Monoclonal Antibodies in Cancer Therapy: 25 Years of Progress
In 1983, it was apparent that a major problem with current modalities of cancer treatment was the lack of specificity for the cancer cell. It was predicted that a major advancement in treatment of cancer would be the development of a class of agents that would have a greater degree of specificity for the tumor cell. Based on many animal studies and the treatment of fewer than 100 patients, it was evident in 1983 that monoclonal antibodies would be that major advance.
The first patient treated in the United States with monoclonal antibody therapy was a patient with non-Hodgkin's lymphoma. Nadler described the treatment using a murine monoclonal antibody designated AB 89. Although treatment was not successful in inducing a significant clinical response, it did represent the first proof of principle in humans that a monoclonal antibody could induce transient decreases in the number of circulating tumor cells, induce circulating dead cells, and form complexes with circulating antigen, all with minimal toxicity to the patient. Antibody could be detected on the surface of circulating lymphoma cells, and free antigen in the serum decreased with each infusion of antibody. After two courses of milligram doses of AB 89, a final and third course with 1.5 g of antibody was administered during a 6-hour period. A marked reduction in circulating antigen was noted, but these studies suggested to the authors that the quantity of circulating antigen was too great to effectively deliver AB 89 to the patient's tumor cells in a therapeutically effective manner.2
In the Journal of Clinical Oncology review article cited earlier,evidence was reviewed from animal tumor models that clearly demonstrated both specificity and therapeutic efficacy with little serious toxicity. Whereas passive serotherapy of human cancer had shown little success, it was apparent in the earlier review that monoclonal antibodies could be used in the treatment of leukemia and lymphoma. In 1983, a review of the literature revealed approximately 10 published studies and one in-press article of therapeutic trials of monoclonal antibody therapy in humans. All of these studies used murine monoclonal antibodies and were phase I/II studies. Most were in leukemia or lymphoma, but the earliest solid tumor studies were also underway in melanoma and GI cancer.
By 1983, the pioneers in monoclonal antibody research believed that a new era of cancer therapy had begun, and for the first time, true specific and targeted therapy was underway using hybridoma technology to produce monoclonal antibodies with exquisite specificity. It was also apparent, based on animal model studies, that monoclonal antibodies could be a vehicle to bring immunoconjugate therapy to the clinic by conjugating monoclonal antibodies to drugs, toxins, and radioisotopes using the specificity of the monoclonal antibody to carry enhanced killing capacity directly to the tumor cells. Thus, the era of monoclonal antibody therapy, as well as immunoconjugate therapy, had begun.
Although there was much excitement (and skepticism) about this new treatment modality (the use of a form of biologic therapy with great specificity in patients with advanced cancer) there were also problems and limitations. As presented, there were clinical toxicities with murine monoclonal antibodies, most of which were secondary to the interaction with the target antigen. However, the major limitation was their immunogenicity. Murine proteins are highly immunogenic, and it was soon found that only a few infusions of these foreign proteins could be given to patients with cancer because of the development of human antimouse antibody. Another problem quickly became apparent, in that some of the antigens on cancer cell surfaces modulated off the surface and into the circulation when antibody attached. Modulation could also cause internalization of the complex. It was recognized that this could represent a therapeutic advantage by using the antibody as carrier to internalize the toxic component of an immunoconjugate, potentially making it more therapeutically active.In 1983, few specific antigens found only in cancer cells had been identified, and there was much debate about the specificity of these antigens. Many of the antigens to which monoclonal antibodies were made were embryonic antigens or shared antigens found on cancer cells and some normal cells. Therefore, although the specificity of the antibody was exquisite for the antigen, the specificity for the antibody or immunoconjugate for cancer was not absolute. One fairly clear exception occurred early in the 1980s when Levy et al developed monoclonal antibodies to the idiotype of B-lymphoma cells. The first patient given this anti-idiotypic antibody had a complete response to therapy, and his lymphoma went into a sustained remission that lasted for years. As a direct result of these early studies with anti-idiotypic antibodies, there is now a series of idiotype vaccines that are in phase III trials in patients with low-grade follicular lymphomas.These anti-idiotype vaccines will likely be the first truly custom-tailored, personalized anticancer vaccines to be approved for therapeutic use.
The major limitation of murine monoclonal antibody therapy was the immunogenicity of the mouse protein; a variety of investigators postulated that for monoclonal antibody therapy to be truly successful, human or humanized antibodies would be necessary. It was also known 25 years ago that the half-life of murine antibodies in the circulation was brief, and because of human antimouse antibody, became briefer with each infusion of murine monoclonal antibody. Previous studies of human immunoglobulin in clinical trials had demonstrated a much longer half-life for human immunoglobulin, which predicted that once human or humanized antibodies were available, the therapeutic efficacy of monoclonal antibodies and their immunoconjugates might be considerably enhanced.
How has the field of monoclonal antibody and immunoconjugate therapy fared since the predictions of the early 1980s? Twenty-five years later, considerable progress has been made in this field. The US Food and Drug Administration has approved 21 monoclonal antibody products, with six of these biologic drugs approved specifically for cancer. It was a landmark date in November 1997 when rituximab became the first monoclonal antibody approved specifically for cancer therapy In addition to these six unconjugated monoclonal antibody therapies, one drug immunoconjugate, gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst, Madison, NJ), has been approved. This humanized monoclonal antibody to CD33 is approved for use in acute myelogenous leukemia and uses the antibody conjugated to calicheamicin, a potent enediyene antibiotic originally isolated from a Micromonospora echoinospora.Two radioisotope-antibody conjugates, ytrrium-90 ibritumomab tiuxetan (Zevalin; Cell Therapeutics Inc, Seattle, WA) and iodine-131 tositumomab (Bexxar; GlaxoSmithKline, Middlesex, United Kingdom) have been approved. The murine form of these antibodies was retained in order to expedite clearance from the circulation. Both radiolabeled antibodies target the CD20 antigen on lymphoma cells.Unlike the immunoconjugates, which are currently infrequently used, each of the six unconjugated antibodies approved for cancer therapy is currently frequently used in the treatment of humans with cancer. The use of techniques to humanize or chimarize monoclonal antibodies to decrease their murine components has been an important advance in the field. These molecules have a long half-life in the blood stream, and can interact with human complement or effector cells of the patient's immune system. They behave in a manner similar to naturally occurring immunoglobulin and work along the lines of our normal antibody-based immune response as effective agents in treating patients with cancer.
Rituximab has become the largest-selling biologic drug in clinical oncology, and is active in a variety of human lymphomas and chronic lymphocytic leukemia.This is a chimeric monoclonal antibody targeting the CD20 antigen found on both normal B cells and on most low-grade and some higher grade B-cell lymphomas. It is effective as a single agent in induction and maintenance therapy. It is primarily used, however, in combination with standard chemotherapies in the treatment of patients with non-Hodgkin's B-cell lymphomas and chronic lymphocytic leukemia.
A second monoclonal antibody that has proven highly effective in the clinic is trastuzumab, a humanized antibody that reacts with the second part of the human epidermal growth factor receptor 2. Like rituximab, it is effective as a single agent in induction and maintenance therapy, but is used primarily in conjunction with chemotherapy for patients with human epidermal growth factor receptor 2/neu–positive breast cancer.
Alemtuzumab is a humanized monoclonal antibody targeting the CD52 antigen found on B lymphocytes and is used primarily for chronic lymphocytic leukemia. Like the two previously cited monoclonal antibody therapies, alemtuzumab is effective as induction and maintenance therapy. Alemtuzumab is also reactive with T lymphocytes, and unlike the other two antibodies, it is typically not combined with chemotherapy because of the increased risk of infection.
Another humanized monoclonal antibody, bevacizumab, has been applied more broadly in human solid tumors because it targets vascular endothelial growth factor, which is the ligand for a receptor found on blood vessels. Because this receptor is on endothelial cells, bevacizumab seems to be effective by reducing the blood supply to tumor nodules, thereby slowing or interrupting growth. Initially approved for advanced colorectal cancer, it is now used in a variety of human solid tumors including cancers of the lung, kidney, and breast.
The last two antibodies approved for clinical use were cetuximab (a chimeric antibody), and panitumumab (a completely human antibody). Both target the epidermal growth factor receptors found on a variety of human tumors. Cetuximab was originally approved for use in combination with chemotherapy in metastatic colorectal cancer. It also enhances chemotherapy and radiation therapy of squamous cell cancers of the head and neck. Panitumumab was approved based on its single-agent activity in refractory colorectal cancer and is being combined with chemotherapy as well.
At the end of 2007, 25 years of clinical studies have resulted in the approval of six unconjugated, humanized, or chimeric monoclonal antibodies for cancer therapy along with one drug immunoconjugate and two radioisotope immunoconjugates. Although few in number, these monoclonal antibodies are changing the face of cancer therapy, bringing us closer to more specific and more effective biologic therapy of cancer as opposed to nonspecific cytotoxic chemicals.
Modern recombinant techniques have made it possible to rapidly produce both chimeric antibodies and humanized antibodies, and totally human antibodies are also being produced. Identification of surface receptors that are integral to proliferation and apoptosis has provided more targets for monoclonal antibodies beyond those originally identified by the murine immune system. In 2008, there are more than 100 monoclonal antibody–based biologic drugs in hundreds of clinical trials. Many of these are in phase II and phase III and will be coming before the US Food and Drug Administration for approval in the next few months and years. At long last, immunoconjugates are proving efficacious with acceptable toxicity and will extend our diagnostic and therapeutic armamentarium from mainly unconjugated monoclonal antibodies to a broad array of highly active and specific immunoconjugates.
On this silver anniversary for our 1983 review, "Monoclonal Antibodies in Cancer Therapy, " we can confidently predict that progress toward more specific and less toxic therapy for human cancer is in our near future. The developments during the past 25 years in both biologic drugs and targeted small molecules place us on the verge of more cures with less toxicity for our patients with cancer.