Monoclonal Antibodies in the Management of Prostate Cancer:

An Introduction

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 availablity 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 Patients initially diagnosed with node-positive disease
   
• 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
   
• 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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