First Antibody Treatment For COVID-19

Scientists in the UK have just recruited the first participants in the world to be part of a new long-acting antibody study. If the treatment is effective, it could give those who have already been exposed to SARS-CoV-2 protection from developing COVID-19.

We know that this antibody combination can neutralise the virus,explains University College London Hospitals (UCLH) virologist Catherine Houlihan. So we hope to find that giving this treatment via injection can lead to immediate protection against the development of COVID-19 in people who have been exposed – when it would be too late to offer a vaccine.”

This might not be the first antibody treatment for COVID-19 you’ve heard of. Outgoing US President Donald Trump was given monoclonal antibodies when he came down with the disease, and in the US two different antibody treatmentscasirivimab and imdevimab – received emergency approval back in November. But those antibody treatments are given to patients with mild or moderate COVID-19, who risk progressing to a severe version of the disease.

In a clinical trial of patients with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalisation or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo,the FDA explained in a press statement when the drugs were approved. This new antibody therapy, called AZD7442 and developed by UCLH and AstraZeneca, is a little different. AZD7442 is a combination of two monoclonal antibodies AZD8895 and AZD1061, which both target the receptor binding domain of the SARS-CoV-2 spike protein.

By targeting this region of the virus’s spike protein, antibodies can block the virus’s attachment to human cells, and, therefore, is expected to block infection,” the team wrote on the US ClinicalTrials.gov website.  “Amino acid substitutions have been introduced into the antibodies to both extend their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc effector functionin order to decrease the potential risk of antibody-dependent enhancement of disease.”

Antibodies are little Y-shaped proteins that lock on to a particular section – called an antigen – of a virus, bacterium or other pathogen, and either ‘tag‘ it to be attacked by the immune system, or directly block the pathogen from invading our cells. Normal antibodies are produced by your body after an infection, while monoclonal antibodies are cloned in a lab and can be injected into a person already infected, to give the immune system a hand in the fight.

The researchers are hoping that AZD7442 – which is just starting the Storm Chaser study (the name for its phase 3 trial) – provides protection for those that have been exposed to the virus but do not yet have symptoms. Effectively, they’re trying to stop COVID-19 happening in the first place. “If you are dealing with outbreaks in settings such as care homes, or if you have got patients who are particularly at risk of getting severe COVID, such as the elderly, then this could well save a lot of lives,” said University of East Anglia infectious disease expert Paul Hunter.

Source: https://www.sciencealert.com/

How To Direct Nanoparticles Straight To Tumors

Modern anticancer therapies aim to attack tumor cells while sparing healthy tissue. An interdisciplinary team of researchers at Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and FU Berlin has made important progress in this area: the scientists have produced tiny nanoparticles that are designed to specifically target cancer cells. They can navigate directly to the tumor cells and visualize those using advanced imaging techniques. Both in petri dishes and animal models, the scientists were able to effectively guide the nanoparticles to the cancer cells. The next step is to combine the new technique with therapeutic approaches.The HZDR researchers start out with tiny, biocompatible nanoparticles made of so-called dendritic polyglycerols that serve as carrier molecules.

Radiologic technician and Patient being scanned and diagnosed on CT (computed tomography) scanner in hospital

An interdisciplinary team has modified biocompatible nanoparticles with an antibody fragment, which binds specifically to a protein overexpressed by certain types of cancer cells. By combining the tiny particles with a diagnostic radionuclide, it is, thus, possible to detect and characterize tumor cells via PET.

We can modify these particles and introduce various functions,” explains Dr. Kristof Zarschler, research associate at HZDR’s Institute of Radiopharmaceutical Cancer Research. “For example, we can attach an antibody fragment to the particle that specifically binds to cancer cells. This antibody fragment is our targeting moiety that directs the nanoparticle to the tumor.”

The target of the modified nanoparticles is an antigen known as EGFR (epidermal growth factor receptor). In certain types of cancer, such as breast cancer or head and neck tumors, this protein is overexpressed on the surface of the cells. “We were able to show that our designed nanoparticles preferentially interact with the cancer cells via these receptors,” confirms Dr. Holger Stephan, leader of the Nanoscalic Systems Group at HZDR. “In control tests with similar nanoparticles that had been modified with an unspecific antibody, significantly fewer nanoparticles accumulated at the tumor cells.

The scientists intensively studied the nanoparticles’ behavior both in cell cultures and in an animal model. For this purpose, they provided the nanoparticles with additional reporter characteristics, as Kristof Zarschler explains: “We used two complementary possibilities. In addition to the antibodies, we attached dye molecules and radionuclides to the nanoparticles. The dye molecule emits in the near infrared spectrum that penetrates the tissue and can be visualized with an appropriate microscope. The dye thus reveals where exactly the nanoparticles are located.” The radionuclide, copper-64, fulfils a similar purpose. It emits radiation that is detected by a PET scanner (positron emission tomography). The signals can then be converted into a three-dimensional image that visualizes the distribution of the nanoparticles in the organism.

Using these imaging techniques, researchers have been able to show that nanoparticle accumulation in the tumor tissue reaches maximum two days after administration to mice. The labelled nanoparticles are subsequently eliminated via the kidneys without being a burden for the body. “They are apparently ideal in size and properties,” says Holger Stephan. “Smaller particles are filtered out of the blood in just a few hours and thus only have a short-term impact. If, on the other hand, the particles are too big, they accumulate in the spleen, liver or lungs and cannot be removed from the body via the kidneys and bladder.” The interplay between the nanoparticles with an exact size of three nanometers and the attached antibody fragments evidently has a positive influence on the distribution and retention of the antibody in the organism as well as on its excretion profile.

Source: https://www.hzdr.de/

Blood Vessels Can Contribute To Tumor Suppression

A study from the Institute of Pharmacology and Structural Biology in Toulouse (France) has introduced a novel concept in cancer biology : Blood vessels in human tumors are not all the same and some types of blood vessels found in the tumor microenvironment (i. e. HEVs) can contribute to tumor suppression rather than tumor growth(Cancer Res 2011).

 A better understanding of HEVs at the molecular level, which is one of the major objectives of the research team, may have an important impact for cancer therapy.

Dendritic cells, which are well known for their role as antigen-presenting cells, play an unexpected and important role in the maintenance of HEV blood vessels in lymph nodes (Nature 2011). In addition, the scientists discovered the frequent presence of HEVs in human solid tumors, and their association with cytotoxic lymphocyte infiltration and favourable clinical outcome in breast cancer. They also showed that IL-33 is a chromatin-associated cytokine (PNAS 2007, 453 citations) that function as an alarm signal (alarmin) released upon cellular damage (PNAS 2009, 312 citations). Inflammatory proteases can generate truncated forms of IL-33 that are 30-fold more potent than the full length protein for activation of group 2 innate lymphoid cells (PNAS 2012, 133 citations, PNAS 2014).

An important objective  is now to further characterize IL-33 regulation and mechanisms of action in vivo, through the use of multidisciplinary approaches.

Source: http://www.ipbs.fr/