Signs Of Progress Stimulate Monoclonal Antibody Research

"I'm not at all surprised at the time it's taken for monoclonal antibodies to move forward," says Patrick Scannon, president of Xoma Corp., a San Francisco-based biotechnology company that specializes in monoclonal antibody--or MAb--therapeutics. "I was always incredulous about the so-called magic bullet claims." The bold claims to which Scannon refers began springing up in 1975, the same year that the monoclonal antibody was first developed. Essentially bioengineered forms of antibodies--the natural proteins in animals and humans made by immune cells to fight against infection--MAbs were hailed by immunologists and biotech entrepreneurs as a great new component in the medical armamentarium because of their ability to find specific pathological targets in the body. MAbs could act therapeutically, said experts at the time, when linked to toxins to form immunotoxins--antibodies chemically joined to poisons--that would then search out and destroy disease-causing cells in the body. MAbs themselves, without toxins, could also bind to certain disease-causing cells in the body and prevent their pathology; or, it was pointed out, MAbs could soak up poisons from bacterial infections that may be present in a patient. What's more, it was argued, the precision with which MAbs could be targeted allowed them to act with few side effects in combating a wide range of diseases, including disorders affecting internal organ systems and those caused by infectious agents. During the past decade and a half, however, the task of fulfilling the promise of MAbs turned out to be far more difficult than many people imagined back in 1975. Progress in MAb-related product development has been impeded not only by technical complications and time-consuming clinical trials, but also by the obstacles along the path toward regulatory approval of this novel biotechnical agent. Indeed, while hundreds of researchers in universities, medical centers, and biotech companies have been working steadily on MAbs as therapeutics for diseases as diverse as arthritis and cancer, to date only one MAb has been fully approved by the Food and Drug Administration (FDA) as a drug and only two have received preliminary approval. But now the picture is changing for the better, scientists and entrepreneurs agree. A recent spate of regulatory approvals, combined with scientific advances allowing the creation of more effective immunotoxins, could yield an environment in which the "magic bullet" would, at last, be headed toward its target. The Regulatory Pathway While FDA has developed procedures to deal with therapeutic MAbs, the clinical trial period, testing the efficacy, dosage, and safety of a new drug, and the FDA review period afterward, are still time-consuming processes. Preclinical testing in the laboratory and with animals to assess the safety and biological activity of a drug take around 3 1/2 years. Phase I studies, that usually involve 20 to 80 healthy volunteers to determine safety and dosage of a drug, take around one year. Phase II studies, involving 100 to 300 patient volunteers to evaluate a drug's effectiveness and side effects, can take two years. Phase III studies on 1,000 to 3,000 patients, verifying the effectiveness and monitoring the adverse reactions from long-term use, take three years. After the clinical trials, the FDA review process, which involves analysis of over 100,000 pages of scientific documentation about the drug, can take about 2 1/2 years. With novel agents, like biotechnology products, the review process can take longer. All told, the approval time for a new drug takes, on average, 12 years. That some monoclonal antibodies have been cleared by FDA for therapeutic use helps smooth the path for future products, say industry watchers. The first fully approved MAb drug is Orthoclone OKT3, manufactured by Ortho Pharmaceutical Corp. of Raritan, N.J. This drug, approved in 1986, treats kidney transplant rejection by blocking T cells from attacking donor kidney cells. Full approval for another MAb drug, Centoxin, is expected by next year, according to it's maker, Centocor Inc., a Malvern, Pa.-based biotechnology company. Already given preliminary FDA approval, Centoxin treats bacterial sepsis, an often-fatal complication of surgery patients and burn victims (see accompanying story). The path to getting a recent preliminary FDA approval for Xoma's immunotoxin Orthozyme CD5+, however, was rocky, says Scannon. "Educating the FDA about the new technology and giving them enough time to gather more experience with these drugs," was very time consuming, he says. Orthozyme CD5+ is an immunotoxin (IT) made of a mouse monoclonal antibody linked to a toxin, to be used in treating graft versus host disease (GvHD) in bone marrow transplant patients. Transplanted bone marrow often rejects its new host by sending T cells to attack the host's tissues, commonly damaging the liver, gastrointestinal tract, and skin. Approximately half of all patients who develop GvHD die as a result. Xoma's CD5+ zeros in on what is called the CD5 protein found on 95 percent of the attacking T cells, and destroys the cells without hurting other tissues, according to Xoma scientists. If fully approved by FDA, which seems highly likely to Scannon, after the committee's approbation, this drug will be the first immunotoxin to be approved for treatment of any disease. Upon FDA approval of the new drug, Ortho Biotech, a subsidiary of Johnson and Johnson is licensed to market the product. Xoma is also conducting clinical trials, testing CD5+ on such autoimmune diseases as rheumatoid arthritis, in which T cells attack the synovial tissue around joints, and Type I diabetes, in which T cells destroy the islet cells of the pancreas, preventing insulin production. Immunotoxin Challenges Besides the regulatory path being less bumpy, second-generation ITs are beginning to overcome the problems that researchers had with first-generation ITs. Initial experiments and trials with early immunotoxins proved disappointing, requiring scientists to go back to the bench after being at the bedside. These troublesome first-generation ITs were generally made of the toxic A chain of ricin, a poison produced by the castor bean, linked through a disulfide bond to the MAb targeted for a specific disease-implicated cell. Clinical studies showed, however, that the link between the MAb and the toxin was easily broken. And the ricin A chain tended to bind to liver cells, preventing the IT from circulating in the blood to reach target sites. Certain solid tumors, such as melanoma, breast, and colon cancers were not readily accessible to the circulating IT. Also, ITs, often made of mouse MAbs, triggered an immune response in the patient, rendering the drug inactive after one dose. Ellen Vitetta, director of the Cancer Immunobiology Center at the University of Texas Southwestern Medical Center in Dallas, and colleagues are a few of the researchers solving the problems of the first-generation ITs. They have focused their attention on trials in patients with malignant B-cell lymphoma. This disease is ideal for IT research because, among other reasons, B-cell lymphoma cells travel in the bloodstream and are very accessible to circulating ITs. In addition, patients with this disease are so immunosuppressed, they are unlikely to mount an antibody response to the mouse-derived IT. What Vitetta has done is make a strong sulfide bond linkage between the antibody and the toxin that is not easily cleaved by enzymes in the blood. And the carbohydrates on the ricin A chain that normally would bind to liver cells were chemically removed, significantly improving the drug's antitumor activity. The results of a Phase I trial, published earlier this year in Cancer Research (51:4052-58, 1991), showed that 40 percent of patients had partial remissions that reduced their number of tumor cells by 50 percent or more. But the patients suffered from side effects that Vitetta believes is due to dosage. Variations of the ricin/monoclonal antibody fusion are also being tested. Ira Pastan, chief of the laboratory of molecular biology at the National Cancer Institute in Bethesda, Md., has created an IT that uses a toxic protein from the bacteria Pseudomonas as the poisonous portion of the IT. According to Vitetta, third-generation strategies aim to make better, more specific, and less expensive ITs. New solutions, however, create new problems. She says: "There seems to be a return from the clinic to the lab to work out some basic problems, such as determining better dosage regimens using mixtures of ITs or understanding [their] side effects."

Signs Of Progress Stimulate Monoclonal Antibody Research

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