CHAPTER 7

1.What are the structural differences between the five

immunoglobulin classes?
2. (a) What are key differences in PK/PD between
MABs and small molecule drugs?
(b) Why do IgGs typically show nonlinear PK in the
lower plasma (serum) concentration range?
3. What is a surrogate MAB and how can it potentially
be used in the drug development process of MABs?
4. Which other modes of actions apart from ADCC
antibody dependent cellular cytotoxicity are known
for MABs? What are the key steps of ADCC?
5. Why do IgGs have a longer in vivo half-life compared
with other Igs?
6. What are the development phases for antibody therapeutics?
What major activities are involved in the
each phase?

Jawaban
The following structural properties distinguish
MABs:
The molecular form can be different for the 5
immunoglobulin classes: IgG, IgD, and IgE are
monomer; IgM appears as pentamer or hexamer,
and IgA are either monomer or dimer.
Consequently, the molecular weight of the
different Igs is different (IgG 150169 kD, IgA
160300 kD, IgD 175 kD, IgE 190, IgM 950 kD).
2. (a) I. Metabolism of MABs appears to be simpler
than for small molecules. In contrast to small
molecule drugs, the typical metabolic enzymes
and transporter proteins such as cytochrome
P450, multidrug resistance (MDR) effl ux pumps
are not involved in the disposition of MABs.
Therefore, drugdrug interaction studies for
those disposition processes are only part of the
standard safety assessment for small molecules
and not for MABs. Monoclonal antibodies,
which have a protein structure, are metabolized
by proteases. These enzymes are ubiquitously
available in mammalian organisms. In contrast,
small molecule drugs are primarily metabolized
in the liver.
II. Because of the large molecular weight, intact
MABs are typically not cleared by the renal
elimination route in the kidneys. However,
renal clearance processes can play a major role
in the elimination of small molecule drugs.
III. Pharmacokinetics of MABs usually is dependent
on the binding to the pharmacological
target protein and shows nonlinear behavior
as consequence of its saturation kinetics.
IV. In general, MABs have a longer half-life (in
the order of days and weeks) than small molecule
drugs (typically in the order of hours).
V. The distribution of MABs is very restricted
(volume of distribution in the range of 0.1 L/

kg). As a consequence, MABs do have limited

access to tissue compartments as potential target
sites via passive, energy-independent distribution
processes only (e.g., brain).
(b) At lower concentrations, MABs generally show
nonlinear pharmacokinetics due to receptormediated
clearance processes, which are characterized
by small capacity of the clearance
pathway and high affi nity to the target protein.
Consequently at these low concentrations, MABs
exhibit typically shorter half-life. With increasing
doses, these receptors become saturated, and the
clearance as well as elimination half-life decreases
until it becomes constant. The clearance in the
higher concentration range, which is dominated
by linear, nontarget- related clearance processes,
is therefore also called nonspecifi c clearance in
contrast to the target- related, specifi c clearance.
3. A surrogate MAB has similar antigen specifi city and
affi nity in experimental animals (e.g., mice and rats)
compared to those of the corresponding human
antibody in humans. It is quite common that the
antigen specifi city limits ADME studies of humanized
monoclonal antibodies in rodents. Studies
using surrogate antibodies might lead to important
information regarding safety, mechanism of action,
disposition of the drug, tissue distribution, and
receptor pharmacology in the respective animal species,
which might be too cumbersome and expensive
to be conducted in nonhuman primates.
Surrogate MABs (from mouse or rat) provide a
means to gain knowledge of ADME and PD in preclinical
rodent models and might facilitate the dose
selection for clinical studies.
4. Apart from ADCC, monoclonal antibodies can exert
pharmacological effects by multiple mechanisms
that include direct modulation of the target antigen,
complement-dependent cytotoxicity (CDC) and
apoptosis.
The key steps of ADCC are (1) opsonization of the
targeted cells, (2) recognition of antibody-coated targeted
cells by Fc receptors on the surface of monocytes,
macrophages, natural killer cells, and other
cells, and (3) destruction of the opsonized targets by
phagocytosis of the opsonized targets and/or by
toxic substances released after activation of monocytes,
macrophages, natural killer cells, and other
cells.
5. IgG can bind to neonatal Fc receptor (FcRn) in the
endosome, which protects IgG from catabolism via
proteolytic degradation. This protection results into
a slower clearance and thus longer plasma half-life
of IgGs. Consequently, changing the FcRn affi nity
allows to adjust the clearance of MABs (higher affi nity
lower clearance), which can be employed to
tailor the pharmacokinetics of these molecules.
6. Pre-IND, phase I, II, III, and IV are the major development
phases for antibody therapies. Safety pharmacology,
toxicokinetics, toxicology, tissue cross

reactivity, local tolerance, PK support for molecules

selection, assay support for PK/PD, and PK/PD
support for dose/route/regimen are major activities
in the pre-IND phase. General toxicity, reproductive
toxicity, carcinogenicity, immunogenicity, characterization
of doseconcentrationeffect relationship,
material comparability studies, mechanistic modeling
approach, and population pharmacokinetics/
CHAPTER 17
1. From the name tositumomab and 131I tositumomab,
what can one infer about the type of drug
and origin?
2. The epidermal growth factor receptor inhibitors
have a unique side effect profi le which may also
demonstrate a pharmacodynamic effect. Describe
the profi le and what development of this side effect
may mean in terms of treatment effectiveness.
3. Describe the theory of angiogenesis and how vascular
endothelial growth factor inhibitors may counteract
this important mechanism of cancer
development.
4. Bevacizumab is an angiogenesis inhibitor. List what
is known about bevacizumab in terms of thrombotic
and bleeding concerns. Are there any guidelines on
duration of time between bevacizumab use after
major surgery? What are they?
5. Describe the clinical literature that supported the
FDA approval of panitumumab? What indication
does it currently have?
6. Keeping rituximabs mechanism of action in mind,
which of the following disease states would rituximab
likely not show any benefi t and why?
(a) Autoimmune hemolytic anemia
(b) Cutaneous T-cell lymphoma
(c) Immune thrombocytopenic purpura
(d) Rheumatoid arthritis
7. Which of the epidermal growth factor inhibitors
require that patients test positive for the KRAS
wild-type?
8. Trastuzumab and pertuzumab require a positive test
for the expression of which receptor?
9. List the three black box warnings associated with
rituximab use.

Answers
1. From the name tositumomab and 131I tositumomab,
one can infer several characteristics of this
drug. First, it is a monoclonal antibody of murine
origin, as designated by its suffi x of omab. Second,
the drug is conjugated or radiolabeled since the
drug name contains a second word containing one
of the periodic elements.
2. The epidermal growth factor receptors (EGFR) inhibitors
all share a common side effect profi le that is dermatologic
in origin. Generally, patients will present
with an acneiform rash that cannot be successfully

treated with over-the-counter acne agents. This rash

is due to the fact that EGFR is overexpressed in many
cancers as well as normal skin and hair follicles.
Therefore, in some cases, the development of a rash
may be associated with clinical effi cacy of the drug
3. For tumors to grow larger than 2 mm 3 , they must
begin to grow their own blood supply, both to provide
oxygen and carry away wastes, a process
known as angiogenesis. Several growth factors are
necessary to stimulate angiogenesis; one of the most
potent is vascular endothelial growth factor (VEGF).
Bevaciz umab is a VEGF inhibitor that prevents
VEGF from binding to receptors, which subsequently
prevents angiogenesis and tumor growth.
Many think that VEGF inhibitors will be very successful
in early stage disease where they can prevent
large tumor growth, although bevacizumab is currently
used more in a metastatic and late stage
setting.
4. Evidence suggests that at least 28 days must elapse
between a major surgery and subsequent bevacizumab
administration. This is because antiangiogenesis
inhibitors are associated with vascular dysfunction
by their mechanism of action. There have been wound
healing concerns, excessive bleeding, and even clotting
concerns with the use of bevacizumab in clinical
trials. Concomitant use of warfarin was shown to be
safe in one recent clinical trial.
5. Panitumumab is currently indicated for the treatment
of patients with EGFR-expressing, metastatic
colorectal carcinoma with disease progression on or
following fl uoropyrimidine-, oxaliplatin-, and
irinotecan- containing chemotherapy regimens (i.e.,
third- or fourth-line use). This approval was based
on a phase III trial ( n = 463) that randomized patients
to receive panitumumab monotherapy or best supportive
care. The mean progression-free survival was
96 days for the panitumumab group and 60 days for
the BSC alone group. Eight percent of patients in the
treatment arm exhibited a partial response and no
observable response was detected in the control arm.
6. Cutaneous T-cell lymphoma. This is because rituximab
is a chimeric monoclonal antibody that binds
to the antigen CD20 (cluster of differentiation 20),
which is found on B lymphocytes (B cells).
7. In the treatment of colorectal cancer, both panitumumab
and cetuximab are rendered ineffective by
the activating KRAS mutation. Therefore, tumor tissue
should be tested for KRAS and only those
patients with a wild-type KRAS are likely to benefi t
from EGFR inhibitor MAB therapy.
8. Use of trastuzumab and pertuzumab requires a positive
test for the HER-2/neu protein (i.e., a positive
result either on fl uorescence in situ hybridization
(FISH) or immunohistochemistry (IHC) 2+) as clinical
effi cacy in the pivotal approval trials was related
to overexpression of this protein.
9. Fatal infusion reactions, tumor lysis syndrome

(TLS), and severe mucocutaneous reactions.

CHAPTER 19
1. Monoclonal antibodies are used for several reasons
in solid organ transplantation. What benefi t do they
provide over polyclonal antibodies?
2. The rational development and use of monoclonal
antibodies in solid organ transplantation is focused
on the prevention of host recognition of donor tissue
(rejection). What are the two ways in which the host
immune system recognizes donor tissue and may
cause tissue damage?
3. What are the molecular targets for monoclonal
antibodies currently used in solid organ
transplantation?
4. Monoclonal antibodies are used at various times in
solid organ transplantation. Describe the reasons
why a monoclonal antibody would be administered
before transplant, at the time of transplant, or following
transplant?
5. There are several important pharmacokinetic
parameters that must be considered when administering
monoclonal antibodies to solid organ transplant
recipients. What are these pharmacokinetic
parameters?
6. Muromonab has a characteristic infusion-related
reaction. Why does this reaction occur and how can
it be attenuated?
7. Daclizumab and basiliximab are two monoclonal
antibodies directed against the alpha subunit of the
interleukin-2 receptor. What is the difference
between these two antibodies?
8. There are several benefi ts, as well as several risks
associated with the use of monoclonal antibodies in
solid organ transplantation. What are these benefi ts
and risks?

Answers
1. Monoclonal antibodies provide targeted immunosuppression.
The advantage monoclonal antibodies
offer over polyclonal antibodies is that the receptor
target is known. Polyclonal antibody development
involves the introduction of human lymphocytes
into an animal host immune system. The animal will
then develop polyclonal antibodies directed against
human lymphocyte cell surface targets. As a consequence,
each inter-batch variability and potency
may vary. Although signifi cant outcome data exists
with the use of polyclonal antibodies, monoclonal
antibodies have a known target allowing for in vivo
and in vitro pharmacokinetic and pharmacodynamic
data to aid incorporation into novel immunosuppression
regimens.

2. The two ways in which the host immune system recognizes

donor tissue. Complement-dependent
antibody- mediated rejection occurs when the host
(recipient) develops or has preformed antibodies
against the donor tissue. Preformed antibodies will
aggregate to the implanted tissue and initiate the complement
cascade, which facilitates cell lysis. The majority
o these antibodies are usually directed against the
major histocompatibility complexes (MHC) located on
the surface of the donor tissue. An absolute contraindication
to transplantation is the presence of preformed
antibodies against MHC complex I, which is located
on the surface of all nucleated cells. The second way in
which the host immune system attacks donor tissue is
through T-cell-mediated rejection. This occurs when
the donor tissue is recognized as foreign by host antigen
presenting cells. Antigen presenting cells present
donor tissue antigens to the T cells which stimulates
T-cell proliferation and graft infi ltration leading to
infl ammation and arteritis.
3. Alemtuzumab (Campath-1H ) targets the CD52
receptor, located on peripheral blood lymphocytes,
natural killer cells, monocytes, macrophages, and
thymocytes.
Daclizumab (Zenapax ) targets the CD25 alpha
subunit of the IL-2 receptor, located on activated T
lymphocytes.
Basiliximab (Simulect ) targets the CD25 alpha
subunit of the IL-2 receptor, located on activated T
lymphocytes.
Muromonab-OKT3 (Orthoclone-OKT3 ) targets
the CD3 receptor located on CD2-, CD4-, and CD8positive lymphocytes.
Rituximab (Rituxan ) targets the CD20 receptor
located on B lymphocytes.
Eculizumab (Soliris ) targets C5 in the complement
pathway.
4. The administration of monoclonal antibodies prior
to transplant is called desensitization. This strategy
is reserved for highly sensitized patients, meaning
they have high titers of circulating antibodies
against donor-specifi c antigens. Monoclonal antibodies
that target cells which produce these antibodies
are employed, in conjunction with
plasmapheresis and pooled human immune globulins.
Removal of these antibodies may facilitate successful
transplantation across this immunologic
barrier.
Monoclonal antibodies administered at the time
of transplant are called induction. Induction is provided
at the time of transplant to decrease the ability
of the host immune system to respond to implantation
of foreign tissue. In addition, monoclonal antibodies
which provide profound T-cell depletion
given at the time of transplant may facilitate the
need for certain maintenance immunosuppressants.
Following transplantation, monoclonal antibodies
may be used to treat cell-mediated or antibodymediated

rejection. Cell and antibody infi ltrates

found in biopsy specimens in correlation with the
clinical status of the patient will dictate the type,
dose, and duration of the monoclonal antibody
chosen 5. The volume of distribution, biological half-life, and
total-body clearance can differ signifi cantly between
solid organ transplant recipients. Careful consideration
of these pharmacokinetic parameters must be
employed to maximize the effi cacy and minimize the
toxicity associated with administration of these
agents. For example, weight-based dosing in obese
patients must be carefully considered, and biological
markers of effi cacy should be evaluated to determine
the appropriate dose and dosing schedule. In addition,
monoclonal antibodies are also removed by
plasma exchange procedures, such as plasmapheresis,
which may be performed during the perioperative
period. Therefore, it would be prudent to administer
the monoclonal antibody following the plasma
exchange prescription to avoid removal of the drug
and avoid a possible decrease in effi cacy.
6. Muromonabs infusion-related reaction occurs
because when the molecule binds to the CD3 receptor.
It actually activates the cell prior to inducing
apoptosis. T-cell activation leads to increased production
of infl ammatory cytokines and when the cell undergoes apoptosis these cytokines are
released
causing a cytokine release syndrome. This cytokine
release syndrome is characterized by fever,
chills, rigors, diarrhea, and potentially capillary leak
leading to pulmonary edema. Often times this reaction
is the worst when the largest number of cells are
present, namely, the fi rst dose. However, this reaction
can occur after several days of dosing. This
reaction can be attenuated by administration of corticosteroids,
histamine blockers, and cyclooxygenase
antagonists. Pharmacotherapy aimed at reducing
the production or the interaction of cytokines with
their receptors may decrease the severity of the cytokine
release syndrome.
7. Structure activity relationship : Daclizumab has a binding
capacity of 3 10 9 M 1 versus basiliximab which
has a binding capacity of 1 10 10 M 1 . Therefore,
basiliximab is three times more potent than
daclizumab.
8. Dosing : Daclizumab is dosed based on weight, while
basiliximab is given as a 20 mg dose. The dosing
schedule varies based on the type of solid organ
transplanted as well as concomitant immunosuppression
given. These agents, however, are only
approved for prevention of acute rejection in kidney
transplant recipients.
9. Benefi ts include targeted immunosuppression, no
batch variability, and low antigenicity in humanized
products. The risks associated with any type of
immunosuppression include an increased risk for
infection, as well as malignancy. Patients who
receive monoclonal antibodies which specifi cally
target a cell line, such as muromonab, are associated

with a signifi cantly increased risk of posttransplant

lymphoproliferative disease. Appropriate antimicrobial
prophylaxis and vigilant screening for posttransplant
malignancy may allow for safe and
effective use of these monoclonal antibodies in solid
organ transplantation.

CHAPTER 20

Questions
1. Are targeted biologic therapies for autoimmune diseases
only to be used once drugs like corticosteroids
and methotrexate have had an adequate trial of use
and have failed to control the patients symptoms?
2. What is the primary clinical concern with the immunogenicity
of biologic therapies?
3. What is the most likely explanation for why a patient
who receives a dose of omalizumab might have an
increase in their total serum IgE level for many
weeks after the fi rst dose?
4. Why do some cell subsets in the peripheral blood
increase after dosing with natalizumab?
5. If a trial reports an ACR70 of 20 % on active drug,
what does that mean?
6. What does PASI 75 mean?
7. Given that there are currently fi ve anti-TNF biotherapeutic
agents on the market, how would you
compare and contrast them?
8. What are the key differences in the indication for use
of rituximab vs. abatacept in RA?
9. What is the mechanism of action for ustekinumab in
treating plaque psoriasis?
Answers
1. Though the standard of care in diseases like RA is
still to start with older DMARDs like methotrexate,
the decision of when to start or switch therapies is
complex and impacted by individual issues linked
to clinical response like tolerance/adherence to a
particular therapeutic regimen, severity and course
of disease and its progression, and concomitant
medications and medical issues. It is likely that the
standard of care will continue to change and incorporate
earlier use of biologic therapies that can modify
the disease course with fewer generalized side
effects.
2. If a biologic therapy is highly immunogenic, there is
a concern that an increasing number of patients
exposed to the drug, particularly upon repeated
exposure after a hiatus, because their antidrug antibodies
could sometimes neutralize the majority of
the drug and they would not likely get the full dose
or effect. Though less likely there are also rare examples
of antidrug antibodies resulting in an autoimmune
or allergic-type reaction.
3. Therapeutic monoclonal antibodies that target soluble
molecules like IgE form complexes. Though

immune complexes are typically cleared from the

blood more quickly than monomeric IgG, soluble
target molecules typically have a shorter serum halflife
than IgG. So an assay detecting the soluble target
(in this case IgE) that can detect target even when it
is bound to the drug (which is typically an longerlived
IgG) will show more target present in the
serum post-dosing as compared to baseline. This is
called a carrier effect. Assuming the drug neutralized
the bound target, the test detecting the target
can be misleading, because the target, though present,
is effectively inactive.
4. Natalizumab is a monoclonal antibody that blocks
lymphocyte movement between the blood and tissues
(traffi cking); when this movement is effectively
blocked in one direction (from the blood into
the tissues), an apparent increase in the peripheral
lymphocyte population will be evident on assessment
by fl ow cytometry (or perhaps even on a CBC
with differential) post-dosing.
5. An ACR70 of 20 % means the 20 % of the patients
had a 70 % improvement in their RA disease.
6. The PASI score stands for Psoriasis Area and Severity
Index. This tool allows researchers and dermatologists
to put an objective number on what would otherwise
be a very subjective idea: how bad is a
persons psoriasis. The PASI evaluates the degree of
erythema, thickness, and scaling of psoriatic plaques
and estimates the extent of involvement of each of
these components in four separate body areas (head,
trunk, upper, and lower extremities).
If in a clinical study a certain proportion of patients
experienced a 75 % reduction in their PASI scores, it
is reported as a percentage of people achieving
PASI 75.
7. Although the fi ve anti-TNF biologics have broadly
similar effi cacy and safety profi les in RA, there are
signifi cant differences in the fi ve anti-TNF agents
particularly with respect to dosing characteristics
and also in the details of the approved indications
for use.
Infl iximab is the only anti-TNF agent given
intravenously, has the longest dosing interval, and
is the fi rst FDA-approved anti-TNF agent for IBD
indication. All the other anti-TNF agents are
administered by subcutaneous administration. It is
a chimeric monoclonal antibody that neutralizes
TNF- and has approvals in the most indications
(rheumatoid arthritis, psoriatic arthritis, ankylosing
spondylitis, adult and pediatric ulcerative
colitis, adult and pediatric Crohns disease, and
psoriasis).
Etanercept is a dimeric soluble fusion protein and
has approvals for use in several indications (rheumatoid
arthritis, polyarticular juvenile rheumatoid
arthritis, psoriatic arthritis, ankylosing spondylitis,
and psoriasis). It is used as weekly injection.
Adalimumab is a human monoclonal antibody

that neutralizes TNF- and has FDA approvals for

use in patients with rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis, psoriasis, and
Crohns disease. It is used at a frequency of every
week or every other week.
Golimumab is a human monoclonal antibody
that neutralizes TNF- and has FDA approvals for
use in patients with rheumatoid arthritis, psoriatic
arthritis, and ankylosing spondylitis. It is used at a
frequency of every month.
Certolizumab pegol is a recombinant, humanized
antibody Fab fragment, with specifi city for human
tumor necrosis factor alpha (TNF), conjugated to
an approximately 40-kDa polyethylene glycol
(PEG2MAL40K). It has been approved by FDA for
the treatment of rheumatoid arthritis and Crohns
disease.
8. Rituximab in combination with methotrexate is
indicated for the treatment of adult patients with
moderate to severe rheumatoid arthritis who have
had an inadequate response to one or more TNF
antagonist therapies. Abatacept is indicated for use
as monotherapy or in combination with DMARDS
in patients with moderate to severe active rheumatoid
arthritis who have had an inadequate response
to DMARDs or TNF antagonists.
9. IL-12 and IL-23 are naturally occurring cytokines
that are involved in infl ammatory and immune
responses, such as natural killer cell (NK) activation
and CD4+ T-cell differentiation and activation.
Ustekinumab, a human IgG1 monoclonal antibody
that binds with high affi nity and specifi city to the
p40 protein subunit used by both the IL-12 and
IL-23, can prevent human IL-12 and IL-23 from
binding to the IL-12R1 receptor chain of IL-12
(IL-12R1/2) and IL-23 (IL-12R1/23R) recreceptor
complexes on the surface of NK and T cells.

CHAPTER 24

Questions
1. What was the disease target for the fi rst gene therapy
clinical trial? What vector was selected for gene
transfer?
2. Identify and describe fi ve transcription regulatory
elements (TRE) discussed in the chapter.
3. Several clinical trials involve gene transfer for treating
malignant glioma. One approach involves the use
of a recombinant retrovirus expressing the HSV-tk
transgene. Another involves the use of a recombinant
adenovirus expressing the p53 transgene.
(A) Which of the fi ve current strategies to treat
cancer by viral gene therapy does each of these
trials employ? Describe the principle behind
each strategy.
(B) List 2 advantages and 2 disadvantages associated
with the vector used in each of these

trials.
(C) Outline potential drawbacks to the use of each
of these strategies for cancer therapy.
(D) What other approaches could have been
selected to prevent the growth and spread of
malignant tissue? Explain the principle behind
each.
4. What is the purpose of the packaging cell line during
the production of recombinant viral vectors for
gene transfer? What is the risk associated with using
packaging cell lines for vector production?
5. Provide two examples of how gene therapy is used
to modulate the immune system to fi ght infection.
6. Describe one clinical trial for retrovirus-based gene
therapy and adenovirus-based gene therapy, and
identify the most signifi cant adverse effects that
have been reported for each trial.
7. Identify the three marketed gene therapy products
in the world and describe the mechanism of actions
of each product.

Questions
1. What was the disease target for the fi rst gene therapy
clinical trial? What vector was selected for gene
transfer?
2. Identify and describe fi ve transcription regulatory
elements (TRE) discussed in the chapter.
3. Several clinical trials involve gene transfer for treating
malignant glioma. One approach involves the use
of a recombinant retrovirus expressing the HSV-tk
transgene. Another involves the use of a recombinant
adenovirus expressing the p53 transgene.
(A) Which of the fi ve current strategies to treat
cancer by viral gene therapy does each of these
trials employ? Describe the principle behind
each strategy.
(B) List 2 advantages and 2 disadvantages associated
with the vector used in each of these
trials.
(C) Outline potential drawbacks to the use of each
of these strategies for cancer therapy.
(D) What other approaches could have been
selected to prevent the growth and spread of
malignant tissue? Explain the principle behind
each.
4. What is the purpose of the packaging cell line during
the production of recombinant viral vectors for
gene transfer? What is the risk associated with using
packaging cell lines for vector production?
5. Provide two examples of how gene therapy is used
to modulate the immune system to fi ght infection.
6. Describe one clinical trial for retrovirus-based gene
therapy and adenovirus-based gene therapy, and
identify the most signifi cant adverse effects that
have been reported for each trial.
7. Identify the three marketed gene therapy products
in the world and describe the mechanism of actions

of each product.

interfere
with virus infection and replication. (iii)
Overexpression of known antigenic epitopes of
the pathogen by DNA vaccination to stimulate an
immune response.
6. (i) One trial employed aerosol administration of a
recombinant adenovirus expressing cystic fi brosis
transmembrane conductance regulator (CFTR)
to treat cystic fi brosis (CF). Another trial employed
a recombinant retrovirus expressing recombinant
adenosine deaminase (ADA) to transduce autologous
T lymphocytes isolated from patients for
treating ADA defi ciency-induced severe combined
immunodefi ciency (ADA-SCID). (ii) CF
trial. Massive immune response to the recombinant
viral vector.
ADA-SCID trial. Lymphoproliferative leukemia
caused by insertional mutagenesis.
7. Gendicine is a recombinant adenoviral vector which
expresses p53 tumor suppressor and is used to treat
patients with head and neck squamous cancers.
Oncorine is a recombinant adenoviral vector which
contains a deletion in the E1B 55 K region and only
replicates in p53 defi cient cancer cells. Oncorine kills
tumor cells through viral replication, expression of
cytotoxic proteins, and cell lysis.
Cerepro is a recombinant adenoviral vector encoding
herpes simplex type-1 thymidine kinase (TK).
Cerepro is used for treating malignant glioma
together with ganciclovir through gene-directed
enzyme-prodrug therapy.