Transcript phl_425_targeted_and_biological_therapy_of_cancer

TARGETED AND BIOLOGICAL THERAPY OF CANCER
PHL 425
Dr. Mohamed M. Sayed-Ahmed
1- Monoclonal Antibody Drugs
For Cancer Treatment
What is a monoclonal antibody:
A monoclonal antibody is a laboratory-produced
molecule that's carefully engineered to attach to
specific defects in your cancer cells. Monoclonal
antibodies mimic the antibodies your body
naturally produces as part of your immune
system's response to germs, vaccines and other
invaders.
How do monoclonal antibody drugs work
1- Make the cancer cell more visible to the
immune system.
The immune system attacks foreign invaders in your body, but it
doesn't always recognize cancer cells as enemies. A monoclonal
antibody can be directed to attach to certain parts of a cancer cell. In
this way, the antibody marks the cancer cell and makes it easier for
the immune system to find.
The monoclonal antibody drug Rituximab attaches to a specific
protein (CD20) found only on B cells, one type of white blood cell.
Certain types of lymphomas arise from these same B cells. When
Rituximab attaches to this protein on the B cells, it makes the cells
more visible to the immune system, which can then attack.
Rituximab lowers the number of B cells, including your healthy B
cells, but your body produces new healthy B cells to replace these.
The cancerous B cells are less likely to recur.
RITUXIMAB (Rituxan)
• A recombinant chimeric murine/human antibody directed
against the CD20 antigen, a hydrophobic transmembrane
protein located on normal pre-B and mature B lymphocytes.
•
Following binding, rituximab triggers a host cytotoxic immune
response against CD20-positive cells.
• Rituximab is used in the treatment of B-cell
Non-Hodgkin's lymphomas.
• MECHANISM OF ACTION:
• Complement fixation
• ADCC
• Direct cytotoxicity via apoptotic pathway activated by binding
to CD20.
Alemtuzumab
(al-em-to-zoo-mab)
(MabCampath®)
Alemtuzumab is humanized monoclonal antibody that
targets CD52, a glycoprotein highly expressed on both BCLL
cells
and
normal
B
and
T
cells.
Therefore, CLL seemed the optimal setting for this new
agent, as it is primarily a malignancy of the peripheral
blood
and
bone
marrow.
Alemtuzumab (Campath-1H) was approved by
the FDA for the treatment of B-cell CLL unsuccessfully
treated
by
alkylating
agents
and
fludarabine.
The mechanism of action of alemtuzumab is not well
understood,
but
it
is
presumed
to
work
via ADCC, CDC, and/or apoptosis.
Alemtuzumab-How is it given
MabCampath is given as a drip (infusion) through a fine tube (cannula)
inserted into a vein in arm or back of the hand. Each drip takes
approximately two hours. It can also be given as an injection under the
skin (subcutaneously).
Some people have an allergic reaction to MabCampath. To reduce the
risk of a reaction the first few doses are given slowly. You may also be
given some antihistamines, paracetamol and sometimes a small dose of
steroids before the infusion. These will help to reduce the risk of reactions.
If you do have a reaction, the infusion can be stopped and started again
once the symptoms are over.
You will be asked to stay in hospital for a few hours after the infusion, or
possibly overnight, to be monitored. The dose of MabCampath is
increased over a few days until the recommended dose is achieved. This
usually takes three to seven days and is known as dose escalation. Once
the recommended dose is achieved the treatment is given three times a
week (e.g. on Monday, Wednesday and Friday). Most people have
treatment for 4–12 weeks.
2- Block growth signals:
Chemicals called growth factors attach to receptors
on the surface of normal cells and cancer cells,
signaling the cells to grow. Certain cancer cells make
extra copies of the growth factor receptor. This
makes them grow faster than the normal cells.
Monoclonal antibodies can block these receptors and
prevent the growth signal from getting through.
Cetuximab
Cetuximab (Erbitux), a monoclonal antibody
approved to treat colon cancer and head and neck
cancers, attaches to Epidermal Growth Factor
Receptors (EGFR) on cancer cells that accept a
certain
growth
signal
(EGF).
Cancer cells and some healthy cells rely on this
signal to tell them to divide and multiply. Blocking
this signal from reaching its target on the cancer
cells may slow or stop the cancer from growing.
How Cetuximab Works
Cetuximab attaches itself to the EGFRs and prevents the receptors
from being activated. This stops the cells from dividing. It therefore has
the potential to stop the cancer cells from growing. It works in a
different way from both chemotherapy and hormonal therapy.
Cetuximab may also make the cancer cells more sensitive to
chemotherapy.
Tests may be done to find the level of EGFR in the body before
cetuximab is given. This can help the doctors to know whether you are
likely to benefit from this treatment. Testing can be done at the same
time as diagnosis of the cancer, or samples of cancer cells from
previous biopsies or surgery may be used.
Cetuximab is given by a drip into the vein (intravenously) through a
fine tube (cannula) inserted into a vein. The first dose is given slowly,
usually over two hours. After this, doses are given weekly and this
normally takes about an hour. The first dose is usually larger than the
weekly maintenance treatments. You may be given other medicines
before cetuximab to lessen the side effects during treatment.
Panitumumab (ABX-EGF)
Panitumumab belongs to a subgroup of monoclonal antibodies, known
as epidermal growth factor receptor (EGFR) inhibitors.
Epidermal growth factor (EGF) is a protein that is present in the body.
There are receptors for EGF on the surface of many types of cancer
cell. When EGF binds to these receptors, chemical signals are triggered
which cause the cells to grow and reproduce.
Panitumumab attaches itself to the EGFR, and prevents it from being
activated. This stops the internal chemical signalling, and inhibits the
growth of cancer cells that have the EGFR on their surface.
Tests may be done to check the level of EGFR present in the tumour;
these will tell if you are likely to benefit from panitumumab. Testing can
be done at the same time as diagnosis, or samples of cancer cells from
previous biopsies, or surgery, may be used.
TRASTUZUMAB (Herceptin)
TRASTUZUMAB is a recombinant humanized monoclonal
antibody directed against the human epidermal growth
factor receptor 2 (HER2).
After binding to HER2 on the tumor cell surface,
trastuzumab induces an antibody-dependent cell
mediated cytotoxicity (ADCC) against tumor cells that
overexpress HER2.
HER2 is overexpressed by many adenocarcinomas,
particularly
breast
adenocarcinomas.
This therapy requires the obligation of HER-2 tumour typing
following any surgical intervention of an invasive breast cancer.
The activity of trastuzumab is directed against the human epidermal
growth factor receptor-2 (HER-2).
Herceptin® must only be administered to female HER-2-positive
patients, i.e., in whom the tumours overexpress the HER-2 protein or
amplify the HER-2 gene.
Monitoring of HER-2 in tumours is essential: The overexpression of
HER-2 must be searched for using immunohistochemisty (IHC) in
embedded tumour fragments, or using genic amplification in situ
hybridisation (FISH1 or CISH2 technique). IHC, the search for genic
amplification must be positive to be able to envisage such
3- Stop new blood vessels from forming:
Cancer cells rely on blood vessels to bring them the
oxygen and nutrients they need to grow. To attract blood
vessels, cancer cells send out growth signals.
Monoclonal antibodies that block these growth signals
may help prevent a tumor from developing a blood
supply, so that it remains small. Or in the case of a tumor
with an already-established network of blood vessels,
blocking the growth signals could cause the blood
vessels to die and the tumor to shrink.
The monoclonal antibody bevacizumab (Avastin) targets
a growth signal called vascular endothelial growth factor
(VEGF) that cancer cells send out to attract new blood
vessels.
BEVACIZUMAB (Avastin)
• A recombinant humanized monoclonal
antibody directed against the vascular
endothelial growth factor (VEGF), a proangiogenic cytokine.
• Bevacizumab binds to VEGF and
inhibits VEGF receptor binding, thereby
preventing the growth and maintenance
of tumor blood vessels.
4- Deliver radiation to cancer cells:
By combining a radioactive particle with a monoclonal
antibody, doctors can deliver radiation directly to the
cancer cells. This way, most of the surrounding
healthy cells aren't damaged.
Radiation-linked monoclonal antibodies deliver a low level
of radiation over a longer period of time, which
researchers believe is as effective as the more
conventional high-dose external beam radiation.
Y
90 -Ibritumomab
(Zevalin)
(90Y) Yttrium-90 (it-ree-um).
90Y-Ibritumomab (Zevalin), approved for nonHodgkin's lymphoma, combines a monoclonal
antibody with radioactive particles.
The ibritumomab monoclonal antibody attaches to
receptors on cancerous blood cells and delivers the
radiation. Yttrium-90 produces radiation that is strong
enough to destroy cancer cells. It can also affect
normal cells.
A number of monoclonal antibody drugs are available to
treat various types of cancer. Clinical trials are studying
monoclonal antibody drugs in treating nearly every type of
cancer
How zevalin works and given
As Zevalin enters the bloodstream, the monoclonal antibody
portion recognises and attaches to the CD20 protein. Energy is
then released from the yttrium radioisotope, damaging or killing
the B-cell. Zevalin attacks both normal and abnormal (malignant)
B-cell lymphocytes. However, the body quickly replaces any
normal white blood cells that are damaged, so the risk of side
effects from this is very small.
Zevalin is used with Rituximab. Together they lock onto a protein
called CD20, which is found on the surface of one of the main
types of normal white blood cells (B-cell lymphocytes). CD20 is
also present on the surface of most of the abnormal B-cell
lymphocytes, which occur in many types of non-Hodgkin
lymphoma. The monoclonal antibodies attack both normal and
abnormal (malignant) B-cell lymphocytes.
How zevalin works and given
Zevalin is given as a single 'one-off' treatment and not as repeated
courses of treatment.
It consists of two components, given approximately one week apart:
Retuximab and Zevalin
Rituximab is given on the first day of treatment to reduce the number of
normal healthy B-cells. This prevents the Zevalin from attaching to and
destroying healthy, non-cancerous cells. Rituximab is given as a drip into
a vein (intravenous infusion). It is given slowly over a few hours. You will
be given some steroids and antihistamines beforehand to reduce the risk
of an allergic reaction.
You will receive a second infusion of rituximab about one week after your
first dose. Within four hours of this infusion you will go to the nuclear
medicine or radiotherapy department to have the Zevalin treatment. This
is given by drip and takes about ten minutes.
131I-tositumomab
(toss-i-to-mo-mab), (Bexxar)
Nonmyeloablative use of an 131I anti-CD20
murine antibody, is well tolerated and highly
effective in the treatment of relapsed or refractory
low-grade, follicular, or transformed B-cell NHL
(B-NHL). BEXXAR has a radioactive substance
called iodine131 attached to it. The monoclonal
antibody in BEXXAR, tositumomab, attaches to a
protein found on the surface of the B-cells. As a
result, the radioactive iodine delivers radiation directly
to these cells. This destroys the lymphoma B-cells.
Unfortunately it may also affect some normal cells.
Gemtuzumab (gem-to-zoo-mab)
Gemtuzumab ozogamicin (GO, Mylotarg) consists of a
recombinant, humanized anti-CD33 monoclonal antibody
conjugated to calicheamicin, a potent antitumor antibiotic.
Within the acidic environment of lysosomes after
internalization, calicheamicin dissociates from the antibody
and migrates to the nucleus, where it binds within the minor
groove of DNA and causes double-stranded DNA breaks.
It is mainly used as part to treat some types of acute
myeloid leukaemia (AML).
It carries a chemotherapy drug called ozogamicin directly to
the cancer cells. As the chemotherapy is only delivered to
cells showing the CD33 protein it may not affect normal cells
within the body.
FDA-APPROVED MONOCLONAL ANTIBODIES TARGETS and INDICATIONS
Antibody
Trade Name
Target Antigen
FDA Indication
Rituximab
Rituxan
CD20
B-NHL
90Y-Ibritumomab
Zevalin
CD20
B-NHL
131I-tositumomab
Bexxar
CD20
B-NHL
Alemtuzumab
Campath
CD52
CLL
Gemtuzumab
ozogamicin
Mylotarg
CD33
AML
Cetuximab
Erbitux
EGFR
metastatic
CRC
Panitumumab
ABX-EGF
EGFR
metastatic
CRC
Trastuzumab
Herceptin
HER2/neu
Metastatic
Br CA
FDA-APPROVED MONOCLONAL ANTIBODIES
Rituximab (Rituxan) was the first mAb approved by the FDA in 1997 for the treatment
of relapsed or refractory low-grade or follicular CD20-positive B-cell non-Hodgkin's
lymphoma (B-NHL).
Alemtuzumab (Campath-1H) was approved by the FDA for the treatment of
fludarabine-refractory B-cell CLL.
Patients with metastatic Her-2 Neu overexpressing metastatic breast carcinoma can
receive targeted therapy with trastuzumab (Herceptin).
Bevacizumab and cetuximab recently received FDA approval for the treatment of
metastatic colorectal carcinoma.
Gemtuzumab ozogamicin (Mylotarg), an antibody-drug conjugate, was approved by
the FDA in 2000 for the treatment of CD33-positive, relapsed acute myeloid leukemia
(AML) patients
90Y-ibritumomab tiuxetan (Zevalin) was the first radiolabeled antibody approved for
cancer therapy. Subsequently, 131I-tositumomab (Bexxar) was approved by the FDA
for the treatment of relapsed or refractory low-grade follicular or transformed CD20positive B-cell NHL.
ANGIOGENESIS INHIBITORS
ANGIOGENESIS INHIBITORS
Angiogenic Factors
1- Angiogenin
2- vascular endothelial growth factor (VEGF)
3- Fibroblast growth factor (FGF)
4- Transforming growth factor-β (TGF-β)).
5- platelet derived growrh factor (PDGF)
These stimulate endothelial cell proliferation,
migration and invasion resulting in new vascular
structures sprouting from the patient's blood vessels.
Cell adhesion molecules, such as integrins, are critical
To the attachment and migration of endothelial cells to
The extracellular matrix.
Endogenous anti-angiogenic factors
1- Endostatin: It induces apoptosis in endothelial cells
and inhibition of their migration to sites of neovascularisation,
probably by interfering with endothelial cell adhesion
2- Angiostatin: Like endostatin, it directly induces apoptosis of
endothelial cells by disrupting the normal adhesion contacts
between the endothelial cells. Angiostatin also acts by
inhibiting VEGF and basic fibroblast growth factor (bFGF).
3- Interferon-alfa: has an anti-angiogenic effect by inhibiting
endothelial cell migration. It has been successfully used to
treat haemagiomas, refractory giant cell tumours and
angioblastomas.
ANGIOGENESIS INHIBITORS
ANGIOGENESIS INHIBITORS
1- BEVACIZUMAB (Avastin)
• A recombinant humanized monoclonal
antibody directed against the vascular
endothelial growth factor (VEGF), a proangiogenic cytokine.
• Bevacizumab binds to VEGF and
inhibits VEGF receptor binding, thereby
preventing the growth and maintenance
of tumor blood vessels.
2- NEOVASTAT
• A multifunctional antiangiogenic agent derived from
shark cartilage with potential antineoplastic activity.
• Shark cartilage extract AE-941 competitively inhibits
the binding of pro-angiogenic vascular endothelial
growth factor (VEGF) to its cell receptor, thereby
inhibiting endothelial cell proliferation.
• This agent also inhibits matrix metalloproteinases
(MMPs), stimulates tissue plasminogen activator
(tPA), and activates caspase-mediated apoptotic
pathways in endothelial cells.
3- COMBRETASTATIN A4 PHOSPHATE
• A water-soluble prodrug derived from the African
bush willow (Combretum caffrum) with tumor
vascular-targeting activity.
• In vivo, combretastatin A4 phosphate is
dephosphorylated to its active metabolite,
combretastatin A4, which binds to tubulin and
inhibits microtubule depolymerization, resulting in
morphological changes in proliferating endothelial
cells.
• As a result, the permeability of tumor vasculature is
increased, leading to reduced tumor blood flow and
ischemic necrosis of tumor tissue.
MATRIX METALLOPROTEINASE INHIBITORS
1- MARIMASTAT
An orally-active synthetic hydroxamate with
potential antineoplastic activity. Marimastat
covalently binds to the zinc(II) ion in the active site
of matrix metalloproteinases (MMPs), thereby
inhibiting the action of MMPs, inducing extracellular
matrix degradation, and inhibiting angiogenesis,
tumor growth and invasion, and metastasis.
This agent may also inhibit tumor necrosis factor-alpha
converting enzyme (TACE), an enzyme involved in
tumor necrosis factor alpha (TNF-alpha) production that
may play a role in some malignancies as well as in the
development of arthritis and sepsis.
2- PRINOMASTAT
• A synthetic hydroxamic acid derivative with
potential antineoplastic activity.
• Prinomastat inhibits matrix
metalloproteinases (MMPs) (specifically,
MMP-2, 9, 13, and 14), thereby inducing
extracellular matrix degradation, and
inhibiting angiogenesis, tumor growth and
invasion, and metastasis.
• As a lipophilic agent, prinomastat crosses
the blood-brain barrier.