Magic bullets they're not, but heat-seeking, warhead-carrying, radar- evading missiles -- maybe.
A human antibody is shown above with binding regions in color. In humanized MAbs, only the binding regions are of mouse origin.
Monoclonal antibodies have not yet lived up to the expectations that surrounded them 15 years ago when they entered clinical trials, but they have gone high-tech. MAb researchers have tacked on elements such as toxins, replaced whole sections of the molecule, and re-engineered the antibodies in other ways as they search for the ideal MAb: one that will seek out the best targets on the surface of cancer cells and then destroy the cells, leaving normal cells unscathed.
Now some of these high-tech MAbs have made their way from laboratory to clinic and, at a 3-day symposium sponsored by the Cancer Research Institute in New York last month, researchers were voicing cautious optimism.
Dr. Oliver W. Press
(Courtesy Cancer Research Institute and UV Studios)
"We've got a tool that will prove to be useful," said Oliver W. Press, M.D., from the University of Washington in Seattle, who reported dramatically high response rates in B-cell lymphoma using radiolabeled MAbs. "We're not there yet, but that doesn't mean we should throw away the implement."
The idea behind monoclonal antibodies is beguilingly simple. Many cancer cells carry antigens or proteins on their membranes that are different from, or at least appear in larger numbers than, the antigens on normal cells. Antibodies, tailored to recognize these cancer-associated antigens, bind to them. Then, carrying out their classic antibody role, MAbs summon other immune system components to destroy the cancer cell.
A hundred years ago, Paul Ehrlich envisioned this magic-bullet scenario, and 20 years ago, when a method emerged for mass-producing antibodies using mouse cells, many researchers -- and reporters -- thought that his vision would soon be realized. But the first generation of MAbs ran into trouble in the clinic, where responses were few and transient. By the late 1980s, many early backers had become skeptical.
In the case of MAbs, such data are now coming primarily from studies in lymphoma and leukemia. The radiolabeled MAb used by Press and his colleagues in Seattle produced complete responses in 85% of patients with relapsed B-cell lymphoma.
Another 10% of the patients in this trial, which employed high doses of the MAb in conjunction with bone marrow transplants, had partial responses. Press said that a larger phase II trial, which will combine the radiolabeled MAb with chemotherapy, is now accruing patients. Another radiolabeled-MAb success story comes from the University of Michigan Medical Center, where Mark Kaminski, M.D., and his colleagues obtained complete remissions in 14 of 28 patients with refractory B-cell lymphoma and partial or complete responses in 22, or 79%, of the 28 patients. The remissions have been durable, Kaminski said, with some patients still free of disease more than 2 years after treatment.
More good news has emerged from Memorial Sloan-Kettering Cancer Center in New York, where David Scheinberg, M.D., Ph.D., and his colleagues have used a radiolabeled MAb, called M195, to treat leukemia in conjunction with chemotherapy prior to bone-marrow transplants. Of the 27 patients in this trial with relapsed or refractory acute or chronic myelogenous leukemia, 26 achieved complete remission.
The addition of a radionuclide is not the only engineering that M195 has undergone. Molecular biologists also have stripped it of most of its mouse components and replaced them with human components. This humanized version of M195, now showing activity in clinical trials for myelogenous and other leukemias, is part of a trend that may be responsible for the growing number of MAb success stories.
In fact, the development of humanized MAbs may be the single biggest step forward for the field in the past 2 decades, according to Jeffrey Schlom, M.D., a longtime researcher with MAbs at the National Cancer Institute. The problem with pure mouse antibodies is that they trigger the production of human antibodies that block the mouse antibodies and prevent them from reaching cancer cells. In clinical trials, this human antibody to mouse antibody, or HAMA, response kicks in several weeks after the initial MAb injection. Thus, repeat doses, after the first few weeks, have much less effect than the first dose.
"[Success after only] one dose is too much to ask of any therapy," said Schlom. MAbs that are chimerized (part human) or humanized (mostly human) minimize the problem and are having success in the clinic, he said. At the New York seminar, Aya Jakobovits, M.D., of Cell Genesys, Foster City, Calif., reported that a fully human antibody is also under development.
Dr. Gert Riethmüller
(Courtesy Cancer Research Institute and UV Studios)
On the other hand, unmodified mouse antibodies are having some success in spite of the HAMA problem. A MAb called 17-1A, for example, reduced mortality in colon cancer patients by 30% compared with no post-operative therapy in a trial led by Gert Riethmü&ller, M.D., from the University of Munich's Institute of Immunology. As a result of this trial, 17-1A was approved for marketing in Germany in December 1994 -- the first therapeutic MAb for cancer to win approval in any country.
No one is sure why the non-humanized 17-1A worked while others have failed, but Harvard Medical School's Robert Mayer, M.D., who is working on plans to test 17-1A, pointed out that several MAb doses can be given over a short time period before the HAMA response kicks in. Moreover, immunosuppressive drugs may also minimize the HAMA response. In the meantime, a humanized version of 17-1A is under development, Riethmller said.
The success of 17-1A highlights another major direction for monoclonal antibodies: their use in minimal residual disease, in which only very small amounts of tumor cells remain after other therapy. "It's a matter of getting to the right target, the early disseminated cells," said Riethmü&ller.
Lloyd Old
(Courtesy Cancer Research Institute and UV Studios)
Others agreed. "Micrometastatic cells may be the most accessible targets," said Lloyd Old, director of the Cancer Research Institute's Scientific Advisory Council. "There are compelling arguments to focus on minimal residual disease."
Meanwhile, more and more sophisticated MAbs continue to emerge from laboratories. Two of the NCI-sponsored cooperative groups are recruiting B-cell lymphoma patients for a randomized trial with a MAb conjugated to a plant toxin called ricin. The conjugate has been engineered to block ricin's ability to bind to normal cells, thus solving at least partially the toxicity problem that plagued ricin in earlier trials. One of the trial's lead investigators, Michael Grossbard, M.D., of Massachusetts General Hospital Cancer Center in Boston, said that early results could be in by 1997.
Dr. Ira Pastan
Immunotoxins have also made it to the clinic at the National Cancer Institute, where the bacterial toxin, Pseudomonas exotoxin, was first joined chemically, and later fused, with a MAb. The chemically conjugated version produced only a few responses in a phase I trial, said NCI's Ira Pastan, M.D. But the fused version, created using genetic engineering techniques, has so far proved 10 times more active than the conjugate and is less toxic. Still in the laboratory at NCI, Pastan said, are immunotoxins targeted at the erbB and interleukin-2 receptors on cancer cells.
Toxins, radionuclides, and human components are only three of the intricacies that MAbs are acquiring on the way to the clinic. Bispecific MAbs -- two joined antibodies -- have also entered trials and at least one antibody has been conjugated to a chemotherapeutic agent. The next generation of MAbs will also include antibodies fused to T cells and antibodies aimed at growth factor receptors on cancer cells, in an effort to interfere with cell division.
Yet veteran MAb researchers, mindful of earlier disappointments, are waiting for a lot more clinical data before they predict success beyond lymphoma and leukemia. "Perhaps," Old said in his opening remarks at last month's seminar, "in vivo veritas should become the motto for our field."
-- Caroline McNeil