Release date: 2017-05-02
Positron-emission tomography (PET) imaging using antibodies can help researchers observe potential cancer locations in mice and other animals.
New technologies help researchers understand the mechanisms of the immune system.
The development of anticancer drugs is very tortuous: at first, the prospects of cell experiments and mouse experiments are very optimistic; however, subsequent monkey experiments are very frustrating: monkeys are targeted at targeting and killing pancreatic cancer cells. The drug was poisoned.
The drug's R&D team member, Simon Williams of Genentech, Calif., said the team tested the collected tissue samples but found no signs that the drug was toxic. When the researchers imaged the living body and tracked the spread of the drug in the animal, they finally found the crux: the antibody-based drug was mainly absorbed by the bone marrow of the animal, which killed the white blood cells of the bone. In view of this, the researchers gave up the drug.
When biopharmaceuticals enter the living, researchers often don't know what will happen next. From early trials to final clinical use, they are not sure how effective the drug is. Sometimes patients respond to drugs; sometimes they don't. Regardless of the outcome, the researchers want to know why. But usually they lack the right research tools.
Imaging scientists and cancer researchers are now trying to solve this problem. They combined traditional PET (Positron-emission tomography) technology with antibodies and similar molecules to create a new technology called immunoPET. Researchers say that as cancer treatment becomes more precise and complex, tools for assessing efficacy also need to be continuously improved. Modern biotherapy is only available for some patients, but doctors cannot reliably predict which part of the patient is suitable for this treatment. A biopsy can only tell you what happened to a part of a tumor, and immunoPET can provide a snapshot of all the tumors in your body.
Traditional PET uses radiotracers to observe human tissue function, while immunoPET uses antibodies to identify target cells. With the proliferation of cancer immunotherapy and the increasing popularity of therapeutic strategies to mobilize the immune system against tumors, there is a growing interest in this emerging imaging technology in the cancer field. But designing an immunoPET imaging probe is not easy. Factors such as radiotracer selection, antibody design, and imaging kinetics require careful consideration. Fortunately, scientists have made some progress. Now they can identify an increasing number of immune cells and cancer tissues and are adapting antibody structures to improve their properties. New treatment and imaging strategies are on the horizon.
Sam Gambhir, director of radiology at Stanford University and a molecular imaging researcher dedicated to early detection and management of cancer, points out that this "immune toolbox" is necessary. Most of the treatment interventions they do are blindly shot, not knowing if the treatment is effective, especially in the early stages. Can people only see if the tumor really shrinks? But if you don't shrink, you don't know what went wrong. This means that people may not know what to do next.
Unlimited PET
In a narrow sense, immunoPET is a tool that uses antibodies or related molecules as imaging agents. Researchers have chosen an antibody or similar molecule to identify cells of interest - such as PD-L1, which helps cancer cells from attack by the immune system, or CD8 that marks killer T cells. When an antibody is injected into an animal, the antibody will spread throughout the body until it reaches the target cell and binds to it.
To "see" these cells, the researchers labeled antibodies with shorter half-life radioisotopes (usually zirconium-89 or iodine-124 with half-lives of 3.27 and 4.18 days, respectively). These PET tags emit positrons - the antimatter of electrons. When a positron collides with an electron in the body, a pair of gamma ray particles are generated, which are separated from each other at a high speed. As long as the pair of particles are detected at the same time, the position and abundance of the target in the body can be displayed. Researchers can overlay these data into computed-tomography (CT) or magnetic resonance imaging scans (MRI scans) images to determine the anatomical location of the antibody tag.
Biologists and clinicians are using immunoPET to explain why some patients respond to treatment, while others are unable to respond.
For example, a few years ago, medical oncologist Elisabeth de Vries of the University Medical Center Groningen in the Netherlands performed immunoPET imaging on 56 patients with advanced breast cancer. This group of patients received treatment with trastuzumab emtansine (Kadcyla). Kadcyla is a conjugating drug which is composed of an anti-cancer antibody trastuzumab which binds to the tumor protein HER2 and a chemotherapeutic drug targeting a target cell. Using radiolabeling, the team found that 29% of patients had tumors that did not absorb antibodies in large amounts. This means that patients are less likely to benefit from treatment; in fact, the median survival of this group of patients was 2.8 months, and the final trial ended in failure. The median survival of patients who received more antibodies to the tumor was 15 months. De Vries et al. and three Dutch research institutes are conducting a trial to test whether this pre-imaging can improve the treatment of 200 newly diagnosed women with metastatic breast cancer. The trial is expected to complete volunteer recruitment later this year.
In another study, de Vries et al. demonstrated that antibodies can reach gliomas when cancer has impaired the blood-brain barrier. This suggests that, contrary to conventional wisdom, antibody-based therapies may be effective against gliomas. De Vries pointed out that traditional theory holds that antibody molecules are so large that they cannot cross the blood-brain barrier, but this is not the case.
Many cancers develop rapidly, and when they spread or metastasize to other parts of the body, they may be different from the original tumor. Therefore, it is not enough to perform biopsy on only one metastatic tumor. The ability of ImmunoPET to scan the whole body also helps to solve this problem. Jason Lewis, director of the Center for Molecular Imaging and Nanotechnology at Memorial Sloan Kettering Cancer Center in New York City, said that cancer patients often have more than one metastases, and there may be more than one, but you It is not possible to conduct a biopsy of these transfers. But now with immunoPET, researchers and doctors can image these metastases. In a radioPET study conducted in 2016, Lewis et al. identified two women with HER2-positive metastases whose primary tumors were HER2-negative; the two patients responded to trastuzumab treatment.
Auxiliary immunotherapy
Antoni Ribas, a medical oncologist and melanoma researcher at the University of California, Los Angeles, points out that immunotherapy being developed may also benefit from immunoPET. For example, in immunological checkpoint inhibition therapy, a receptor on the surface of a tumor cell interacts with a receptor on the surface of a T cell, thereby suppressing the immune function of the T cell. The immunological checkpoint inhibitor binds to one of the two receptors and inhibits its activity, thereby activating T cells surrounding the tumor to perform tumor killing function.
However, Ribas said that a basic hypothesis of this killing mechanism is the recognition of killer T cells located near the tumor by the cell surface protein CD8. but it is not the truth. With immunoPET, you can determine if the immune system can be activated. If no CD8 cells are present at the tumor, then a checkpoint inhibitor cannot activate the T cells. Such patients will need other treatment options.
Images of PET and CT superimposed at different time points after injection of PET tracer in mice. BLK: blank control group; NBLK: experimental group.
Ribas pointed out that immunological checkpoint treatment may cause annoying side effects when immune cells are over-activated and other tissues are damaged. For example, intestinal inflammation is a common side effect of the melanoma checkpoint inhibitor drug ipilumumab (Yervoy). He speculates that perhaps immunoPET allows clinicians to observe the side effects of these side effects as early as possible.
Clinical issues such as this have led Ribas to collaborate with Anna Wu, the imaging scientist at the University of California, Los Angeles, the co-founder of California imaging company Imagiin, who is currently working on improving antibodies and optimizing immunoPET. In 2015, Wu's team and Ribas et al. used immunoPET to track killer T cells in mice in three immunotherapy experiments. Radiolabeled probes - Antibody fragments that target the CD8 receptor show that T cells accumulate in the tumor and alter the distribution of the tumor in other parts of the body.
Wu pointed out that ImmunoPET can even reveal the effectiveness of treatment in the early stages of treatment before the tumor begins to shrink. In fact, after the initial treatment, the tumor may not shrink, but it will become larger - when immune cells infiltrate the tumor and cause swelling of the tissue, researchers and clinicians sometimes mistake the treatment for treatment. ImmunoPET can reveal differences between cell types and show therapeutic efficacy before tumor cells begin to die significantly.
Williams said that in drug development laboratories, immunoPET can help researchers decide if they should continue to develop an antibody. In preclinical work, immunoPET confirmed the potential of an antibody called STEAP1. The antibody targets metastatic prostate cancer cells whose linked drugs kill cancer cells. In an early (unpublished) clinical trial, imaging showed that antibody components could even reach metastases, such as bone, in tissues that were once considered inaccessible. A frequently discussed question in the field of immunotherapy is: Can antibodies be transported to bone metastases? The imaging results gave us a positive answer.
Williams' immunoPET helps to study the case of the major toxic side effects of antibody-drug conjugates mentioned at the beginning of this article on non-human primates to find out why the drug is so deadly.
Fast delivery
The researchers pointed out that monoclonal antibodies produce very beautiful images of immunoPET. However, the entire process of delivering the antibody to the tissue of the target and excluding the monoclonal antibody that is not bound to the target cell, resulting in a good contrast and specificity, may take a week.
In some cases, this time scale is acceptable. For example, in drug development, researchers need to decide whether to continue developing drug candidates, and generally do not have time to wait for new, faster imaging agents to come out. Williams pointed out that management must decide: Do we want to continue the clinical phase 3 trial? If imaging can't be done in a limited time, it makes no sense.
Antibodies can specifically bind to cellular targets and visualize them in PET
But in terms of clinical aspects, time is the primary consideration for imaging testing. Sidhar Nimmagadda, a molecular imaging scientist at Johns Hopkins University, said that general PET is used in patients with advanced cancer, and these patients often have metastases. For such a serious patient, clinical decision-making needs to be made as soon as possible, and the week is still too long.
Therefore, researchers are also working to develop molecules with better precision than antibodies, but with smaller molecular weight and better pharmacokinetics. For example, Wu's lab has designed elongated antibody variants called "minibodies" and "diabodies." These antibodies retain portions of the traditional mAb that interact with the antigen (referred to as variable domains), but remove portions that come into contact with other parts of the immune system, such as cells that scavenge bacteria and debris. These antibodies retain only the ability to bind to the target molecule. Wu pointed out that patients can be imaged within one day after injection of this antibody.
Wu also said that these protein variants have other useful properties. For example, whether they can be excreted through the liver or kidneys depends on their size. In order to improve contrast and obtain a clear image of pelvic tumors, clinicians will select antibodies that are cleared by the liver; for pancreatic cancer, antibodies that are cleared by the kidneys are more appropriate. Wu can also alter these engineered antibody fragments to be as close as possible to human endogenous proteins, reduce the resulting immune rejection (because they are not natural human proteins), or make radioisotope markers in a uniform manner Attachment to proteins helps to ensure consistent and reliable antibody viability. Wu pointed out that this is the task of protein engineers. As long as you want to produce recombinant protein, you can optimize all the properties of the protein.
Other laboratories, such as the laboratory of molecular biologist Hidde Ploegh at Boston Children's Hospital, used the antibodies to llamas, alpacas and camels to obtain a faster pharmacokinetic imaging agent for PET. The antibodies produced by these camel species contain only one type of strand, and unlike conventional antibodies, they consist of two chains and weigh only one-tenth the weight of conventional antibodies. But they are also easier to remove than conventional antibodies and have a deeper depth of penetration in the tissue.
Radiologist and molecular imaging scientist Martin Pomper pointed out that any method that allows patients to image within hours and then leave the hospital is worth encouraging. Pomper is the director of the Department of Nuclear Medicine and Molecular Imaging at Johns Hopkins University, where Nimmagadda works.
But Pomper and Nimmagadda believe that the best clinical approach is not about antibodies or antibody variants, but smaller peptides and other low molecular weight molecules. The team developed a radiolabeled peptide that binds to PD-L1 and can be imaged within two hours. The team is currently developing smaller imaging agents.
Label two-step method
Another strategy to maintain antibody accuracy is to take a two-step approach. The researchers injected antibodies into the patient and waited for a week to wait for antibodies that did not bind to the target to be excreted. A second, smaller labeled probe is then injected which rapidly binds to the first injected antibody. The half-life of the radioisotope used in this method is shorter, for example, fluorine-18 or copper-64 having a half-life of less than 2 hours and 12.7 hours, respectively, can be used.
This method depends on the production of "bispecific" antibodies. This antibody has two binding sites - one site that binds to a protein target (such as PD-L1) and the other site to a radiolabeled probe.
Steven Larson, director of the Molecular Pharmacology Program at the Memorial Sloan-Kettering Cancer Center, points out that, like immunoPET, the two-step strategy is not new. However, advances in imaging and antibody engineering have made the two-step strategy an exciting product. Larson believes that this approach can inject new life into the old treatment strategy of radioimmunotherapy (using antibody-specific, targeted delivery of radiotoxic drugs to tumors). According to Larson, modern imaging allows physicians to accurately calibrate doses to avoid damage to normal tissue.
He also added that if the parenchyma is not found early, then the patient is difficult to completely heal. They want to cure cancer in this way and think it is very feasible.
According to Gambhir, researchers who develop and test cancer therapies often don't realize that imaging technology is a very useful tool. But they are learning. A paper published in January showed that in immunotherapy trials, engineered T cells can be tracked by PET imaging agents after reaching gliomas. After the article was published, he received a lot of advice from the industry. The pharmaceutical company's phone, Gambhir, has received a soft hand. As soon as the drug company saw the test results on the human body, it was excited.
Source: Mystery of Life
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