The healing miracle of double-characteristic antibodies.

Text . . .
, May 28, Science magazine reported on the cancer-fighting story of a lymphoma patient named Amy Boland. Amy Boland battled lymphoma for many years and received CAR-T therapy, but it still recurred, eventually disappearing after receiving bispecific antibody treatment, and has not yet relapsed.. Boland was told 12 years ago that he had a lump under his armpits and was told he had lymphatic cancer. She went through multiple times during her subsequent treatment, and routine chemotherapy helped her shrink the lymphoma tumor, which then returned. A series of treatments, such as bone marrow transplants and immunoosis inhibitors, either failed or only temporarily eased her symptoms. In a recent CAR-T trial, doctors collected her T-cells and designed them in vitro to make them more targeted to kill Boland's cancer cells. After the designed T-cells were fed back into her body, the cancer disappeared, but returned two years later." There seems to be no cure that really works for her," said Stephen Schuster, an oncologist at the University of Pennsylvania.
October 2018, Boland joined a clinical trial to try another way to use her immune system to kill tumor cells. The clinical trial, led by Schuster, focused on the efficacy of a bispecific antibody drug, mosunetuzumab (Roche's CD3 x CD20 double resistance). Mosunetuzumab binds the "natural T cells" to the side of the "molecular rope" structure, binding the lymphoma cells, thus pulling the "natural enemies" together to play a targeted attack effect of immune cells.
just like earlier in the treatment of CAR-T, Boland felt unwell after the initial injection and had to spend several nights in the hospital, but the antibody quickly eased her condition. To this day, more than a year after the drug was discontinued, Boland, 60, seems to be living a normal life away from cancer.
"I feel good, i really appreciate it," Boland said. The clinical trial, involving
Boland, also made headlines in December 2019. At the 2019 Annual Meeting of the American Society of Hematology (ASH), Schuster reported that of 124 patients who had failed other therapies, 46 were non-Hodgkin's lymphoma patients who developed the disease and had reduced tumors after being injected with mosunetuzumab. At the same meeting, data from another small clinical trial showed that bispecific antibodies were equally effective against multiple myeloma in another blood cancer. "Bispecific antibodies against cancer have become super popular," said Janice Reichert, executive director of the
Antibody Association.
scientists have been working on bispecific antibody anticancer drugs for decades, the first clinical success of which was 12 years ago, and this result has been a rapid advance in this field over a period of time, and the lack of CAR-T therapy has been the first to make a splash, in part because of the challenging design and production of bi-antimolecules. However, biotech companies have now been able to make these bi-anti-class macromolecule drugs safer and more effective, and these antibodies are being tested in dozens of clinical trials in the hope that they will compete with or surpass CAR-T therapies. "If bispecific antibodies work like CAR-T cells, it will be a huge step forward and a fundamental change," said Robert Brodsky, a medical hematologist at Johns Hopkins University in
. One of the main advantages of bispecific antibodies is that they can be pre-produced. In contrast, CAR-T therapy requires personalized preparation of CAR-T cells for each cancer patient. The process is costly and takes too long for some seriously ill patients.
However, for some blood cancers, bispecific antibodies do not provide patients with long-term remission similar to those observed in CAR-T therapy. As with CAR-T therapy, some patients die in trials testing bispecific antibodies, possibly because the drug triggered an over-immune response. Bispecific antibodies may not be as effective in treating solid tumors, such as colon and lung cancer, as they are for blood and lymphoma, and CAR-T cells have the same defects.
" there are many well-known problems in the field of antibodies. But it's also a fast-growing area, and a lot of really smart people are working on it. Paul Carter, an antibody researcher at Roche subsidiary Genentech, said.
monoclonal antibodies have a long history as a cancer treatment. When combined with antigens on viruses, bacteria, or other microorganisms, the Y-protein can directly destroy and remove pathogens, or it can signal to the immune system to attack pathogens. The researchers first learned to use this natural system by replicating a specific antibody that can be attached to a specific antigen in tumor cells, suggesting that tumor cells can be killed by non-T-cell components of the immune system. Some of the most effective and best-selling anticancer drugs are monoclonal antibodies, including the breast cancer drug herceptin .toutzumab.
newer anti-cancer strategies use T-cells. For humans, tumor cells can exhibit sufficient exogenousity and sometimes train T cells to attack them. CAR-T cells are a receptor that can target cancer cell antigens for T cells, enabling a more powerful response. Checkpoint inhibitors are a class of drugs that depress T-cell inhibition and also activate T-cells to attack tumor cells.
bispecific antibodies provide a third way to utilize T cells. In the mid-1980s, researchers began designing antibodies with two tips, one binding to tumor cell antigens and the other matching the CD3 protein on the surface of the T cell. The idea is to link T cells directly to tumor cells, skipping the steps that T cells need to learn to attack cancer. In 1985, two reports in the journal Nature said the bispecific antibody could destroy cancer cells in a petri dish and shrink tumors in mice, which undoubtedly inspired research in the field.. But when bispecific antibodies were transferred from cells and experimental animals to cancer patients for testing, that excitement disappeared. In early clinical trials, although an antibody showed the ability to shrink lymphoma, researchers had to stop administering the drug before reaching a final result because the manufacturer of the antibody had run out of drugs. The production of bispecific antibody drugs was difficult at the time, and in order to obtain the ideal bispecific antibodies, scientists had to perform difficult screenings of multiple versions of the molecules they obtained.
bispecific antibodies can sometimes cause serious side effects, including liver damage and an over-immune response, in which white blood cells secrete a large number of toxic cytokine signals. Such cytokines "storms" can cause fever and, in severe cases, organ damage (CAR-T cells can cause the same over-immune response).
two immunologists, Peter Kufer and Gert Riethm?ller, of the University of Munich, have pushed forward the idea that many colleagues seem to fail: a simplified bispecific antibody whose two tips are connected by a flexible peptide rather than a traditional stem. The simplified design makes it easier to make antibodies, but because of the absence of stem, the kidneys remove them from the blood within 2 hours. In the first clinical trial of this antibody, non-Hodgkin's lymphoma patients must wear a pump that continues to inject antibodies. Nevertheless, in a trial led by Micromet, co-sponsored by the German biotech company Riethm?ller and led by Micromet, all seven patients with lymphoma received this small dose of the double anti-drug had all achieved tumor reduction. Patrick Baeuerle, Micromet's chief scientific officer, expressed surprise and called the drug a bispecific T-cell joint(bispecific T cell engager, biTE ®). The small study, published in the journal Science in 2008, attracted strong interest from biotech companies and academia.
"The whole field is aware that this is a big deal and we want to be a part of it." John Desjarlais, chief scientific officer of Xencor, a biotech company, said.
around the same time, CAR-T therapy began to show impressive results in some leukemia patients, raising interest in other simpler immunotherapy, such as bispecific antibodies. Like CAR-T cells, BiTE-stimulated T cells release a toxic molecule called granelase and perforated, which pierces tumor cells and causes them to self-destruct. "I think bispecific antibodies are like 'spot' CAR-T cells," said Elad Sharon, a senior researcher at the Cancer Treatment Assessment Program at the U.S. National Cancer Institute at
.
2009, the first bispecific antibody against cancer was approved in Europe. It was originally used to remove malignant cells in some cancer patients that cause celiac fluid, but it didn't work very well, so the drug was only on the market for a few years. Amgen acquired Micromet in 2012, and the dual anti-drug Blincyto, developed on the latter's BiTE ® platform, doubled the life span of patients with advanced acute lymphoblastic leukemia. Research in the field of double resistance has since regained momentum. Since 2014, the FDA has approved the drug to treat several adult and child diseases. Amway is currently testing BiTE drugs for other cancers, including myeloma, lung, prostate and brain cancers.
others are eager to improve BiTE by using protein engineering technology to make the bispecific antibodies needed. Some companies have restored the stem of the antibody, so that the protein stays in the blood longer, but after modification, it becomes less toxic to the liver. Cancer patients like Boland no longer need to wear a bag filled with a pump, and now they can drip the drug intravenously every three weeks.
the scientists also added a second copy of the tumor antigen binding site to a tip of the antibody (see above). This special design, known as the "2-plus-one" bispecific antibody, is designed to make the antibody more selective to cancer cells and is less likely to target healthy cells carrying small amounts of cancer antigens.
to reduce the risk of causing cytokine storms, the researchers also designed a bispecific antibody that captures an immune cell called natural killer cell (NK) instead of T-cells. Some companies have started or are preparing clinical trials of these antibodies that bind to the NK cell surface protein CD16. "NK cells, if activated, will be very effective tumor cell killers, and the release of cytokines caused by these immune cells will be significantly reduced," said Dmitri Wiederschain, head of cancer immunology at
Sanofi. "。
these new versions of bispecific antibodies are now easier to synthesize. "Antibody engineering has matured so that it is possible to make these molecules quite effective, " says biochemist Christoph Rader.
According to Janice Reichert, executive director of the Antibody Association, more than 60 T-cell-directed bispecific antibodies for cancer are undergoing early or late clinical trials. Ampressreported reported last year that in some patients with advanced prostate cancer, its BiTE showed signs of shrinking the tumor.
for bispecific antibodies, solid tumors are challenging, in part because solid tumors often lack unique antigens to allow antibody capture. Many tumors are also surrounded by blood vessels, tissues, and immune cells, which form a barrier that T cells are not easily penetrating. However, nai-Kong Cheung of memorial Sloan Kettering Cancer Center said the results of the mouse study showed that some bispecific antibodies can carry T-cells into tumors. His lab has systematically adjusted design factors, such as how to arrange binding sites to understand what optimizes the effectiveness of molecules.
, some companies also want to enhance attacks on solid tumors with a bispecific antibody that binds both CD3 and the T-cell surface to another protein called "second signal" protein (CD28). "Because an antibody designed to bind CD28 left six healthy volunteers at risk for cytokine release syndrome in a 2006 UK clinical trial, the industry has been afraid to touch a protein called CD28 for years," said Israel Lowy, senior vice president of Regeneration. "
however, new research suggests that it is possible to use CD28 safely. Last year in the journal Nature Cancer, a Sanofi team reported that a three-specific antibody that matched CD28, CD3 and cancer antigens eliminated myeloma in mice. Other companies have broken down this "task" by manufacturing two bispecific strains: one that targets tumor antigens and CD28 or the other growth signal receptors; "We hope that this costimulating bispecific antibody will help us respond in solid tumors," Lowy said.
The combination of the two drugs can reduce ovarian tumors in mice and slow the growth of prostate tumors, Regenerative Yuan reported in the January issue of Science Translational Medicine.
will the next generation of bispecific antibodies overshadow CAR-T therapy? Carl June of the University of Pennsylvania, a pioneer of CAR-T therapy, is skeptical. He points out that many leukaemia patients who have been treated with blinatumomab will eventually relapse because cancer cells are resistant to the drug, so oncologists use it primarily as a "bridge" until the most seriously ill patient sits on stem cell transplants or CAR-T cells. The bispecific antibodies may not work in cancer patients where many T-cells are removed or depleted, June adds, because there are too few immune cells left to attack cancer cells. In contrast, CAR-T therapy replenishes the immune system by cultured cells in vitro.