Download Monoclonal Antibodies In Hematology

Monoclonal Antibodies In Hematology
Manoranjan Mahapatra, Rajan Kapoor
I
n the present era of targeted therapy, monoclonal
antibodies (mAb) are result of the idea of a “magic bullet”
which was first proposed by Paul Ehrlich, who, at the
beginning of the 20th century, postulated that, if a compound
could be made that selectively targeted a disease-causing
organism, then a toxin for that organism could be delivered
along with the agent of selectivity. Monoclonal antibodies
(mAb) are monospecific antibodies produced by a single
clone of cells against a specific target antigen. With advent
of recombinant technology, mouse-human chimeric and fully
human mAb have been synthesized, thereby improving
the efficacy and safety of these agents. These mAb can be
classified as mouse, chimeric (human-mouse), humanized
and fully human depending on their structure. As in other
fields of medicine, mAb have proven their efficacy in
various malignant and benign hematologic disorders. In this
review we are going to focus mainly on therapeutic uses of
commonly used mAb in hematologic diseases.
Table I. Common diagnostic uses of monoclonal
antibodies
USE IN HEMATOLOGY
A) Diagnostic: Immunophenotyping (flow cytometry and
immunohistochemistry) using mAb against various cellular
antigens has become an integral part in diagnosis of various
hematologic disorders. These have been summarized in
Table I. With improvement in hybridoma technology it is
possible to design these antibodies against practically any
antigen expressed by normal or malignant cell.
B) Therapeutic: Large numbers of mAb are being
introduced for treatment of various hematologic disorders.
Characteristics of common ones are summarized in Table
II. Most of the mAb have been developed against specific
Fig.1: The B cell has a large number of associated cellsurface antigens that can be exploited as targets for
monoclonal-antibody therapy
456
Medicine Update-2011
antigens of cancer cells. Classic example is B lymphocyte
which has many cell-surface associated antigens which can
be exploited as targets for mAb therapy.
cell to self destruct.
In addition to above it is also thought to sensitize cells to
chemotherapy induced lysis.
Some of the commonly used monoclonal antibodies (mAb)
used in hematological practice are discussed below:
Clinical use:
Hematologic malignancies: It has proven efficacy in a wide
variety of mature B-cell malignancies, including all CD20
positive B-cell lymphoma histologies. The greatest benefit
of rituximab is demonstrated when it is used in combination
with chemotherapy. In phase III trials in patients with indolent
or aggressive B-cell NHL, rituximab in combination with
chemotherapy (e.g. R-CHOP or R-CVP) was more effective as
first- or second-line therapy compared with chemotherapy
alone in response rates, providing tumor remission, and
extending patient survival2,3. Likewise, in patients with
CLL, rituximab in combination with chemotherapy (e.g.
fludarabine and cyclophosphamide) seems to be more
effective than chemotherapy alone as either first- or secondline treatment4,5. In view of unequivocal benefit rituximab
containing regimens are considered first line treatment of
all CD 20 positive B cell malignancies.
Rituximab
In Nov 1997, Rituximab was the first chimeric human-mouse
anti- CD 20 mAb to be approved by the US food and drug
administration (FDA) for relapsed/refractory B cell non
Hodgkin lymphoma (NHL). After more than a decade of its
use it remains one of the biggest therapeutic advancements
in treatment of majority of B cell NHL. It is a prototype
of all the monoclonal antibodies currently being used in
hematology.
Mechanism of action: Despite widespread use, exact
mechanism of action of rituximab is still illusive. Postulated
mechanisms are as follows1:
a. Complement dependent cytotoxicity: Anti- CD20
antibody binding activates the complement cascade,
which triggers assembly of the membrane attack complex
and, subsequently, osmotic cell lysis.
b. Antibody dependent cellular cytotoxicity: Following
binding of anti-CD20 antibody to the cell, the Fc receptor
of the immunoeffector cells (i.e. natural killer cells, T
cells, and macrophages) recognizes and attaches to the
Fc receptor on the antibody, subsequently leading to cell
death via various mechanisms.
c. Apoptosis: Antibody binding delivers signals directing the
Immune hematological disorders: B cells play a central role
in development and perpetuation of various autoimmune
diseases6. Rituximab by its anti B cell action is a rational
choice in these disorders. In hematology, rituximab has
proven its efficacy in immune thrombocytopenic purpura
(ITP), autoimmune hemolytic anemia (AIHA) and thrombotic
thrombocytopenic purpura (TTP). Treatment results in these
hematologic disorders has been summarized in Table III.
Adverse events: Rituximab has been associated with
Table II. Characteristics of monoclonal antibodies being used in hematology
Medicine Update-2011
457
Table III. Treatment results with rituximab in benign hematologic disorders
both immediate and late onset adverse events thereby
necessitating close monitoring and observation. These
adverse events have been summarized in Table IV . Though
uncommon, severe or life threatening events have also
been reported after rituximab administration with 2.9%
deaths attributable to rituximab8. Respiratory complications
are the commonest cause of deaths. Patients with pre
existing chronic respiratory insufficiency are more prone
for respiratory complications8. Major concern is latent viral
infections which may be reactivated.
Table IV. Major adverse events with rituximab
OTHER MONOCLONAL ANTIBODIES
Gemtuzumab ozogamicin (Mylotarg): mAb against CD
33 antigen which is expressed on leukemic blasts in 80%
of AML patients. It binds to the CD 33 Ag, resulting in
internalization of Ag-Ab complex. Following internalization,
the calicheamycin derivative is released inside the myeloid
cell which then binds to DNA resulting in double strands
break and cell death. Non hematopoietic cells are not
affected. In patients with CD33+ AML in untreated first
relapse, remissions (CR plus CR with incomplete platelet
recovery) were obtained in approximately 30 percent,
with median overall survivals of around 5 months11. The
recommended dose is 9 mg/m2 given by two-hour IV infusion,
with a second dose two weeks later. Trials employing this
agent in addition to standard induction chemotherapy for
previously untreated AML and acute promyelocytic leukemia
have been reported12. Serious adverse events include fatal
anaphylaxis, prolonged thrombocytopenia, hepatic venoocclusive disease and acute respiratory distress syndrome.
Alemtuzumab (Campath-1H): antibody directed against
CD52, is used for the treatment of relapsed/refractory CLL13.
While responses may be seen in approximately one-third
of patients with disease that is refractory to fludarabine,
the majority of these responses are partial remissions. It
is given in 30 mg/dose 3 times/week for a total duration
of therapy of up to 12 weeks. Significant side effects are
myelosuppression, reactivation of latent viral infections,
respiratory tract infections and hypotension.
Eculizumab: It is a humanized monoclonal antibody that
binds to the C5 component of complement and inhibits
terminal complement activation14. Eculizumab has been
approved for the reduction of hemolysis in patients with
PNH. Dose is 600 mg every 7 days for the first 4 weeks,
followed by 900 mg 7 days later; then maintenance:
900 mg every 14 days thereafter. It is mandatory to give
meningococcal vaccination prior to initiation of treatment.
Major drawbacks are cost and the duration of treatment
which till now is recommended as a lifelong therapy. In
addition there is increased susceptibility to encapsulated
organisms like meningococci.
Radioimmunotherapy: Radioimmunotherapy (RIT) refers
to the use of monoclonal antibodies that are linked to
radioisotopes (eg, yttrium-90 or iodine-131). Two of these
have been approved for the treatment of patients with
relapsed or refractory follicular lymphoma (FL), including
patients with rituximab-refractory FL:
 Ibritumomab tiuxetan (Zevalin) is a murine anti-CD20
monoclonal antibody conjugated to Yttrium-90.
 Tositumomab (Bexxar) is a murine anti-CD20 monoclonal
antibody conjugated with radioactive Iodine-131.
Prospective trials of these agents demonstrate response
rates of 60 to 80 percent in previously treated disease15.
458
Medicine Update-2011
FUTURE CHALLENGES
It is likely that targeted therapy with monoclonal antibodies
is likely to replace conventional chemotherapy in
management of hematologic malignancies. Although highly
effective, resistance invariably develops to most of these
agents. Pharmacogenomics by studying genetic makeup of
patient as well as molecular profiling of patient’s cancer
will help in designing tailor-made mAb. Other challenge
is eradication of minimal residual disease which may be
addressed by making more specific and potent mAb.
REFERENCES
1.
Manches O, Lui G, Chaperot L, et al. In vitro mechanisms of action of
rituximab on primary non-Hodgkin lymphomas. Blood 2003;101:949954
2.
Cvetkovic RS, Perry CM. Rituximab: a review of its use in nonHodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs
2006;66:791-820.
3.
Herold M, Haas A, Srock S, et al. Rituximab added to firstline
mitoxantrone, chlorambucil, and prednisolone chemotherapy
followed by interferon maintenance prolongs survival in patients
with advanced follicular lymphoma: an East German Study Group
Hematology and Oncology Study. J Clin Oncol 2007;25:1986-1992
4.
Keating MJ, O’Brien S, Albitar M, et al. Early results of a
chemoimmunotherapy regimen of fludarabine, cyclophosphamide,
and rituximab as initial therapy for chronic lymphocytic leukemia.
J Clin Oncol 2005;23:4079-4088.
5.
Tam CS, Wolf M, Prince HM, et al. Fludarabine, cyclophosphamide,
and rituximab for the treatment of patients with chronic lymphocytic
leukemia or indolent non-Hodgkin lymphoma. Cancer 2006;106:24122420.
6.
Stasi R. Rituximab in autoimmune hematologic diseases: Not just a
matter of B cells. Semin Hematol 2010, 47: 170-79.
7.
Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy
and safety of rituximab for adults with idiopathic thrombocytopenic
purpura. Ann Intern Med. 2007;146:25-33.
CONCLUSION
Monoclonal antibodies are indispensable in diagnostics of
many hematologic disorders. With advent of monoclonal
antibodies as effective form of targeted therapy we are
closer to realization of Paul Ehrlich’s romantic concept of
“magic bullet” against cancers. By better understanding of
molecular pathogenesis of both benign as well as malignant
hematologic disorders in coming years many hematologic
diseases are going to be targeted by these antibodies,
thereby completely changing management scenario.
8.
9.
10.
11.
12.
13.
14.
15.
Provan D, Butler T, Evangelista ML, Amadori S, Newland AC, Stasi R.
Activity and safety profile of low-dose rituximab for the treatment
of autoimmune cytopenias in adults. Haematologica. 2007;92:1695-8.
Zaja F, Battista ML, Pirrotta MT, et al. Lower dose rituximab is
active in adults patients with idiopathic thrombocytopenic purpura.
Haematologica. 2008;93:930-3.
Gurcan HM, Keskin DB, Stern JN, Nitzberg MA, Shekhani H, Ahmed
AR. A review of the current use of rituximab in autoimmune diseases.
Int Immunopharmacol. 2009;9: 10-25.
Sievers EL; Larson RA; Stadtmauer EA; Estey E et al. Efficacy
and safety of gemtuzumab ozogamicin in patients with CD33positive acute myeloid leukemia in first relapse. J Clin Oncol
2001;19(13):3244-54.
Tsimberidou AM; Giles FJ; Estey E; O’Brien S et al. The role of
gemtuzumab ozogamicin in acute leukaemia therapy. Br J Haematol.
2006 ;132(4):398-409.
Lozanski G; Heerema NA; Flinn IW; Smith L et al. Alemtuzumab is
an effective therapy for chronic lymphocytic leukemia with p53
mutations and deletions. Blood 2004;103(9):3278-81.
Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria.
Lancet. 2009 ;373(9665):759-67.
Wiseman GA; Gordon LI; Multani PS; Witzig TE et al. Ibritumomab
tiuxetan radioimmunotherapy for patients with relapsed or refractory
non-Hodgkin lymphoma and mild thrombocytopenia: a phase II
multicenter trial. Blood 2002 ;99(12):4336-42.