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Monoclonal
Antibodies in the Management of Prostate Cancer: An Introduction
by
E. Michael D. Scott
CoMed
Communications, Inc., 210 West Washington Square, Philadelphia,
PA 19106
Originally
received February 20, 1996; last revised February 26, 1996
What is a monoclonal antibody?
Monoclonal
antibodies, commonly referred to as MABs, were one of the
earliest products of so-called "genetic engineering."
They are complex immunologically active proteins which have been
biologically synthesized in such a way that every single
individual monoclonal antibody of a particular type is exactly
the same as every other monoclonal antibody of that type because
they have all been developed from one particular
"clone" of cells, all of which were identical
(hence the term "monoclonal").
Monoclonal antibodies are developed from genetically engineered
cells which normally make specific antibodies to specific
abnormal materials ("antigens") in a normal host
organism. For example, if you catch the flu, your body makes
antibodies which are specific to the precise type of influenza
virus (the antigen) which has infected you. It is now (at least
theoretically) possible to isolate the cell making that specific
antibody, and grow that cell in such a way as to make large
quantities of the particular antibody to that specific virus.
This would be a monoclonal antibody to that flu virus. Of course
there are all sorts of technical reasons why it may be difficult
or impossible to make any one specific MAB in this manner, but
the principle has been well established.
Why are MABs useful?
Monoclonal
antibodies are the closest thing we have found so far to
"magic bullets," which can be carefully targeted to
reach specific sites in specific organ systems. Here is a good
way to think about this.
Imagine that you are a doctor and you know that your patient has
prostate cancer which has escaped from the prostate, but you
don't know where it has escaped to, because none of the present
forms of diagnosis (bone scan, MRI, etc.) are sufficiently
sensitive. Now imagine that someone has developed a monoclonal
antibody that will attach itself with 100% accuracy to the
surface of any prostate cancer cell (the antigen carrier). This
would mean two things.
-
First,
it would mean that you could link some form of diagnostic
marker to that monoclonal antibody, which might allow you to
identify exactly where in the body your patient had prostate
cancer cells.
-
Second,
it would mean that you could link some form of therapeutic
agent to that monoclonal antibody, which might allow you to
target and kill every prostate cancer cell in the body
(potentially without affecting any normal, healthy cells in
the body), because the MAB would only link itself to
prostate cancer cells.
Now
you shouldn't get too excited by this. While the potential
of MABs is enormous, the actual implementation of this
technology has taken years since monoclonal antibodies were
first developed in the 1970s. There have been a small number of
major successes, and all too many disappointments and failures.
Do
MABs really work?
One
therapeutic monoclonal antibody has been available for years.
Muromonab-CD3 (commonly known by its commercial name, Orthoclone
OKT3, or just OKT3) has been used since the mid 1980s in the
treatment of selected patients receiving transplants. It helps
to prevent certain types of transplant rejection. The speed with
which this product was developed and brought to market made many
people think that by now there would be hundreds of MABs in
diagnostic and therapeutic use. Life is not that simple!
By contrast, in the late 1980s and early 1990s many people were
betting that a company called Centocor would gain permission to
market a product (then known as HA-1A) based on MAB technology
which was expected to be able to treat severely ill patients who
have a disorder known as toxic shock syndrome -- usually caused
by one or another of a specific class of bacterial infections.
Unfortunately, despite huge expectations, the product could not
shown to be effective in the US, and Centocor lost hundreds of
millions of dollars. However, the product was approved in
certain European countries, where it is known as nebacumad
(trade name, Centoxin), and, perhaps more importantly, the
technology which the company developed is still in use, and
recently they have received permission to market a
different product known as abciximab (trade name, ReoPro), which
can be used as an adjunct to treatment for patients undergoing
certain types of cardiovascular surgery. In patients receiving
percutaneous transluminal coronary angioplasty or atherectomy,
abciximab reduced the incidence of acute cardiac ischemic
complications for those individuals at high risk for abrupt
closure of the treated coronary vessel.
Referring specifically to the field of cancer, there have
recently been a number of developments which have allowed us to
become more positive about the future uses of MABs. In 1993 two
groups (from the University of Washington in Seattle, WA, and
the University of Michigan in Ann Arbor, MI) provided early,
promising data on the use of an MAB known as anti-CD20 (or
anti-B1) linked to radioactive iodine-131 in the treatment of
patients with a form of cancer known as non-Hodgkin's lymphoma [1,
2].
In 1995, the University of Michigan group provided an update on
their earlier results. In their patients (who were considered to
be patients with poor prognosis because they had nearly all
failed one or more prior chemotherapies), Kaminski reported that
14 of 28 (50%) had a complete remission which lasted for an
average of 15 months with minimal or modest toxic side effects [3].
At the same conference, the University of Washington group
reported on a new group of patients who were perhaps slightly
less sick but all of whom had also relapsed following
chemotherapy. In these patients they had combined the use of the
monoclonal antibody with a technique known as "stem cell
rescue", and approximately 85% of the patients demonstrated
complete responses with more than 90% of the patients surviving
for an average of 2 years [4].
Clearly the results from these small trials show significant
promise, and anti-CD20 linked to iodine-131 is now in expanded
clinical trials for treatment of non-Hodgkin's lymphoma.
A fourth study has indicated the value of a different monoclonal
antibody (known as 17-1A) in the management of minimal residual
disease in patients who had undergone surgery for a specific
stage of colorectal cancer. Riethmüller and his colleagues
demonstrated that treatment with 17-1A in this selected group of
patients clearly increased survival by 30% and decreased the
disease recurrence rate by 27% at 5 years, with minimal toxic
side effects [5].
This product has now been approved for clinical use in several
European countries, but is not yet available in the US (although
it is currently undergoing multicenter trials).
The use of monoclonal antibodies in the diagnosis and treatment
of prostate cancer was reviewed by Bander in 1994 [6].
It is not the objective of this article to reconsider that early
work, but rather to give a perspective for interested patients
on more recent and ongoing work.
Of
mice and men
A
major problem with developing and growing monoclonal antibodies
has been that it is relatively easy to do using mouse antibodies
but much harder using human antibodies. Cell biologists,
biochemists, and molecular biologists have now worked out how to
overcome these problems, but it is still much easier to use
mouse antibodies. Muromonab-CD3, for example, is a pure mouse
monoclonal antibody, as is 17-1A. Another way to approach the
problem has been through the synthesis of so-called "chimeric"
MABs, in which elements of human and mouse antibodies are
combined to develop cross-species MABs.
This is important because of human immunology. If one introduces
pure non-human MABs into a man or a woman, most people will have
an immunological reaction to those MABs because their bodies
will recognize these proteins as "foreign" or
"not self." This can also mean that it is only
possible to use these products within a short window of time
(perhaps 1 or 2 weeks) in any particular individual because of
the consequent immunobiological reaction.
It will only be when we are able to use pure human-based MABs on
a regular basis that we will completely overcome the problems of
immunological rejection of such agents. In the meantime, our
current technology and the use of chimeric MABs has already
reduced these shortcomings to acceptably low levels.
MABs in prostate cancer diagnosis
We
may be close to seeing the approval of the first monoclonal
antibody for use in the diagnosis of prostate cancer. This
monoclonal antibody, originally known as "7E11" when
first isolated by Dr Gerald Murphy and his colleagues at Roswell
Park Cancer Center in Buffalo, New York, was licensed by the
Cytogen Corporation and initially renamed as CYT 356.
By attaching this monoclonal antibody to a radioactive isotope
(indium-111), Cytogen has developed an immunodiagnostic agent
which appears to be able to identify some (but certainly
not all) sites of prostate cancer outside the prostate in a
manner which has a greater degree of accuracy than other
currently available methods. In particular, the use of this
technique may make it possible to identify patients with
positive lymph nodes without carrying out a lymphadenectomy
(laparoscopic or otherwise). This could make it a great deal
easier to decide whether or not to operate on or give radiation
therapy to certain patients with cancer which has escaped the
prostate.
In addition, the Cytogen MAB-based diagnostic may have a value
in helping doctors and their patients to decide when and if the
patient's prostate cancer has progressed to a metastatic state.
However, this new agent is known to be neither 100% sensitive to
nor 100% specific for prostate cancer.
If Cytogen Corp. receives approval to market this new
immunodiagnostic agent in the US, it will be known as capromab
pendetide (trade name, Prostascint). Other MABs are currently
being used in attempts to develop other diagnostic tests for
prostate cancer, although the current status of these potential
tests is unknown.
MABs in prostate cancer treatment
The
Cytogen MAB (CYT 356) and other MABs (e.g. CC49, a
"pan-carcinoma" MAB) have or are currently being used
in attempts to produce MAB-based therapeutic agents for prostate
cancer and many other cancers. However, it is very important
that the reader appreciate some of the constraints on this work.
In the first case, how a specific MAB targets a
particular type of prostate cancer cell will inevitably
influence the ability of that MAB to deliver a therapeutic
effect. For example, CYT 356 targets a molecular site which is inside
prostate cancer cells and not on the cell surface. This makes it
much harder (and perhaps impossible) for the MAB to act on every
prostate cancer cell because the MAB needs to pass through the
cell membrane in order to act on each cell, and all cells have
mechanisms designed to stop inappropriate molecules from
crossing through their cell membranes.
Secondly, much of the work which has been carried out to date
has been based at least as much on the availability of
individual MABs as on their potential value in the treatment of
prostate cancer. While all of this work is valuable as we
attempt to learn more about how MABs may be utilized in the
treatment of prostate cancer in the long term, some of it can
easily be misunderstood when it comes to its true potential
clinical value. One early-stage clinical trial currently being
conducted uses a chimerized mouse-human MAB known as C225 in
conjunction with the chemotherapeutic agent doxorubicin. This
MAB was developed by Imclone, a New York-based biotechnology
company, and was intended for use in the treatment of cancers in
which high levels of epidermal growth factor receptor (EGFr) are
expressed, such as head and neck cancers. Since prostate cancer
is not known to express high levels of EGFr, one is tempted to
wonder whether C225 + doxorubicin will really have any
significant benefit in prostate cancer, although the data which
may be collected in this trial could be significant in helping
us to understand how to move forward with this general
form of therapy (i.e., the combination of an MAB with a
chemotherapeutic agent).
Similarly, a trial of the radiolabeled MAB CC49, which was
carried out at the University of Alabama, has been mentioned
earlier in this article. This trial showed no clinically
significant responses [7],
but other trials of CC49 are ongoing. No detailed information
about these trials is currently available, but one must have
doubts as to the value of these trials since the target antigen
is known to be only weakly expressed by prostate cancer.
With respect to the development of good MAB-based therapeutic
agents for the management of prostate cancer, it would appear
reasonable that a number of specific issues need to be clearly
recognized by patients who agree to participate in trials of
such agents:
-
The
patient's prostate cancer should clearly express the target
antigen for the therapeutic or carrier MAB. In other words,
whether the MAB is itself therapeutically active, or whether
it is linked to a drug or other agent which is expected to
be therapeutically active, it will be of little value if it
is not highly specific for the target antigen and if the
patient's prostate cancer cells do not consistently produce
appropriate levels of that antigen.
-
Although
MAB-based therapies are certainly likely to work in patients
who have progressed to hormone-refractory disease, it seems
much more likely that MAB-based therapies will work best in
patients with earlier stages of disease. Thus, we might
conceive of MAB-based therapies having their greatest value
in the management of
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Patients
initially diagnosed with node-positive disease
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Patients
undergoing curative surgery or radiation who are at high
risk of extracapsular disease or node-positive disease
(based on, for example, the Partin
tables); this would imply the use of MAB-based
therapeutics as adjuvant therapy
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Patients
who show a rising PSA after curative treatment who are
believed to be failing such treatment because of either
localized prostate cancer in the pelvic area or
micrometastatic sites of prostate cancer.
-
The
MABs which are most likely to have the greatest clinical
benefit are probably going to be those which are clinically
active in their own right. In other words, they will be MABs
which do not need to be "linked" to drugs or to
radioactive isotopes because they will work directly to kill
prostate cancer cells through immuno-biochemical mechanisms
of action.
One
trial, at New York Hospital-Cornell Medical Center, is currently
using an MAB-based therapeutic (known as Prost 30) in an
adjuvant therapeutic role, i.e., in patients who, shortly after
surgery, are considered to be at high risk of relapse. This is a
very similar scenario to the colon cancer trial carried out by
Riesthmüller et al. [5].
Whether this trial will indicate any benefit for this type of
therapy, and the precise nature of the MAB, are not known to the
author at this time. We may see more information on this topic
presented at either the American Urological Association or at
the American Association for Cancer Research annual meetings
later this year.
Waiting
for the future
It
seems highly likely that in time we will see the development of
a broad range of MAB-based diagnostics and therapeutics for
different cancers in general and for prostate cancer in
particular. However, it also seems highly likely that this
development will take several more years yet. It is an
unfortunate fact in the history of science and medicine that
while great leaps can be made in our ability to treat
specific disease almost overnight, most advances in medical
science are in fact based on years and years of careful study
with the full complement of trial and error.
Today's prostate cancer patients need to appreciate that if they
decide to participate in clinical trials of monoclonal
antibody-based therapeutics, we are still at the very earliest
stages of understanding the development and use of these agents.
Thus the results are probably more liable to be disappointing
than they are to be successful. Clinical researchers obviously
need appropriate patients to participate in these trials if we
are to find answers to all the questions about how to improve
the management of prostate cancer patients, but patients should
not let themselves be misled into having false hopes of major
advances which may not be justifiable on the basis of current
knowledge.
References
1.
Kaminski MS, Zasadny KR, Francis IR,et al. Radioimmunotherapy of
B-cell lymphoma with [131I]anti-B (anti-CD20)
antibody. New Engl J Med 1993; 329: 459-465.
2. Press OW, Eary JF, Appelbaum FR, et al.
Radiolabeled-antibody therapy of B-cell lymphoma with autologous
bone marrow support. New Engl J Med 1993; 329:1219-1224.
3. Press OW, Eary J, Martin P, et al. High dose
radioimmunotherapy of relapsed B cell lymphomas [abstract].
Paper presented at the international symposium on
"Monoclonal Antibiodies and Cancer Therapy: The Next
Decade", New York, NY, October 1995: S19.
4. Kaminski MS. Non-myeloablative
radioimmunotherapy of B-cell lymphoma with radiolabeled antiCD20
antibodies [abstract]. Paper presented at the international
symposium on "Monoclonal Antibiodies and Cancer Therapy:
The Next Decade", New York, NY, October 1995: S27-28.
5. Riethmüller G, Schneider-Gädicke E,
Schlimok G, et al. Randomized trial of monoclonal antibody for
adjuvant therapy of resected Dukes' C colorectal cancer. Lancet
1994; 343: 1177-1183.
6. Bander NH. Current status of monoclonal
antibodies for imaging and therapy of prostate cancer. Semin
Oncol 1994; 21: 607-612.
7. Meredith RF, Bueschen AJ, Khazaeli MB, et al.
Treatment of metastatic prostate carcinoma with radiolabeled
antibody CC49. J Nucl Med 1994; 35: 1017-1022.
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