• Deploying Antibodies to Deliver Targeted Radiation Energy

    Alpha Emitters

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    亿豪彩票网Identifying the enemy: Body cells track down malignant cells by their telltale surface structures, known as antigens. Y-shaped recognition molecules (antibodies) bind to them.

Although much progress has been made in recent years, there still remain significant challenges to effectively treating many types of cancer. Bayer researchers are working on the development of targeted radiation therapies using biomolecules which specifically deliver alpha radiation to the tumor cells.

Story check

  • Challenge:
    Radiation therapy is one of the most important methods for treating cancer. However, alpha radiation damages healthy body cells as well as the diseased ones.
  • Solution:
    Bayer researchers combine different antibodies depending on the type of tumor being treated with radioactive thorium 227. The thorium conjugate acts as a molecular vehicle that transports the radiation directly to the site of action.
  • Benefits:
    The thorium conjugate exerts a targeted effect on the tumor, leaving healthy cells largely unharmed.

亿豪彩票网Radiation therapy is one of the most powerful weapons against tumors and is part of the treatment for one in two cancer patients. The ionizing radiation used in this form of therapy kills cancer cells by damaging the cellular genetic material and disrupting cell division, two effects which ultimately lead to cell death. As a result, tumors may shrink or even disappear completely. The radiation’s damaging effects however are not just limited to the tumor cells. On its way to the tumor the radiation beam passes through normal tissue and may therefore impact healthy body cells.

亿豪彩票网So why not deliver radiation directly to the tumor? This could potentially minimize damage to healthy cells and make the therapy even more effective. This is the approach that researchers at Bayer are pursuing with the development of targeted thorium conjugates (TTCs). TTCs represent a new class of targeted alpha therapy. These alpha emitters, as they are termed, are radioactive elements that emit very energy-rich radiation in the form of alpha particles over a short distance.

Using targeted alpha emitters to destroy cancer cells
The first major breakthrough with alpha emitters for Bayer was the development of a drug based on radium-223, which is effective against bone metastases. Building on the success of this ‘bone-seeking’ agent used in the treatment of prostate cancer, a Bayer team led by Alan Cuthbertson, head of Thorium Research at Bayer Pharmaceuticals in Oslo, is aiming to further expand the pipeline of targeted alpha therapies by utilizing the radionuclide thorium-227, a product of the same production process as radium-223.

亿豪彩票网Cuthbertson’s team firstly select tumor specific antigens – protein structures found in large numbers on the surface of tumor cells but not on normal tissue. Secondly, antibodies that recognize and bind precisely to these antigens are identified. (Antibodies are a key component of the human immune system which normally dock onto disease pathogens and mark them as invaders ready for destruction.) These antibodies are used as carriers for the alpha-emitting radionuclides.

The research team then prepares antibody conjugates by coupling them using a molecule called a ‘chelator’ which holds on to the thorium radionuclide. Together they form an extremely stable antibody chelate complex. The thorium227-loaded antibody, once administered, then delivers the radioisotope directly to its site of action in the tumor.

After arriving at the malignant tissue, the radioactive element decays, releasing its tumor-destroying radiation without causing significant damage to the adjoining healthy tissue.

Dr. Alan Cuthbertson

Targeted cancer treatments: Dr. Alan Cuthbertson and his team in Oslo are working on high-precision cancer drugs that destroy tumor cells with radioactive alpha emitters.

A mechanism that can be applied to different tumors
The thorium-227 chelator complex is the secret of success of the TTC platform. By ‘fixing’ the chelator and thorium227 labeling processes and varying the antibody, scientists can adapt the technology to target a wide range of cancer types. That makes this modality extremely versatile. In addition, a major advantage of thorium conjugates is that the antibodies circulate via the blood flow, searching for their antigen at the site of the tumor in the body. “They may even attack tumors that are too small to be picked up by imaging techniques, such as very-early-stage metastases,” explains Cuthbertson. Furthermore, due to the destructive power of the alpha particle, TTCs have the potential to eradicate tumors which have become resistant to standard treatments.

亿豪彩票网Another crucial advantage of radiation therapy with antibodies compared with chemotherapy is that radiation also kills dormant cells. By contrast, many of the agents used in chemotherapy are only effective against dividing cells, which means that dormant cells avoid attack and can later regrow and cause a relapse. Furthermore, the effect of this radiation therapy is localized; it only penetrates about two to ten cell layers, while drug chemotherapy works throughout the body.

Thorium conjugates in clinical testing in four indications
亿豪彩票网TTCs are a cornerstone of oncology research at Bayer. A total of four TTC projects are currently being investigated in preclinical studies or Phase I clinical trials. In each of these projects, the researchers are investigating the treatment of a specific tumor type with the corresponding antibody chelate complex.

The frontrunner project targets an antigen with the abbreviation CD22 (cluster of differentiation-22). This protein molecule is found on the surface of certain lymph node cancer cells. “The CD22-TTC is our most advanced candidate,” explains Cuthbertson. “It targets non-Hodgkin lymphoma.” His team has been exploring this substance for a number of years now (see research 29). The first trials involving patients began in 2015. “The active substance is currently still in the dose escalation phase.” This is where researchers successively increase the administered dose of an investigational agent to test how much of the substance can be tolerated by patients without excessive side effects.

The PSMA-TTC (prostate-specific membrane antigen-targeted thorium conjugate) builds on radium research in prostate cancer at Bayer. The antigen PSMA is expressed by prostate cancer cells in all stages of the disease and by metastases. This new TTC program delivers alpha emitters directly to the tumor cell enabling treatment of primary, visceral tumors as well as bone metastases.

Body cells that have turned malignant begin to divide uncontrollably. The changes that are taking place inside the cell are reflected on the exterior as well, by specific surface markers that can be used as a target for new drug products.

Different types of radiation

Radioactivity refers to the ability of certain atomic nuclei (so-called radionuclides) to transform into other nuclei without outside intervention. This process is known as nuclear decay. Energy-rich, ionizing radiation – alpha, beta, gamma or neutron radiation – is released during this process:

Alpha radiation is a type of particle radiation consisting of double positively charged helium nuclei. When atomic nuclei undergo radioactive decay, they emit alpha particles at a speed of about 15,000 kilometers per second. The rays can only travel a few centimeters in air and the energy can be absorbed by a sheet of paper (i.e. they cannot penetrate through a sheet of paper or human skin).

Beta radiation is a type of particle radiation involving electrons or their antiparticles (positrons). The particles emerge from disintegrating atomic nuclei at nearly light speed and can travel several meters in air or penetrate a few millimeters into plastic, aluminum or human tissue.

Gamma radiation is a type of energy-rich electromgnetic radiation of short wavelengths. The shorter the wavelength (and thus the higher the frequency), the more energy-rich the radiation. These rays move at light speed and can only be effectively weakened by centimeter-thick lead walls or thick concrete walls. Unlike alpha and beta radiation, the composition of the atomic nucleus does not change in gamma radiation.

亿豪彩票网A third TTC currently in Phase I clinical testing is MSLN-TTC (mesothelin-targeted thorium conjugate). In animal studies it was shown to be effective against several tumor types as a monotherapy. It may also be used in combination with active substances that inhibit the repair of DNA damage in cancer cells. This antigen has low expression in normal tissue and is overexpressed in mesothelioma (connective tissue tumors found above all in the pericardium, pleura and peritoneum) and in ovarian, lung, pancreatic and certain breast cancer tumors. This makes the molecule a suitable target for the antibody-chelate complex.

Currently in the preclinical phase, the HER2-TTC (human epidermal growth factor receptor 2 targeted thorium conjugate) is effective against tumors that are resistant to other medications targeting this receptor. HER2 is overexpressed in various cancer types and is one of the most studied targets for the treatment of breast and stomach cancer. The advantage: the rudimentary nature of the high-energy alpha-particle induces complex DNA damage in HER2-positive tumor cells which have become resistant to other drugs.

Cuthbertson and his team are hopeful that the new TTC technology will translate the observed preclinical efficacy into the clinic and thus will shape the future of systemic radiotherapy. Cuthbertson is confident. “I see great potential in the targeted thorium conjugate platform, particularly for the treatment of refractory tumors that fail to respond to standard therapies.”

While TTCs may not represent a panacea, they do offer hope for many patients suffering from difficult to treat forms of cancer.

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