Alemtuzumab

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Alemtuzumab ?

Monoclonal antibody
Type
Whole antibody
Source
Humanized (from rat)
Target
CD52
Clinical data
Trade names
Campath
AHFS/Drugs.com monograph
MedlinePlus
a608053
Pregnancy cat.
B2 (AU)
Legal status
?
Pharmacokinetic data
Half-life
~288 hrs
Identifiers
CAS number
216503-57-0
ATC code
L01XC04
DrugBank
DB00087
UNII
3A189DH42V
ChEMBL
CHEMBL1201587
Chemical data
Formula
C6468H10066N1732O2005S40
Mol. mass
145453.8 g/mol
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Alemtuzumab (marketed as Campath, MabCampath or Campath-1H and currently

under further development as Lemtrada) is a monoclonal antibody used in the treatment
of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell
lymphoma. It is also used in some conditioning regimens for bone marrow
transplantation, kidney transplantation and Islet cell transplantation.
Alemtuzumab binds to CD52, a protein present on the surface of mature lymphocytes,
but not on the stem cells from which these lymphocytes are derived. After treatment with
alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction.
Alemtuzumab is used as second-line therapy for CLL. It was approved by the US Food
and Drug Administration for CLL patients who have been treated with alkylating agents
and who have failed fludarabine therapy. It has been approved by Health Canada for the
same indication, and additionally for CLL patients who have not had any previous
therapies.
It is also used under clinical trial protocols for treatment of some autoimmune diseases,
such as multiple sclerosis, in which it shows promise.[1][2] Alemtuzumab was withdrawn
from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch
aimed at multiple sclerosis.[3]
A complication of therapy with alemtuzumab is that it significantly increases the risk for
opportunistic infections, in particular, reactivation of cytomegalovirus.

Description
Alemtuzumab (Campath-1H) is a recombinant DNA-derived humanized monoclonal
antibody that is directed against the 2128 kDa cell surface glycoprotein CD52.

Indications and use

Indications and use
Alemtuzumab is indicated for the treatment of B-cell chronic lymphocytic leukemia (BCLL) in patients who have been treated with alkylating agents and who have failed
fludarabine therapy. It is an unconjugated antibody, thought to work via the activation of
antibody-dependent cell-mediated cytotoxicity(ADCC).[4]

Sanofi acquisition and change of license controversy

In February 2011, Sanofi-Aventis, since renamed Sanofi, acquired Genzyme, the
manufacturer of alemtuzumab.[5] The acquisition was delayed by a dispute between the
two companies regarding the value of alemtuzumab. The dispute was settled by the
issuance of Contingent Value Rights, a type of stock warrant which pays a dividend only
if alemtuzumab reaches certain sales targets. The warrants trade on the NASDAQ-GM
market with the ticker symbol GCVRZ.

In August 2012, Genzyme surrendered the licence for all presentations of alemtuzumab,[6]
pending regulatory approval to re-introduce it as a treatment for multiple sclerosis. There
is concern[7] that Genzyme will later bring to market the same product at a much higher
price than before.

Research or off-label use

Multiple sclerosis
In 2008 early tests at Cambridge University suggest that alemtuzumab might be useful in
treating and even reversing the effects ofmultiple sclerosis.[8] Promising results were
reported in 2011 from a phase III trial against Rebif. A combination trial with Copaxone
is being considered, and is expected to work synergistically.[2]

Graft-versus-host disease
A 2009 study of alemtuzumab in 20 patients with severe steroid-resistant acute intestinal
graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT)
demonstrated improvement. Overall response rate was 70%, with complete response in
35%. In this study, the median survival was 280 days. Important complications following
this treatment included cytomegalovirus reactivation, bacterial infection, and invasive
aspergillosis infection.[9]

Contraindications and precautions

Alemtuzumab is contraindicated in patients who have active systemic infections,
underlying immunodeficiency (e.g., seropositive for HIV), or known Type I
hypersensitivity or anaphylactic reactions to Campath or to any one of its components.

Adverse reactions
Alemtuzumab has been associated with infusion-related events including hypotension,
rigors, fever, shortness of breath, bronchospasm, chills, and/or rash. In post-marketing
reports, the following serious infusion-related events were reported: syncope,
pulmonary infiltrates, ARDS, respiratory arrest, cardiac arrhythmias, myocardial
infarction and cardiac arrest. The cardiac adverse events have resulted in death in some
cases.[10]
It is also possible that perturbation of suppressor T cell populations by Campath-1H may
precipitate autoimmune disease.[citation needed]

History
The origins of alemtuzumab date back to Campath-1 which was derived from the rat
antibodies raised against human lymphocyte proteins by Herman Waldmann and

colleagues in 1983.[11] The name "Campath" derives from the pathology department of
Cambridge University.
Initially, Campath-1 was not ideal for therapy because patients could, in theory, react
against the foreign rat protein determinants of the antibody. To circumvent this problem,
Greg Winter and his colleagues humanised Campath-1, by extracting the hypervariable
loops that had specificity for CD52 and grafting them onto a human antibody framework.
This became known as Campath-1H and serves as the basis for alemtuzumab.[12]
Campath as medication was first approved in 2001. It is marketed by Genzyme, which
acquired the world-wide rights from Bayer AG in 2009. Genzyme was bought by Sanofi
in 2011. In August/September 2012 Campath was withdrawn from the markets in the US
and Europe. This was done to prevent off-label use of the drug to treat multiple sclerosis
and to prepare for a relaunch under the trade name Lemtrada, with a different dosage
aimed at multiple sclerosis treatment, this is expected to be much higher-priced.[3]

References
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Abatacept
Clinical data
Trade names
Orencia
AHFS/Drugs.com monograph
MedlinePlus
a606016
Pregnancy cat.
C (U.S.)
POM (UK), -only (U.S.)
Legal status
Routes
Intravenous
Pharmacokinetic data
Half-life
13.1 days
Identifiers
CAS number
213252-14-3
ATC code
L04AA24
DrugBank
DB01281
UNII
7D0YB67S97
KEGG
D03203
ChEMBL
CHEMBL1201823
Chemical data
Formula
?
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Abatacept (marketed as Orencia) is a fusion protein composed of the Fc region of the

immunoglobulin IgG1 fused to the extracellular domain of CTLA-4. It is a molecule
capable of binding with more avidity to CD80 (B7-1) than to CD86 (B7-2). Abatacept is
a selective co-stimulation modulator as it inhibits the costimulation of T cells. It was
developed by Bristol-Myers Squibb and is licensed in the United States for the treatment
of rheumatoid arthritis in the case of inadequate response to anti-TNF therapy.

Medical uses
Abatacept is currently approved for use in people with rheumatoid arthritis who have had
an inadequate response to one or more DMARDs.[1] It is useful in delaying the
progression of structural damage and reducing symptoms of rheumatoid arthritis.
However, it should not be used in combination with anakinra or TNF antagonists.[2]

Clinical trials for additional indications

Abatacept had a phase III trial[3] for the treatment of patients suffering moderate to severe
active ulcerative colitis, where response to standard treatment has failed to bring about
remission. The trial was due to run until 2009 but after review of interim results was
terminated early due to lack of efficacy.[4]
Abatacept is (As of 2008) in trial[5] for the treatment of Type 1 Diabetes. In diabetic
patients in the "honeymoon phase" of the disease, Abatacept may protect surviving beta
cells from autoimmune attack.[citation needed]
Abatacept is currently in a phase II trial for Multiple Sclerosis in a joint Bristol Meyers
and NIAID program.
The ACCESS phase II clinical trial,[6][7] sponsored by the National Institute of Allergy and
Infectious Diseases is (As of 2009) studying abatacept treatment in lupus nephritis when
used in combination with cyclophosphamide therapy.
Abetacept in a subcutaneous administration form has been approved by USFDA, for self
administration by the patient.

Mechanism of action
Abatacept prevents antigen-presenting cells (APCs) from delivering the co-stimulatory
signal to T cells to fully activate them. Note that binding of the activation signal without
its complementary co-stimulatory signal also helps to enable downregulation of T cells
by way of T cell anergy. Simple signaling without co-stimulation allows the cell to
recognize the primary signal as "self" and not ramp-up responses for future responses as
well.
Ordinarily, full T cell activation requires 1) binding of the T cell receptor to the antigenMHC complex on the APC and 2) a co-stimulatory signal provided by the binding of

CD28, a T cell protein, to the B7 protein on the APC. Abatacept, which contains a highaffinity binding site for B7, works by binding to the B7 protein on APCs and preventing
them from delivering the co-stimulatory signal to T cells, thus preventing the full
activation of T cells.[8][9]

Derivatives
Abatacept is the basis for the second-generation belatacept currently being tested in
clinical trials. They differ by only 2 amino acids. In organ transplantation, belatacept is
intended to provide extended graft survival while limiting the toxicity generated by
standard immune-suppressing regimens such as calcineurin inhibitors (for example
cyclosporin).

Structure
Abatacept is a fusion protein composed of the extracellular domain of CTLA-4 with the
hinge, CH2, and CH3 domains of IgG1.[2]

Similar agents

Belatacept

References