Tag: monoclonal antibodies

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New Human Monoclonal Antibodies could Fight Influenza B

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Creative artwork featuring colourised 3D prints of influenza virus (surface glycoprotein hemagglutinin is blue and neuraminidase is orange; the viral membrane is a darker orange). Note: Not to scale. Credit: NIAID

Researchers at Vanderbilt University Medical Center have isolated human monoclonal antibodies against influenza B, a significant public health threat that disproportionately affects children, the elderly and other immunocompromised individuals, as they report in the journal Immunity.

Seasonal flu vaccines cover influenza B and the more common influenza A but do not stimulate the broadest possible range of immune responses against both viruses.

In addition, people whose immune systems have been weakened by age or illness may not respond effectively to the flu shot.

Small-molecule drugs that block neuraminidase, a major surface glycoprotein of the influenza virus, can help treat early infection, but they provide limited benefit when the infection is more severe, and they are generally less effective in treating influenza B infections. Thus, another way to combat this virus is needed.

The VUMC researchers describe how, from the bone marrow of an individual previously vaccinated against influenza, they isolated two groups of monoclonal antibodies that bound to distinct parts of the neuraminidase glycoprotein on the surface of influenza B.

One of the antibodies, FluB-400, broadly inhibited virus replication in laboratory cultures of human respiratory epithelial cells. It also protected against influenza B in animal models when given by injection or through the nostrils.

Intranasal antibody administration may be more effective and have fewer systemic side effects than more typical routes – intravenous infusion or intramuscular injection – partly because intranasal antibodies may “trap” the virus in the nasal mucus, thereby preventing infection of the underlying epithelial surface, the researchers suggested.

These findings support the development of FluB-400 for the prevention and treatment of influenza B and will help guide efforts to develop a universal influenza vaccine, they said.

“Antibodies increasingly have become an interesting medical tool to prevent or treat viral infections,” said the paper’s corresponding author, James Crowe Jr, MD. “We set out to find antibodies for the type B influenza virus, which continues to be a medical problem, and we were happy to find such especially powerful molecules in our search.”

Source: Vanderbilt University Medical Center

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Biologics Alone may be Able to Control Severe Asthma

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A European study showed that 92% of patients using the biologic therapy benralizumab could safely reduce inhaled steroid dose and more than 60% could cease entirely. The results, published in The Lancet, could be transformative for severe asthma patients by minimising or eliminating the unpleasant, and often serious, side effects of inhaled steroids.

These include osteoporosis which leads to increased risk of fractures, diabetes and cataracts.

Around 3 to 5% of the 300 million people with asthma worldwide have severe asthma. This leads to daily symptoms of breathlessness, chest tightness and cough, along with repeated asthma attacks which require frequent hospitalisation.

The SHAMAL study was led by Professor David Jackson, head of the Severe Asthma Centre at Guy’s and St Thomas’ and Professor of Respiratory Medicine at King’s College London.

Professor Jackson said: “Biological therapies such as benralizumab have revolutionised severe asthma care in many ways, and the results of this study show for the first time that steroid related harm can be avoided for the majority of patients using this therapy.”

The monoclonal antibody benralizumab targets interleukin-5, reducing eosinophil count, which is elevated in the airway of patients with severe asthma and is critically involved in the development of asthma attacks.

Benralizumab is injected every four to eight weeks.

The SHAMAL study took place across 22 sites in the UK, France, Italy and Germany.

The 208 patients were randomly assigned to taper their high dose inhaled steroid by varying amounts over 32 weeks, followed by a 16 week maintenance period.

Approximately 90% of patients experienced no worsening of asthma symptoms and remained free of any exacerbations throughout the 48 week study.

Similar studies to SHAMAL will be necessary before firm recommendations can be made regarding the safety and efficacy of reducing or eliminating high dose steroid use with other biologic therapies.

Source: King’s College London

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Combining Diagnosis and Treatment into One to Treat Pancreatic Cancer

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Pancreatic cancer cells. Credit: NIH

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, with a 5-year survival rate of less than 10%. Many PDAC tumours go undetected in early stages since they go undetected by conventional imaging methods such as fluorodeoxyglucose positron emission tomography (PET) scans. To tackle this problem, researchers in Japan are combining diagnostic and therapeutic procedures into a single integrated process: ‘theranostics’.

In an article recently published in the Journal of Nuclear Medicine, the Osaka University-led team has developed a ‘radio-theranostics’ strategy that uses a new radioactive antibody to target glypican-1 (GPC1), a protein highly expressed in PDAC tumours. Theranostics, particularly radio-theranostics, has been receiving increasing attention because, by radio-labelling the compounds used to target certain molecules in cancer cells, diagnosis and treatment can be carried out sequentially.

“We decided to target GPC1 because it is overexpressed in PDAC but is only present in low levels in normal tissues,” explains Tadashi Watabe, lead author of the study.

The team used a monoclonal antibody (mAb) designed to target GPC1. The mAb could be labelled with isotopes of zirconium (89Zr) or astatine (211At). First, they injected the 89Zr-GPC1 mAb into a xenograft mouse model, which has a human pancreatic cancer tumour.

“We monitored 89Zr-GPC1 mAb internalisation over seven days with PET scanning,” explains Kazuya Kabayama, the second author of the article. “There was strong uptake of the mAb into the tumours, suggesting that this method could support tumour visualisation. We confirmed that this was mediated by its binding to GPC1, as the xenograft model that had GPC1 expression knocked out showed significantly less uptake.”

The researchers next tested this model with alpha therapy using 211At-GPC1 mAb, a method that could support radioactive label-based delivery of a therapeutic molecule to its target. Administration of 211At-GPC1 mAb resulted in DNA double-strand break induction in the cancer cells, as well as significantly reduced tumour growth. Control experiments showed that these antitumor effects did not occur when mAb internalisation was blocked. Additionally, non-radiolabelled GPC1 mAb did not induce these effects.

“Both radiolabeled versions of the GPC1 mAb we examined showed promising results in PDAC,” says Watabe. “89Zr-GPC1 mAb showed high humoral uptake, while 211At-GPC1 mAb could be used for targeted alpha therapy to support suppression of PDAC tumour growth.”

These highly impactful data demonstrate the potential for using a theranostics approach in PDAC, a disease in dire need of new diagnostic and therapeutic options. In the future, this could lead to early detection of PDAC with PET imaging and systemic treatment with alpha therapy.

Source: Osaka University

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New Omicron Variant Escapes Antibodies and Monoclonal Therapy

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Source: Fusion Medical Animation on Unsplash

The emerging Omicron variant BA.2.75.2 largely evades neutralising antibodies in the blood and resists several monoclonal antibody antiviral treatments, according to a study published in the journal The Lancet Infectious Diseases. The findings suggest a risk of increased COVID infections in the northern hemisphere’s winter, unless the new updated bivalent vaccines help to boost immunity in the population.

“While antibody immunity is not completely gone, BA.2.75.2 exhibited far more dramatic resistance than variants we’ve previously studied, largely driven by two mutations in the receptor binding domain of the spike protein,” said the study’s corresponding author Ben Murrell, assistant professor at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.

The study shows that antibodies in random serum samples from 75 blood donors in Stockholm were approximately only one-sixth as effective at neutralising BA.2.75.2 compared with the now-dominant variant BA.5. The serum samples were collected at three time points: in November 2021 before the emergence of Omicron, in April 2022 after a large wave of infections in the country, and at the end of August to early September after the BA.5 variant became dominant.

The researchers found that only one of the clinically available monoclonal antibody treatments that were tested, bebtelovimab, managed to effectively neutralise the new variant.

BA.2.75.2 is a mutated version of another Omicron variant, BA.2.75. Since it was first discovered earlier this fall, it has spread to several countries but so far represents only a minority of registered cases.

A possible increase in infections

“We now know that this is just one of a constellation of emerging variants with similar mutations that will likely come to dominate in the near future,” Ben Murrell says, adding “we should expect infections to increase this winter.”

Some questions remain. It is unclear whether these new variants will drive an increase in hospitalisation rates. Also, while current vaccines have, in general, had a protective effect against severe disease for Omicron infections, there is not yet data showing the degree to which the updated COVID vaccines provide protection from these new variants. “We expect them to be beneficial, but we don’t yet know by how much,” Ben Murrell says.

Source: Karolinska Institutet

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New Monoclonal Antibody Eptinezumab Success in Hard-to-treat Migraine

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A trial for a new monoclonal antibody, eptinezumab, in the treatment of resistant migraine has demonstrated that it significantly reduced migraine days with acceptable safety and tolerability. The findings were published in The Lancet.

Eptinezumab, which targets calcitonin gene-related peptide, has shown migraine preventive effects starting the day following infusion and acceptable safety and tolerability in phase 3 trials, but benefits in the subpopulations of patients with previous preventive treatment failures were not examined.

In the 24-week double-blind placebo-controlled DELIVER phase 3b trial, the researchers recruited adults with episodic or chronic migraine with at least four monthly migraine days and two-to-four previous preventive treatment failures within the past 10 years. Patients were randomised to either eptinezumab 100mg, eptinezumab 300mg, or placebo. The primary efficacy endpoint was the change from baseline in mean monthly migraine days (captured using a daily electronic diary) in weeks 1–12, assessed in the full analysis set. All participants and study personnel were masked to study drug assignments. A 48-week dose-blinded extension period is ongoing.

In all, 865 patients completed the placebo-controlled period. Compared to baseline, weeks 1–12 saw reductions of 4.8 mean monthly migraine days with eptinezumab 100mg and 5.3 days at 300mg, which was a significantly less than the reduction of 2.1 days with placebo.

Adverse events were reported in 42% of patients in the eptinezumab 100mg group, 41% in the 300mg group, and in 40% in the placebo group. COVID was the most common treatment-emergent adverse event. Serious adverse events were uncommon (five [2%] of 299 in the 100mg group, seven [2%] of 294 in the 300mg group, four [1%] of 298 in the placebo group) and included anaphylactic reaction (eptinezumab 300 mg n=2) and COVID-19 (eptinezumab 100 mg n=1 and eptinezumab 300 mg n=1).

In adults with migraine and two-to-four previous preventive treatment failures, eptinezumab provided significant migraine preventive effects compared with placebo, with acceptable safety and tolerability, indicating that eptinezumab might be an effective treatment option for this patient population. The trial has a dose-blinded extension period which will provide additional long-term safety data in patients with migraine and previous preventive treatment failures.