cooperative groups. Table 3 lists other clinical trials underway sponsored by Genentech. Additional studies are underway in mantle cell lymphoma, multiple myeloma, post-transplant lymphoproliferative disease, CLL, Waldenström's macroglobulinemia, hairy cell leukemia, acute lymphocytic leukemia, and autoimmune diseases.
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Other Antibodies in Clinical Trials
(Table 4)
Campath-1H
Campath-1H is a humanized version of rat monoclonal antibody directed
against the CD52 antigen which is found on all mononuclear leukocytes.
Clinical trials using Campath-1H have been performed over the past 10 years in
multiple disease settings, including non-Hodgkin's lymphoma, chronic
lymphocytic leukemia, multiple sclerosis, and other autoimmune diseases, solid
organ and bone marrow transplants, and GVHD. This drug is associated with
acute infusion reactions (mediated by tumor necrosis factor [TNF],
interleukin-6 [IL-6], and interferon-), prolonged T cell depletion and
opportunistic infections. These complications can be controlled by gradual
escalation of initial doses and prophylactic treatment with anti-inflammatory
and anti-infectious medications.
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Three separate phase II studies have been performed on patients with NHL and CLL. The most recent study involved patients with B-cell CLL who had received prior alkylating agents and fludarabine therapy.15 Ninety-three patients were enrolled in 22 study centers. There was a substantial objective response rate of 33% with resolution of peripheral lymphocytosis in 98% of evaluable patients. The median duration of response has not yet been reached at greater than 7 months of follow-up. Because of the immunosuppressive effects of this monoclonal antibody, serious adverse events occurred that involved infectious complications. This drug is currently under FDA review for the treatment of advanced-stage fludarabine-refractory CLL patients.
hLL2 (Epratuzumab)
This humanized murine antibody is directed against the CD22 antigen present
on normal and malignant B lymphocytes. A phase I/II dose escalation trial has
been completed in patients with relapsed NHL. A maximum dose of 1000
mg/m2 given weekly for 4 weeks was reached. Tumor responses were
seen, no dose-limiting toxicity was observed, and there was no evidence of
immunogenicity. This agent is in further clinical testing for the treatment of
NHL.16
Hu1D10
1D10 is a murine IgG1 monoclonal antibody that binds to a variant of the
HLA-DR beta-chain. The antibody was humanized by CDR grafting. The 1D10
antigen is expressed on lymphocytes, macrophages, and dendritic (mesenchymal)
cells and on most B cell neoplasms. In pre-clinical studies, 1D10
antigen-positive animals demonstrated a decrease in circulating B cells
following infusion of Hu1D10. The Cancer Treatment and Evaluation Program
(CTEP) is currently sponsoring a phase I dose escalation study of Hu1D10 in
patients with relapsed NHL. At each of five dose levels, ranging from 0.15
mg/kg to 15 mg/kg, patients receive a series of 4 infusions over 2 hours on
days 1, 8, 15, and 22. Dose level 3 (1.5 mg/kg) has been reached with
preliminary evidence of efficacy and no unexpected or dose-limiting toxicity
observed.17
HuM291
HuM291 is a humanized murine IgG2 monoclonal antibody against the human CD3
marker. This antibody has undergone preclinical and clinical testing for
various indications, where it was noted to profoundly deplete normal
circulating T cells. It is now under consideration for clinical testing
against CD3-positive T cell lymphomas. In chimpanzee studies, HuM291 induced
virtually complete peripheral blood T cell depletion as early as 6 hours after
its administration at doses ranging from 0.1 to 10 mg (total dose) per 35-50
kg animal. T cell counts increased as the HuM291 concentration in circulation
declined, indicating that the T cell depletion in these animals was
reversible.
A multiple dose escalation study of HuM291 given intravenously to renal transplant patients experiencing acute rejection has entered 14 patients at 5 dose levels (0.0015 mg/kg, 0.0045 mg/kg, 0.015 mg/kg, 0.030 mg/kg, or 0.045 mg/kg). Profound T cell depletion was achieved and the extent and duration of T cell depletion appeared to be dose dependent, with the highest dose leading to 14-28 days of T cell counts below 100 cells/mm3. A multicenter study evaluating the safety and pharmacology of HuM291 administered as a single subcutaneous injection to patients with mild or moderate psoriasis has just begun.
CTEP proposes to initiate evaluation of HuM291 in CD3+ T cell malignancies. An initial phase I dose escalation trial would be designed to identify maximal biologic effect with saturation kinetics. Dosing will start at the highest dose given previously on a multi-dose basis, with the dosing interval to be defined by pharmacokinetics studies from ongoing trials. Subjects will be followed for toxicity, T cell depletion and tumor response.
Antibody-drug conjugate (gemtuzumab; Mylotarg)
Mylotarg is composed of a humanized antibody against the CD33 antigen that
has been chemically conjugated to calicheamicin, a small molecule that kills
dividing cells by DNA intercalation. The CD33 antigen is expressed on myeloid
progenitors and committed precursors but not on myeloid stem cells. It is
expressed on virtually all acute myelogenous leukemia (AML) cells. It has
recently been approved by the FDA for the treatment of recurrent AML in the
elderly. The antibody-drug conjugate has been shown to be well tolerated, to
saturate target sites and to induce a 26% overall remission rate in patients
60 years and older with CD33 positive AML in first relapse. It causes
myelosuppression but does not ablate normal
hematopoiesis.18
Radiolabeled monoclonal antibodies (Bexxar, Zevalin, Lym-1)
Two radiolabeled antibody products are in advanced stages of clinical
development, 131I-tositumomab (Bexxar) and IDEC-Y2B8
(Zevalin).19,20
Both of these antibodies are murine monoclonal antibodies. Both are directed
against the CD20 antigen present on normal and malignant B lymphocytes. Bexxar
is labeled with 131I and Zevalin is labeled with 90Y.
Both have shown impressive anti-lymphoma activity, superior to that found with
unlabeled monoclonal anti-CD20
antibodies.21 Both
of these radiolabeled products, however, have dose-limiting toxicity,
predominantly bone marrow suppression. As with unlabeled antibodies, studies
are underway with these radiolabeled antibodies to determine the optimal
timing, range of diseases that can be treated, and strategies of integration
with other forms of anti-lymphoma therapy. For instance, the Bexxar product
has been studied as primary therapy for patients with low-grade follicular
lymphoma.22 These
studies have shown an impressive response rate. Follow-up studies are under
way to determine the duration of these remissions and the tolerance of these
patients to subsequent therapies. In another example, the Bexxar product has
been studied in conjunction with myeloablative therapy supported by stem cell
transplantation.23
Long-term remissions of disease have been documented, and studies are underway
to interdigitate high-dose Bexxar with conditioning regimens for peripheral
stem cell transplantation.
Lym-1 is a murine antibody that recognizes one of the HLA-D antigens that has been radiolabeled with 131I or with 67Cu.24 Both of these have shown clinical activity in patients with lymphoma and CLL with acceptable toxicity profiles. Similar studies have been performed with an 131I labeled version of the hLL2 anti-CD22 antibody.
III. Therapeutic Results with Abciximab, an Antagonist of the
Platelet GPIIb/IIIa (IIbß3) Receptor
Barry S. Coller, M.D.*
Abciximab (Chimeric 7E3 Fab; ReoPro), the Fab fragment of the mouse human
chimeric antibody 7E3, which inhibits ligand binding to the platelet
GPIIb/IIIa receptor, the Vß3 receptor, and one or more activated
conformations of the Mß2 receptor, was approved for human use as
adjunctive therapy to prevent ischemic complications of percutaneous coronary
interventions in December
1994.1,2,3
In the subsequent 5 years, it has been administered to nearly 1,000,000
patients
worldwide.4 Thus,
considerable information has been accumulated about its pharmacology, safety,
and efficacy. Since it is perhaps the first rationally designed antiplatelet
agent and the first integrin receptor antagonist, the experience gained with
it may also be of more general interest to those involved in drug development,
antiplatelet therapy, and integrin receptor biology. Two low molecular weight
GPIIb/IIIa-specific antagonists (eptifibatide and tirofiban), which are
modeled on the cell recognition sequence arginine-glycine-aspartic acid (RGD)
found in several GPIIb/IIIa ligands, have more recently been approved for
human use for indications similar to those for
abciximab.3,4,5
Given the limitations of space, the following discussion will focus on
abciximab, but recent reviews of these agents are
available.4,5,6
Pharmacokinetics
Abciximab binds with high affinity (
1-5 nM) to both GPIIb/IIIa and
Vß3.1,3,7,8
After the administration of the recommended bolus dose of 0.25 mg/kg,
approximately two-thirds of the drug rapidly binds to platelets, resulting in
blockade of 80% of the GPIIb/IIIa receptors and 80% inhibition of
platelet aggregation in response to ADP (5-20 µM) in a large majority of
patients. Similarly, treatment with the recommended infusion of 0.125
µg/kg/min for 12 hours will sustain 80% receptor blockade in the
majority of patients, but there is more variability in this response than
there is after the bolus
dose.9 The plasma
level of unbound abciximab drops to low levels very rapidly after
administration. Some abciximab becomes internalized after administration and
can be detected on -granule
membranes.10,11
Ex vivo mixing studies, as well as in vivo studies, demonstrate that abciximab
continually redistributes from one platelet to another over a period of
minutes to hours.7
Abciximab is not excreted in significant amounts in the urine; its major
mechanism of catabolism is probably via degradation of platelet-bound antibody
at the time senescent platelets leave the circulation. Abciximab does not
normally significantly shorten platelet survival. Although it does bind to
megakaryocytes,11,12
it does not appear to affect megakaryopoiesis.
These pharmacokinetic data have a number of important practical implications:
50-60% of the normal number of GPIIb/IIIa
receptors,16 do not
have excess bleeding, there is reason to believe that hemostasis is relatively
intact when the receptor blockade decreases below 50%. Thus, to rapidly
reverse the effect of abciximab soon after its administration, it may be
necessary to transfuse nearly as many platelets as are present in the
patient's circulation and spleen (approximately 20 units of platelets in a 70
kg person with a platelet count of 250,000/µ1).
FDA Approved Indications
Abciximab has been approved by the FDA for the following indications:
|
Cost Effectiveness Ratio
Since abciximab treatment in EPISTENT resulted in a mortality advantage at
1 year, it was possible to assess the cost (in dollars) of saving one year of
a patient's life (i.e., a
life-year).19 The
cost per life-year saved by adding abciximab to stent insertion is
$6,200, which can be compared with coronary bypass surgery for left
mainstem coronary artery disease ($7,000), treatment of acute myocardial
infarction with tissue plasminogen activator (t-PA) rather than streptokinase
($33,000), hemodialysis ($35,000), and primary prevention of
vascular disease by lowering cholesterol with a statin compared to diet
($54,000-$140,000).19,23
It also compares favorably with public health measures, such as automobile
seat belts ($150,000) and automobile air bags
($1,700,000).24
Indications Currently Under Investigation
In a randomized, double-blind, phase II study of patients with myocardial
infarction receiving aspirin and heparin, a combination of abciximab and 50 mg
t-PA (which is half the usual dose) was found to result in a higher frequency
of complete blood flow restoration in the affected blood vessel at 60 and 90
minutes after drug administration than treatment with 100 mg of t-PA
alone.25 Abciximab
treatment without a thrombolytic agent resulted in reperfusion rates similar
to those produced by streptokinase alone. Larger studies using combinations of
abciximab and thrombolytic agents are currently underway. Abciximab has also
been used in combination with thrombolytic agents in peripheral arterial
disease.26
In a placebo-controlled phase II study of 74 patients with acute, nonhemorrhagic stroke, treatment with varying doses of abciximab between 3-24 hours after stroke onset resulted in a trend toward improved clinical outcome at 3 months.27 There were no major intracranial hemorrhages in the abciximab-treated patients and no increase in symptomatic parenchymal hemorrhages, but there was an increase in asymptomatic intracranial hemorrhages detected by unscheduled CT scans.
There have been anecdotal reports of beneficial effects of abciximab treatment as adjunctive therapy of cerebral angioplasty and stent placement.28 Patients with a history of heparin-induced thrombocytopenia have undergone PCI with abciximab and an alternative anticoagulant.29,30 In addition, abciximab has been reported to be beneficial in treating patients with Kawasaki disease with large aneurysms and thrombi.31
Safety Considerations
Thrombocytopenia
Abciximab can induce both
pseudothrombocytopenia32
and true
thrombocytopenia.33,34,35
The development of EDTA-dependent pseudothrombocytopenia does not constitute
an indication to stop abciximab therapy. Thus, it is vital that
thrombocytopenia reported by automated platelet counters be confirmed by
analyzing the blood smear for the presence of platelet clumping and, if
necessary, by repeating the platelet count with citrate as the anticoagulant.
Since abciximab is given in conjunction with heparin, it is necessary to also
consider heparin-induced thrombocytopenia in the differential diagnosis. True
thrombocytopenia occurs in several percent of patients treated with abciximab,
and acute, profound thrombocytopenia (platelet count < 20,000/µl within
one day of administration) occurs in between 0.5-1.0% of patients receiving
abciximab for the first
time.33,34,35
In patients who develop acute, profound thrombocytopenia, platelet counts
obtained between 2-4 hours after drug administration nearly always demonstrate
significant decreases from baseline values, so it is crucial that a platelet
count be performed during that time period so that the drug infusion can be
stopped and, if necessary, other measures instituted. Most patients with
severe thrombocytopenia respond well to platelet transfusions, and platelet
count recovery generally starts within 1-2 days; recovery usually occurs
within 5 days, but can take up to 12 days. The mechanism(s) of
abciximab-induced thrombocytopenia has not been conclusively established, but
there are data supporting an immune mechanism in some
cases,36 perhaps
involving the presence of preformed antibodies in the recipient to
neoantigen(s) expressed on GPIIb/IIIa as a result of the binding of abciximab.
Thrombocytopenia that occurs after readministration of abciximab may be
associated with higher titers of
antibodies.36
Platelet activation by abciximab has been proposed as an alternative mechanism
for
thrombocytopenia,37
but a number of laboratories have not been able to confirm abciximab-induced
platelet activation.
Bleeding
In the first phase III study (EPIC), abciximab treatment significantly
increased the risk of major
bleeding.38
Relatively high doses of heparin were used in this study, however, and in the
subsequent EPILOG and EPISTENT studies, in which the heparin dose was reduced
and weight adjusted, there were no significant increases in major
bleeding.6
Pulmonary hemorrhage has been reported as a serious complication of abciximab
treatment and may be difficult to differentiate from other causes of pulmonary
compromise.39
Reported data are inconsistent with regard to whether abciximab treatment
increases the risk of hemorrhage associated with cardiopulmonary bypass
surgery.40,41
There does not appear to be a consensus among cardiovascular anesthesiologists
and surgeons regarding the desirability of preoperative and/or postoperative
platelet transfusions. If hemostasis cannot be secured, however, in view of
the pharmacokinetics of abciximab, it may be appropriate to transfuse a larger
number of platelets than is traditionally given to patients undergoing
cardiopulmonary bypass surgery.
Immune reactions and results with readministration
Approximately 6% of patients receiving abciximab develop human antichimeric
antibody responses
(HACA).7 The
titers, in general, are low and decline over a 6-month period. A study of 164
patients who received abciximab for PCI on two separate occasions separated by
1-570 days found that readministration was associated with high procedural
(> 99%) and clinical (94%) success, no allergic or anaphylactic reactions,
and a risk of acute profound thrombocytopenia of 3% (compared to 0% with first
administration).42
Analysis of the data according to the time interval between the first and
second treatment suggested that the risk of developing thrombocytopenia is
greater with short intervals between doses.
Restenosis
Results from the EPIC study suggested that abciximab treatment decreased
the risk of developing clinically significant restenosis after 6
months.43 A number
of subsequent studies, however, did not support this
finding.44,45
In the most recent study (EPISTENT), abciximab treatment of patients receiving
stents significantly decreased the risk of developing both clinical and
angiographic evidence of restenosis in patients with diabetes at 6 months
(8.1% vs 16.6% target vessel revascularization) and 1 year (14% vs 22%), but
had little effect in non-diabetic
patients.19,20
Mechanisms of Action
Abciximab's primary mechanism of action involves blockade of GPIIb/IIIa
receptors. This decreases platelet thrombus formation and thus decreases the
risk of vasoocclusion at the site of PCI. Blockade of GPIIb/IIIa receptors by
abciximab has additional effects, however, that may also contribute to the
benefits. Thus, abciximab can decrease platelet-mediated thrombin generation
induced by tissue
factor46 and can
prolong the activated clotting time
(ACT),47
indicating a potential anticoagulant
effect.48
Abciximab also decreases thrombin-induced platelet microparticle
formation,46 and
microparticles have been implicated in supporting thrombin generation and
activating endothelial
cells.49 Abciximab
has a number of effects that can facilitate thrombolysis (reviewed
in50
and51), including
1) increasing clot porosity as a result of preventing clot retraction, 2)
decreasing thrombin-mediated activation of a carboxypeptidase
(thrombin-activated fibrinolysis inhibitor, TAFI) that inhibits thrombolysis,
3) decreasing release from platelets of the fibrinolytic inhibitors
plasminogen activator inhibitor-1 (PAI-1) and -2 plasmin inhibitor, and
4) decreasing factor XIIIa-mediated crosslinking of fibrin.
Some of abciximab's beneficial effects may operate not only at the site of vascular injury or plaque rupture, but also at the level of the microvasculature distal to the site of vascular injury or plaque rupture. Thus, abciximab may reduce distal embolization of platelet aggregates and platelet-leukocyte aggregates, as well as discharge into the distal circulation of thrombin formed on the platelet surface and the products of platelet synthesis and/or release (ADP, serotonin, vascular endothelial growth factor [VEGF], thromboxane A2, platelet microparticles); all of these cellular and humoral elements may damage the microcirculation acutely and/or chronically. Experimental data, in fact, demonstrate that abciximab treatment has a cardioprotective effect in an isolated perfused heart model of ischemia and reperfusion.52
One intriguing hypothesis is that the long-term mortality benefit found with short-term abciximab treatment is due to the prevention of acute damage to the microvasculature, which in turn, prevents the development of fibrotic foci in the myocardium that may ultimately result in electrical instability. The strong correlation between myocardial enzyme elevations at the time of PCI and long-term mortality risk found in many, but not all, studies are consistent with this hypothesis.53,54
Clinical data supporting a beneficial effect of abciximab treatment on the
microcirculation include improved peak blood flow and myocardial contractility
2 weeks after stent placement in patients with myocardial
infarctions,55
faster ST-segment resolution after thrombolytic therapy for myocardial
infarction,56 and
prevention of myocardial perfusion abnormalities after rotational
atherectomy.57
Recent evidence suggests that markers of systemic inflammation correlate with
cardiovascular
risk58 and so it
is particularly interesting that PCI and myocardial infarction are associated
with increased surface expression of the leukocyte integrin Mß2;
abciximab not only prevents this increase in Mß2 expression, but
actually decreases expression below baseline
values.59,60
One potentially important link between platelet deposition and a systemic
inflammatory state is the expression of CD40 ligand on the surface of
activated
platelets,61 since
CD40 ligand (CD154) is a potent activator of the immune
response,62 and
perhaps endothelial
cells.61,63
Patients with acute coronary syndromes have increased circulating levels of
soluble CD40 ligand, which probably derives from
platelets.64 It is
intriguing to speculate, therefore, that platelet activation due to vascular
injury may actually initiate systemic inflammation.
The crossreactivity of abciximab with the integrin Vß3, which
is present on many different cell types including endothelial cells, smooth
muscle cells, and platelets, has been suggested to contribute to its
beneficial effects since blockade of Vß3 may decrease both
platelet adhesion to osteopontin (a component of atherosclerotic
plaque)65,66
and platelet-mediated thrombin
generation.46 In
addition, animal model data implicate Vß3 in intimal hyperplasia
after vascular injury (reviewed in
1). To date,
however, there are no data indicating a direct role for Vß3
blockade by abciximab in its effects. Similarly, although in vitro and ex vivo
studies demonstrate the ability of abciximab to bind to an activated
conformation of leukocyte Mß2, there are no direct data linking
this reactivity with the beneficial effects of abciximab (reviewed in
1).
Drug Monitoring
A number of assays have been developed to monitor GPIIb/IIIa antagonist
therapy, and there are positive features and drawbacks to each of the
approaches.9,67,68,69,70,71,72
The author, in conjunction with the scientists at Accumetrics (San Diego, CA),
has participated in the development of one of these assays (Ultegra Rapid
Platelet Function Assay, Accumetrics, San Diego, CA). It is a fully automated,
whole blood, point-of-care test that measures the agglutination of
fibrinogen-coated beads by platelets activated by a thrombin
receptor-activating
peptide.9,73
Preliminary results with this instrument indicate that the vast majority (but
not all) of the patients receiving abciximab achieve high grade receptor
blockade soon after the bolus dose, but there is greater variation in the
response during and after the end of the
infusion.9,72
Moreover, it appears that patients who have less than 70% inhibition of their
platelet function as judged by this assay 8 hours after starting abciximab
have an increased risk of having a major adverse coronary event after
PCI.74 It remains
to be tested, however, whether abciximab dose adjustment based on this assay,
or any other, will result in improved clinical outcomes.
Conclusions
Abciximab has demonstrated efficacy in decreasing both short-term ischemic
complications and long-term mortality in patients undergoing PCI. Its role in
treating unstable angina, however, is uncertain and may depend on whether the
patient undergoes PCI as part of the therapy. Preliminary data are encouraging
about its potential role in treating myocardial infarction in conjunction with
thrombolytic agents and treating stroke, but definitive studies have not yet
been completed. Severe thrombocytopenia is a rare but serious complication,
whose impact can be mitigated by insuring that a platelet count is obtained
2-4 hours after drug administration. Major hemorrhagic complications are also
rare but may also be serious when they occur. Platelet transfusions should be
considered as treatment for both thrombocytopenia and hemorrhagic
complications.
Footnotes
* Chief, Metabolism Branch, NCI, 10 Center Drive, 10/4N115, NIH, Bethesda MD
20892-1374 
* Division of Oncology, Stanford University Medical Center, M207, Stanford CA
94305-5115
* The Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1118, New York NY 10029-6574
Statement of Disclosure:
Dr. Coller is an inventor of abciximab and in accord with Federal law and
the policies of the Research Foundation of the State University of New York,
shares in royalties paid to the Foundation for sales of abciximab. Dr. Coller
is an inventor of the rapid platelet function assay (Accumetrics, San Diego)
and in accord with Federal law and the policies of Mount Sinai School of
Medicine, shares in royalty payments to Mount Sinai from sales of the assay.
Dr. Coller is an advisor to Accumetrics and holds equity in Accumetrics.
Introduction
vß3 on platelets and lymphocytes binds to the
matrix protein osteopontin. J Biol Chem. 1997; 272: 8137
-8140.vß3 regulates platelet and lymphocyte adhesion
to intact and thrombin-cleaved osteopontin. J Biol Chem. 2000; 275: 18337
.
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