Frederick Sweet, Ph.D. is Professor of Reproductive Biology in Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.
Dr. Sweet reports no commercial conflicts of interest.
Release Date: 11/12/2007
Termination Date: 11/12/2010
Estimated time to complete: 1 hour(s).
Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
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- Discuss the diverse concepts that constitute targeted therapy
- Describe recent basic and clinical progress from research on these novel therapies
- Discuss how near or far we are from having more effective new therapies for ovarian cancer "just around the corner."
Ovarian cancer is the fifth leading cause of death from all cancers in women in the United States. Even though overall survival figures have shown improvement during the past few decades with the introduction of new chemotherapy schedules, the majority of patients die of this disease. The relatively new research area of targeted therapy offers promise and hope for more effectively treating ovarian cancer than has been obtained by traditional approaches. Thus the main purpose of this Cyberounds® on targeted therapy is to provide an overview of this rapidly evolving field as it progresses from the research laboratory to the oncology clinic.
The basic concept of targeting therapies against invasive microorganisms and also cancers has been around for more than a century, summarized under Father of Targeted Therapy (below). We almost take for granted the effective targeted therapies against invasive microorganisms, antibacterial and antifungal antibiotics, which are on virtually every pharmacy shelf worldwide. Hopefully soon, we shall have on those shelves more effective anticancer drugs, promised to be just around the corner in reviews such as this one.
Father of Targeted Therapy
The magic bullet concept -- a term first coined at the turn of the 20th century by Paul Ehrlich (1854-1915) -- derives from 19th century German chemists who developed synthetic dyes for selectively staining tissues in histological examination. Some dyes were discovered to be particularly well suited for staining bacteria. The young Ehrlich had been an exceptionally gifted histological chemist who discovered the classical precursor technique to Gram staining bacteria.
Ehrlich had proposed that if a compound could be made that selectively targeted a disease-causing organism -- analogous to how certain dyes selectively stain bacteria -- then a toxin for that organism could be delivered by linking it to the chemical agent that selects the tissue. Meanwhile, in the early and mid-1890s, he worked with his friend Emil Adolf von Behring on developing the diphtheria serum.
In 1896, Ehrlich was made director of the new Institute of Serum Research and Examination [Institut für Serumforschung und Serumprüfung in Steglitz (Berlin)]. The next year, Ehrlich's work on serum led to his famous side-chain theory (Seitenkettentheorie). His theory explained the effects of serum and enabled detection of an antigen. Then in 1899, Ehrlich's Institute was moved to Frankfurt (Main) and extended into the Royal Institute of Experimental Therapy (Institut für experimentelle Therapie) where he continued research on infectious diseases and chemotherapy.
Describing targeted therapy, Ehrlich for the first time used the English expression "magic bullet" in his Harben Lectures.(1) The German word Zauberkugel (comparable to the Freikugel of Weber's opera Der Freischütz) had appeared earlier in his thoughts and publications, based on his "side-chain" theory views. This was also the precursor of our present concept of receptors. Ehrlich had set the standard that a useful drug must not harm the host while it attacks the parasitic invader.
In 1906, Ehrlich discovered the structural formula of atoxyl, a fairly toxic chemical compound that had been shown to be useful in treating sleeping sickness. Following this discovery, he tried to create a less toxic version of this substance. Then in 1908, Ehrlich (together with Ilya Ilyich Mechnikov) received the Nobel Prize in Medicine for his development of effective therapeutics.
However, Ehrlich's first rationally designed magic bullet was Salvarsan (or arsphenamine) discovered with his student Sahachiro Hata, the year after Ehrlich received his Nobel Prize. Salvarsan provided the only cure for syphilis until the mid 20th century. It was replaced after World War II by penicillin and others of the new family of antibiotics.
Ehrlich was first to propose attaching toxins to antibodies that can carry a deadly substance to the site of an invading parasite (or cancer) while sparing normal tissues. His proposal anticipated, indeed inspired development of today's immunotherapy. This concept has been adopted by virtually all modern laboratories using monoclonal antibodies as carriers for analogs of anthracyclines (e.g., daunorubicin), paclitaxel or cisplatin for treating ovarian cancer by this form of targeted therapy.
NIH's Bernhard Witkop notes:(2) "...in the fifth Paul Ehrlich Lecture at the NIH in 1992, Manfred Eigen (Nobel Prize 1967, Paul Ehrlich Prize 1995), spoke about interfering with intercellular transfer of information as a new kind of magic bullet against viral infections. Finally, genes as therapeutic agents are now in the forefront of pharmaceutical research, and promise to be of help in diseases that appeared incurable."
Witkop concluded: "Subsequent speakers who developed "magic bullets" were George Hitchings (1905-1998; Nobel Prize 1988, who lectured in 1990) and Manfred Eigen (Nobel Prize 1967, who spoke in 1992, the same year in which he received the Paul Ehrlich Prize). Stanley Prusiner lectured in 1995, receiving the Paul Ehrlich Prize in the same year, and the Nobel Prize in 1997 for his discovery of prions, dormant 'magic bullets'."
Immunotherapy
Ehrlich had predicted that a promising delivery system for carrying an anticancer drug to its target while bypassing normal tissues would be based on immunology. But such a delivery system required discovering a unique cell surface protein in the targeted cancer. The unique protein would serve as an antigen from which to produce the complementary antibody to serve as a drug carrier.
Excellent progress has been made in developing new treatments for ovarian cancer by using as a delivery system the antibody against the antigen CA125. Originally, the ovarian cancer cell surface antigen had been -- and is still -- used for detecting the CA125 antigen in the blood of women suspected of having ovarian cancer.(3) Also, measuring decreasing blood levels of the antibody during chemo- and/or radiation therapy provides a means of assessing therapeutic progress as the ovarian cancer undergoes remission.
Employing the anti-CA125 antibody in a delivery system for targeted therapy requires using very large amounts (i.e., milligrams to grams) of the antibody protein, compared with its routine use (i.e., ng to μg amounts) for measuring the ovarian cancer antigen in women's blood. Moreover, effective and very efficient chemical methods had to be devised for linking a cancer therapeutic agent to the antibody in this type of a drug delivery system.
Immunotoxins
The potential, practical downsides are that chemical modification of cancer therapeutic agents (e.g., daunorubicin, paclitaxel, cisplatin, etc.) for their linkage to an antibody often reduces their potency. Earlier, work from our laboratory with immunoconjugates of daunorubicin linked to an anti-CA125 antibody emphasized that previously such attempts had been unsuccessful because modifications of the drug weakened or destroyed its efficacy.(4)
Similarly, when therapeutic agents are linked to an antibody (anti-CA125), the location of the linkage in the immunoglobulin often reduces the specificity and/or its avidity for the targeted ovarian cancer cell surface antigen (Figure 1). Thus a great deal of experimentation goes into obtaining an optimized configuration before an antibody-drug complex can show promise for targeted therapy.
Figure 1. Idealized Antibody (Ab)-drug Conjugate.
Schematic of the functional structures in a typical antibody protein (left) and regions where anticancer therapeutic drugs should and should not be linked (right). Even today, most Ab-drug conjugates are formed by randomly linking a drug to the Ab protein -- tending to reduce specificity and avidity by drug molecules occupying the antigen-binding region.
Radioimmunotherapeutics
More recently, a radioisotope-antibody conjugate was administered together with paclitaxel (i.e., paclitaxel) in Phase I trials for treating ovarian cancer by radioimmunotherapy (RIT).(5) A mouse-derived monoclonal antibody, CC49, which targets an ovarian cancer-associated glycoprotein (TAG-72) was conjugated with an analog of 90Y to provide the resulting radioimmunoconjugate 90Y-CC49 (administered with an initial dose of 14 mCi/m2 90Y). At the same time, paclitaxel was administered i.p. to the ovarian cancer patients. The 20 patients treated ranged in ages from 39 to 77 years (median age, 61 years).
Discussion of the results with the radioimmunoconjugate 90Y-CC49 concluded: "partial responses were noted in 2 of 11 patients (18%) with measurable disease treated in the current trial. In addition, the disease-free interval exceeded 12 months in five of nine patients with non measurable disease, and four of these five patients remain cancer free 15+ to 23+ months after treatment."
"This experience provides evidence that this strategy can be administered safely, is well tolerated and has antitumor activity. It also provides solid evidence that IFN α2b enhancement of target antigen expression and i.p. administration of substantial dosages of paclitaxel (100 mg/m2) are well tolerated and do not preclude administration of RIT at maximum or near maximum doses in a combined multimodality format."
More recently, further refinements in combining radioimmunotherapy with paclitaxel in nude mice established that this approach indeed has a synergistic anti-tumor effect on the growth of human ovarian tumor OVCAR-3 xenografts.(6) Synergy was only observed when a tumor-specific antibody was used as a delivery system for radioimmunotherapy. In this case, the combination of radioimmunotherapy using an anti-CA125 monoclonal antibody and chemotherapy with paclitaxel was shown to be effective in an in vivo model of ovarian cancer that may hold promise as a treatment regimen for patients with ovarian cancer.
A Practical Clinical Problem
There is an important practical clinical problem lurking around immunotherapy that is rarely discussed as part of the optimistic conclusions about immunotherapy in the recent literature (or for that matter in NIH grant applications). In two words the problem is antigen shedding. What enables the anti-CA 125 monoclonal antibody to detect and measure the cell surface antigen from ovarian cancer is that the cancerous tumor sheds the CA125 antigen that is detected in the patient's blood.
When the same anti-CA125 monoclonal antibody is incorporated into an anticancer immunotoxin, its function is to carry and target the toxin for bonding to ovarian cancer cells producing CA125 cell surface antigens. Presumably, most molecules of the shed, blood borne CA125 antigenic protein would become bound to and thus neutralize the immunotherapeutic agent. Clearly, antigen shedding constitutes a major problem of a practical clinical nature. For efficacy of immunotherapy, this problem must be solved. The author has speculated on various strategies for dealing with this problem but they are beyond the scope of this Cyberounds®.
Originally, the term targeted therapy had been applied to substances that were a throwback to Paul Ehrlich's magic bullet concept. Purists still regard targeted therapy to derive from a binary molecular structure analogous to military intercontinental ballistics missiles. Part of the molecule is the carrier and cancer-seeking vehicle, while the other moiety is a cytotoxin or lethal radioisotope. More recently, however, the concept has been broadened to encompass targeting entire systems, discussed in the following sections (below).