Category Archives: Immunology

Immunology

New research highlights the importance of the thymus in successful pregnancies – University of Birmingham

Researchers found that during pregnancy, the female sex hormones instruct the thymus to produce Tregs specialised in dealing with physiological changes during pregnancy.

How the immune system adapts to pregnancies has puzzled scientists for decades. Now, findings from an international group of researchers, led by experts at Karolinska Institutet in Sweden, reveal important changes that occur in the thymus to prevent miscarriages and gestational diabetes. The study was published today (23 December 2020) in Nature.

The thymus is a central organ of the immune system where specialised immune cells called T lymphocytes mature. These cells, commonly referred to as T cells, then migrate into the blood stream and tissues to help combat pathogens and cancer. An important T cell subset, known as a regulatory T cell or Treg, is also produced in the thymus. The main function of a Treg is to help regulate other immune cells.

Researchers found that during pregnancy, the female sex hormones instruct the thymus to produce Tregs specialised in dealing with physiological changes during pregnancy. The studywhich involved researchers at Karolinska Institutet, the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna, University of British Columbia in Vancouver, further reveals that RANK, a receptor expressed in the thymus epithelia, is the key molecule behind this mechanism.

The study builds on work by a team at the University of Birmingham as researcher and collaboratorProfessor Graham Andersonfrom the Institute of Immunology and Immunotherapy explains: In 2007, our lab provided the first evidence that RANK plays a critical role in controlling thymus function in the steady state immune system. Now, this new research shows how RANK in the thymus regulates the immune system in pregnancy, which is an exciting new direction.

We knew RANK was expressed in the thymus, but its role in pregnancy was unknown, says first and co-corresponding author Dr. Magdalena Paolino, assistant professor at the Department of Medicine, Solna, Karolinska Institutet.

To get a better understanding, the authors studied mice where RANK had been deleted from the thymus.

The absence of RANK prevented the production of Tregs in the thymus during pregnancy. This resulted in less Tregs in the placentas, leading to miscarriages, continues Magdalena Paolino.

This latest study further shows that in normal pregnancies, the produced Tregs also migrate to the mothers fat tissue to prevent inflammation and help control glucose levels in the body. Pregnant mice lacking RANK had high levels of glucose and insulin in their blood and many other indicators of gestational diabetes, including fetal macrosomia.

Similar to babies of women with gestational diabetes, the newborn pups were much heavier than average, explains Magdalena Paolino.

In addition, the deficiency of Tregs during pregnancy was proven to result in long-lasting transgenerational effects on the offspring, which remained prone to diabetes and overweight throughout their life spans. Giving the RANK deficient mice thymus-derived Tregs that had been isolated from normal pregnancies, reversed all issues including fetal loss and maternal glucose levels and the body weights of the pups.

The researchers also analysed women with gestational diabetes, revealing a reduced number of Tregs in their placentas, much similar to the study on mice.

This research changes our view of the thymus, as an active and dynamic organ required to safeguard pregnancies, Magdalena Paolino says. It also provides new molecular insight for gestational diabetes, a disease that affects many women and which we still know little about. It emphasises the importance of clinics detecting and managing glucose metabolism in pregnant women to avert its long-term effects.

Co-corresponding author Dr. Josef Penninger notes that how rewiring of the thymus contributes to a healthy pregnancy was one of the remaining mysteries of immunology until now.

Our work over many years has now not only solved this puzzle pregnancy hormones rewire the thymus via RANK but uncovered a new paradigmatic function: the thymus not only changes the immune system of the mother to allow the fetus, but it also controls metabolic health of the mother, Josef Penninger says.

The study was possible thanks to a close collaboration between the laboratory of Magdalena Paolino at Karolinska Institutet and the laboratories of Josef Penninger at IMBA and UBC. Researchers from the CeMM Institute and the Medical University of Vienna, as well as from the Universities of Birmingham and Oxford also participated.

For more information please contactMagdalena Paolino, Assistant Professor,Department of Medicine Solna, Karolinska Institutet.

Full paper:RANK links thymic Tregs to fetal loss and gestational diabetes in pregnancy, Magdalena Paolino*, Rubina Koglgruber, Shane J. F. Cronin, Iris Uribesalgo, Esther Rauscher, Juergen Harreiter, Michael Schuster, Dagmar Bancher-Todesca, Blanka Pranjic, Maria Novatchkova, Andrea White, Verena Sigl, Sabine Dekan, Juan P. Fededa, Thomas Penz, Christoph Bock, Lukas Kenner, Georg A. Hollnder, Graham Anderson, Alexandra Kautzky-Willer, and Josef M. Penninger*, Nature, in press 23/12/2020

DOI:10.1038/s41586-020-03071-0.

Grant information:

The researchers were supported by grants from Karolinska Institutet, the Ragnar Soderberg Foundation, the Swedish Research Council, the Swiss National Foundation, The Wellcome Trust, MRC, CRUK, Austrian Science Fund, European Training Network, IMBA, a Canada150 Chair, the T. von Zastrow foundation and the European Research Council.

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New research highlights the importance of the thymus in successful pregnancies - University of Birmingham

Immunology

ACAAI COVID-19 Task Force Members available to discuss allergic reactions to mRNA vaccines – Newswise

Niraj Patel, MD, MS, is Chief of the Division of Pediatric Infectious Disease and Immunology at Levine Childrens Hospital, in Charlotte, North Carolina. He is an Adjunct Associate Professor at the University of North Carolina Chapel Hill. Dr. Patel established the Charlotte Immunodeficiency Center of Excellence in 2009. He is board certified in pediatrics, pediatric infectious diseases, and allergy and immunology.

Dr. Patel chairs the American College of Allergy, Asthma and Immunology COVID-19 Task Force and is available to answer questions about allergic reactions to the mRNA COVID-19 vaccines.

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ACAAI COVID-19 Task Force Members available to discuss allergic reactions to mRNA vaccines - Newswise

Immunology

Update on SOURCE Phase III trial for tezepelumab in patients with severe, oral corticosteroid-dependent asthma – PharmiWeb.com

AstraZeneca and Amgen today announced high-level results from the SOURCE Phase III trial which assessed the efficacy and safety of the potential new medicine tezepelumab compared to placebo in 150 severe asthma patients who required maintenance use of oral corticosteroids (OCS) on top of standard of care (SoC).

The 48-week trial did not meet the primary endpoint of a statistically significant reduction in the daily OCS dose, without loss of asthma control, with tezepelumab compared to placebo. Tezepelumabs effect on other efficacy parameters was similar to those observed in previous trials, including the registrational Phase III NAVIGATOR trial.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: Based on the totality of evidence, including the compelling exacerbation reduction results seen in the registrational NAVIGATOR Phase III trial and the PATHWAY Phase IIb trial, we remain confident that tezepelumab has the potential to improve care for a broad population of severe asthma patients. Our initial analysis of SOURCE in oral corticosteroid-dependent asthma indicates that the trial design may have contributed to the result of the primary endpoint. We are in the process of further analysing the data from SOURCE and look forward to sharing these results with the medical community.

The safety profile of tezepelumab in the trial was consistent with previous trials. Detailed results from the SOURCE trial will be presented at a forthcoming medical meeting.

On 10 November 2020, AstraZeneca and Amgenannouncedpositive results from the NAVIGATOR Phase III trial which met the primary endpoint and demonstrated a statistically significant and clinically meaningfulreduction in the annualised asthma exacerbation rate (AAER) in a broad population of patients with severe asthma, including those with low levels of eosinophils.

Tezepelumab is a potential first-in-class medicine that blocks the action of thymic stromal lymphopoietin (TSLP), an epithelial cytokine that plays a key role across the spectrum of asthma inflammation.1,2Tezepelumab is being developed by AstraZeneca in collaboration with Amgen.

Severe asthmaAsthma is a heterogeneous disease affecting an estimated 339 million people worldwide.3,4Approximately 10% of asthma patients have severe asthma,4,5which may be uncontrolled despite high doses of SoC asthma controller medicines and currently available biologic medicines. Some of these patients may require the use of long-term OCS4-6which can lead to serious short- and long-term adverse effects.7-9Severe, uncontrolled asthma is debilitating and potentially fatal, with patients experiencing frequent exacerbations and significant limitations on lung function and health-related quality of life.4,6,10Due to the complexity of severe asthma, many patients have unclear or multiple drivers of inflammation and may not qualify for or respond well to a current biologic medicine.5,11,12

PATHFINDER clinical trial programmeBuilding on the positive PATHWAY Phase IIb trial, the PATHFINDER Phase III programme includes the registrational NAVIGATOR trial and the supportive SOURCE trial.2,13-16The programme includes additional planned mechanistic and long-term safety trials.

SOURCE is a Phase III multicentre, randomised, double-blinded, parallel-group, placebo-controlled trial for 48 weeks in 150 adult patients with severe asthma who require continuous treatment with inhaled corticosteroids (ICS) plus long-acting beta2-agonists (LABA), and chronic treatment with maintenance OCS therapy.14,16In the trial, patients were randomised to receive tezepelumab 210mg every four weeks or placebo as add-on therapy, with patients maintained on their currently prescribed ICS plus LABA, with or without other asthma controller therapy.14,16

The primary efficacy endpoint was the percentage reduction from baseline in the prescribed daily OCS maintenance dose at 48 weeks while not losing asthma control. Secondary endpoints included the effect of tezepelumab on AAER, lung function, asthma control, quality of life, work productivity and activity impairment.14,16

NAVIGATOR is a Phase III, randomised, double-blinded, placebo-controlled trial in 1,061 adults (1880 years old) and adolescents (1217 years old) with severe, uncontrolled asthma, who were receiving treatment with medium- or high-dose ICS plus at least one additional controller medicine with or without oral corticosteroids. NAVIGATOR met the primary endpoint with tezepelumab added to SoC demonstrating a statistically significant and clinically meaningful reduction in the AAER over 52 weeks in the overall patient population, compared to placebo added to SoC. The trial also met the primary endpoint in the subgroup of patients with baseline eosinophil counts less than 300 cells per microlitre, with tezepelumab demonstrating a statistically significant and clinically meaningful reduction in AAER in that patient population. Similar reductions in AAER were observed in the subgroup of patients with baseline eosinophil counts less than 150 cells per microlitre.13,15,17

Patients who participated in the NAVIGATOR and SOURCE trials were eligible to continue in DESTINATION, a Phase III extension trial assessing long-term safety and efficacy.18

TezepelumabTezepelumab is a potential first-in-class human monoclonal antibody that inhibits the action of TSLP, a key epithelial cytokine that sits at the top of multiple inflammatory cascades and is critical in the initiation and persistence of allergic, eosinophilic and other types of airway inflammation associated with severe asthma.1,2TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles.1,2Expression of TSLP is increased in the airways of patients with asthma and has been correlated with disease severity.2,19Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.2,19Tezepelumab acts at the top of the inflammation cascade and has the potential to treat a broad population of severe asthma patients regardless of their type of inflammation.2,19

AstraZeneca and Amgen collaborationEarlier in 2020, Amgen and AstraZeneca updated the2012 collaboration agreementfor tezepelumab. Both companies will continue to share costs and profits equally after payment by AstraZeneca of a mid-single digit inventor royalty to Amgen. AstraZeneca continues to lead development and Amgen continues to lead manufacturing. All aspects of the collaboration are under the oversight of joint governing bodies. Under the amended agreement in North America, Amgen and AstraZeneca will jointly commercialise tezepelumab; Amgen will record sales in the US and AstraZeneca will record sales in Canada. AstraZenecas share of gross profits from tezepelumab in the US will be recognised as collaboration revenue. In all countries outside the US and Canada, AstraZeneca will solely commercialise tezepelumab. AstraZeneca will record all sales outside of the US as product sales and recognise Amgens share of gross profit as cost of sales.

AstraZeneca in Respiratory & ImmunologyRespiratory & Immunology is one of AstraZenecas three therapy areas and is a key future growth driver for the Company.

AstraZeneca is an established leader in respiratory care, and its inhaled and biologic medicines reached more than 53 million patients in 2019. Building on a 50-year heritage, the Company aims to transform the treatment of asthma and COPD by focusing on earlier biology-led treatment, eliminating preventable asthma attacks, and removing COPD as a top-three leading cause of death. The Companys early respiratory research is focused on emerging science involving immune mechanisms, lung damage and abnormal cell-repair processes in disease and neuronal dysfunction.

With common pathways and underlying disease drivers across respiratory and immunology, AstraZeneca is following the science from chronic lung diseases to immunology-driven disease areas. The Companys growing presence in immunology is focused on five mid- to late-stage franchises with multi-disease potential, in areas including rheumatology (including systemic lupus erythematosus), dermatology, gastroenterology, and systemic eosinophilic-driven diseases. AstraZenecas ambition in Respiratory & Immunology is to achieve disease modification and durable remission for millions of patients worldwide.

AstraZenecaAstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visitastrazeneca.comand follow the Company on Twitter@AstraZeneca.

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Update on SOURCE Phase III trial for tezepelumab in patients with severe, oral corticosteroid-dependent asthma - PharmiWeb.com

Immunology

GlaxoSmithKline/Vir’s and AstraZeneca’ mAbs eyed in early COVID-19 – pharmaceutical-technology.com

A second wave of monoclonal antibodies (mAbs) by GlaxoSmithKline/Vir Biotechnology and AstraZeneca hold scope to show comparable efficacy to FDA-authorised competitors in early COVID-19 disease, experts said. However, to differentiate they need to expand to other populations and settings, which depends on their design modifications translating to the clinic, they added.

The mAbs bid to differ or improve upon Eli Lilly and Regeneron Pharmaceuticals (NASDAQ:REGN) drugs, which were granted FDA Emergency Use Authorizations on 9 and 21 November, respectively, relies on Fc modifications. The mAbs must either improve efficacy in severe disease or have longer efficacy due to improved half-life.

Most experts still expect the second wave of mAbs to be similarly restricted to non-hospitalised, high-risk patients. Lackluster experience was observed in advanced COVID-19 disease due to inflammatory pathways playing a big role with Eli Lillys bamlanivimab and Regenerons casirivimab/imdevimab. While GSK/Virs VIR-7831 could succeed where others failed in this population, expectations remain uncertain as preclinical models remain ill-equipped to predict immune cell activity in patients with severe disease including the inflammatory pathways.

The longer half-life would be most relevant in the prophylactic setting and not provide any add-on as a treatment. However, as COVID-19 vaccines make headway, the potential for prophylactic mAbs is limited, as it is being restricted to immunocompromised, elderly patients or those who cannot receive the vaccine, experts said.

GSK/Virs programme consists of the Phase II/III (NCT04545060) COMET-ICE study for non-hospitalised patients, the National Institutes of Health (NIH)-led Phase III ACTIV-3 (NCT04501978) in hospitalised patients, and a planned prophylaxis or prevention of symptomatic infection trial in 1Q21. Interim data from COMET-ICE may be available as early as January 2021, with primary endpoint results in 1Q21, as per Virs 3Q20 earnings. The interim data is being viewed as a catalyst for the company, said an analyst. The analyst conservatively estimates USD 500m in peak sales for VIR-7831.

AstraZenecas cocktail AZD7442 is in two Phase III trials: PROVENT (NCT04625725) in the pre-exposure prophylaxis setting and STORMCHASER (NCT04625972) in the postexposure prophylaxis setting. Both have 2022 completion dates. No companies responded to requests for comment.

The authorised mAbs have limited efficacy data, but the investigational mAbs will have to show they can improve clinical outcomes in a similar manner to compete, said Dennis Burton, PhD, chair, Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, California. Both bamlanivimab and casirivimab/imdevimab are authorised based on their ability to reduce viral loads and hospitalisations within 28 days after treatment. COMET-ICE is enrolling non-hospitalised patients at high risk of COVID-19 progression or who are ages 55 years and older, and its primary endpoint is driven by disease progression in a 29-day time frame. The COMET-ICE trial results will be closely watched to determine whether VIR-7831 can reduce viral replication and improve clinical outcomes, such as the need for hospitalisation in outpatients, compared to placebo, said a therapeutic antibody expert.

One clinical benefit with the authorised mAbs is seen in patients with milder disease and risk factors like old age and comorbidities, said Michael Diamond, PhD, associate director, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine at St Louis. Despite preclinical animal data with GSK/Vir and AstraZenecas mAbs proving activity, comparisons between the authorised and investigational mAbs in terms of superior or similar efficacy cannot be made conclusively without clinical data, said Dimiter Dimitrov, PhD, director, Center for Antibody Therapeutics, University of Pittsburgh Department of Medicine, Pennsylvania.

Generally, experts expected the most efficacy potential in the non-hospitalised setting. The challenge with late delivery is how the disease is being driven by an inflammatory response at the time of hospitalisation, when the mAbs ability to decrease the viral loads becomes a moot point, Diamond added. As vaccines become more widely available, the bar for antibody treatments will become higher as fewer patients get sick, said the antibody expert. Still, more treatment options are needed for severe COVID-19 patients, so it may be a good idea to evaluate whether modified mAbs may work later in the disease, said Diamond.

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On 23 December, the NIH announced the preliminary results from ACTIV-3, which showed Eli Lillys bamlanivimab failed to provide clinical benefit in hospitalised COVID-19 patients. The study was initially studying bamlanivimab in this setting, but stopped after a Data Safety Monitoring Board noted no clinical benefit in patients treated with the mAb, as per a 26 October announcement. On 30 October, Regeneron halted enrolment in its own hospitalised patient study for patients on high-flow oxygen or mechanical ventilation, but continued enrolling those who require either no or low-flow oxygen.

While Regeneron and Eli Lilly did not make any Fc modifications in their mAb therapies, GSK/Vir and AstraZeneca have done so. VIR-7831s differentiated Fc effector function, which is designed to recruit macrophages and natural killer cells, could be studied in hospitalised patients, a second analyst noted prior to the ACTIV-3 trial inclusion announcement. On 17 December, Vir announced the first patient had enrolled in the ACTIV-3 trial to evaluate VIR-7831s impact on time to recovery among other endpoints.

Recruiting effector cells like natural killer cells and macrophages may be helpful in advanced COVID-19, but there is a risk they could kill normal cells in the lung as well, which could cause further damage, said Dimitrov. Moreover, it is not yet clear whether a mAb blocking the target is preferable for efficacy over a mAb modified to target the immune cells as well, said an immunology expert.

However, information on effector immune cells in animal models can be limited, so predicting effector function in humans based on the preclinical data is difficult, said Burton. VIR-7832 is a GAALIE-engineered mAb. In a mouse model, data demonstrated the selective engagement of an activating Fc receptor on dendritic cells by anti-influenza GAALIE-engineered antibodies induced protective CD8+ T cell adaptive responses (Bournazos, S., et al,. Nature 588, 485490 (2020).

COMET-ICE is a placebo-controlled study. However, once the authorised mAbs are FDA approved, noninferiority studies comparing those to the next investigational mAbs will need to be designed to prove they are clinically equivalent or have significant efficacy in preventing progression to severe disease, said Diamond. VIR-7831 is engineered to potentially enhance lung bioavailability and have an extended half-life. AZ-7442s potential to protect people for six months or more and could work as a therapeutic, the first analyst noted. Since the virus clears within 1421 days, it is not clear if the longer half-life will be an issue in the treatment setting, Diamond said. The extended half-life may be an important feature in mAb prophylactics for those at high-risk who cannot get vaccinated, he added. While mAbs can be used as a prophylactic in the elderly or immunocompromised population, the current vaccines are very effective, said Dimitrov.

Another benefit for Fc modification is how it offers a greater degree of efficacy against potential resistant viral strains. A new variant strain of SARS-CoV-2 called B.1.1.7, which contains a series of mutations including one in the receptor binding domain of the viral spike protein, has been described in the UK this month and is said to be more rapidly transmissible than other strains. If there are mutations leading to new variants, specifically those incapable of being neutralised by a particular mAb, they could be targeted by others, said Dimitrov. The efficacy of monotherapy versus combination in the context of resistance would then depend on the individual mAbs target region and if the escape mutations are noted there, said Diamond.

Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalDatas investigative journalism team. A version of this article originally appeared on the Insights module of GlobalDatas Pharmaceutical Intelligence Center. To access more articles like this,visit GlobalData.

Tablet Presses, Capsule Filling Machines and Customised Tooling for the Pharmaceutical Industry

28 Aug 2020

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GlaxoSmithKline/Vir's and AstraZeneca' mAbs eyed in early COVID-19 - pharmaceutical-technology.com

Immunology

AstraZeneca to acquire Alexion, enhancing presence in immunology – BioPharma-Reporter.com

Boston-based biotech Alexion has been earmarked as a hot takeover target in the biotech sector: thanks to the significant market potential of ultra-rare disorder drugs with less competitive pressure than other sectors. Its leading medicine is soliris, which is approved for use against a range of rare immune disorders.

The value of the deal overtakes Gilead's acqusition of Immunomedics for $21bn in September; and marks AstraZeneca's largest ever acquisition.

AstraZeneca has recently been increasing its efforts in immunology research and the development of medicines for immune-mediated diseases.

As part of the acquisition, AstraZeneca will establish a dedicated rare disease unit in Boston and accelerate worldwide expansion of Alexions portfolio.Combining AstraZenecas capabilities in precision medicine and Alexions expertise in rare-disease development and commercialisation will enable the new company to develop a portfolio of medicines addressing the large unmet needs of patients suffering from rare diseases,says AstraZeneca.

Alexion was founded in 1992 and now employs more than 3,000 people. Led by what AstraZeneca terms its skilful commercial execution in building its blockbuster C5 franchise with soliris, Alexion now has five approved medicines (andexxa, kanuma, soliris, strensiq, and ultomiris) and a pipeline of 11 molecules in 20+ clinical development programs.

It serves patients in more than 50 countries and in 2019 generated a total revenue of $5bn and profit before tax of $2.2bn.

AstraZeneca predicts the combined company will deliver double-digit average annual revenue growth through 2025.

It says the two companies have been on converging paths: AstraZeneca expanding its presence from primary to speciality care, while Alexion has been progressing from ultra-orphan to orphan and speciality conditions.

And the British-Swedish giant also highlights rare diseases as a high-growth therapy area with rapid innovation and significant unmet medical need. Over 7,000 rare diseases are known today, yet only around 5% have US Food and Drug Administration-approved treatments.The global rare disease market is forecasted to grow by a low double-digit percentage in the future.

Alexion is focused in complement biology; with the complement cascade pivotal to the innate immune system. This plays a crucial role in many inflammatory and autoimmune diseases across multiple therapy areas: such as haematology, nephrology, neurology, metabolic disorders, cardiology, ophthalmology and acute care.

Meanwhile, AstraZeneca says its capabilities in genomics, precision medicine and oligonucleotides can be leveraged to develop medicines targeting less-frequent diseases.

AstraZeneca says the combined companies can bring together two rapidly converging, patient-centric models of care delivery with combined strengths in immunology, biologics, genomics and oligonucleotides to drive future medicine innovation.

The boards of directors of both companies have unanimously approved the acquisition. The acquisition is expected to close in Q3 2021, subject to receipt of regulatory clearances and approval by shareholders of both companies. Upon completion, Alexion shareholders will own around 15% of the combined company.

Alexion has pioneered complement inhibition for a broad spectrum of immune-mediated rare diseases caused by uncontrolled activation of the complement system, a vital part of the immune system.

Alexion's franchise includesSoliris(eculizumab), an anti-complement component 5 (C5) monoclonal antibody. The medicine is approved in many countries for the treatment of patients with paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, generalized myasthenia gravis and neuromyelitis optica spectrum disorder.

More recently, Alexion launchedUltomiris(ravulizumab), a second-generation C5 monoclonal antibody with a more convenient dosing regimen.

Alexion's work in immunology extends to other targets in the complement cascade beyond C5 as well as additional modalities, with its deep pipeline including Factor D small-molecule inhibitors of the alternative pathway of the complement system, an antibody blocking neonatal Fc receptor (FcRn)-mediated recycling, and a bi-specific mini-body targeting C5, among others. The FcRn extends the half-life and hence the availability of pathogenic immunoglobulin G (IgG) antibodies.

Originally posted here:
AstraZeneca to acquire Alexion, enhancing presence in immunology - BioPharma-Reporter.com

Immunology

Autoantibody Problems | In the Pipeline – Science Magazine

Heres a preprint from a large team at Yale with a close look at a less-studied aspect of coronavirus infection. Its been well established by now that a feature of severe cases is a misfiring immune response (the cytokine storm, etc.), and one reason that fatality rates have been going down for hospitalized cases is better management of this problem. But the details are still being worked out and since were talking immunology, there are a lot of details.

And it looks like one of those details, potentially a very important one, is a striking correlation with autoantibodies. Those are antibodies to a persons own proteins the sort of friendly fire that you see in autoimmune diseases of all sorts (acute and chronic). This work features a new assay (Rapid Extracellular Antigen Profiling, REAP) against a displayed library of 2,770 extracellular (secreted) human proteins displayed via yeast cells, providing a high-throughput method to check a patients own serum for antibodies to these. 194 subjects (Yale patients and healthcare workers) were screened, with a wide range of disease severity, as compared to 30 uninfected controls. The new assay showed good correlation with standard ELISA assays as a reality check.

It appears that the more severe a coronavirus infection a patient has, the better the chances that they show a wide variety of autoantibodies towards their own cell-surface and secreted proteins (see the figures above). I wrote here about a study that showed that patients with antibodies towards some of their own interferons have a harder clinical course of the disease, and this new paper confirms that work and extends it. A set of patients were examined over time, and it appears that at least 50% of these reactivities were observed early enough in the course of the disease that they may well have been pre-existing. Around 10% of them were seen to increase over time, though, suggesting that the coronavirus infection was bringing on such autoimmune problems. Interestingly, about 15% of the antibody titers seemed to decrease over time, and Im not sure what to make of that.

The paper goes on to make connections between specific autoantibodies and immune function for example, some of the ones that target specific proteins on the surfaces of immune cells are associated in patients with decreased numbers of those cells. The team also looked for correlations between antibodies to specific targets (or those associated with specific tissues) and clinical outcomes. Its a complex thing to untangle, though. If you think about some specific circulating cytokine protein, antibodies to it could help to clear it from the bloodstream more quickly, or to bind to it in a way that keeps it from working (either partially or completely, which seems to be the case for the interferon autoantibodies), or at the other end of the scale, to bind to it in a way that doesnt interfere so much with its function and could even stabilize its levels in the blood.

But overall, there was no well-defined set of COVID-19 antibodies that showed up in infected patients but not in controls, and no obvious ways to match up antibody profiles to specific outcomes. Some of that difficulty, though, may be due to the wide variety of responses seen. Instead of broadly obvious trends, what shows up are a great number of individual responses that can add up to real outcomes, but which are very hard to untangle. Immunology!

One of the things that needs to be done, then, is more extensive profiling in the population. I would assume that ideally youd want to get a good-sized sample of healthy people, profile them for autoantibodies, and then watch over time to see what happens. This isnt just a coronavirus story at that point. Are there people who have greater susceptibility to various diseases, or to worse outcomes, if they have particular autoimmune fingerprints? Or will it still be a big tangled ball of yarn if you try to track these things down? At the least, I would expect that if there is indeed a population who have some sort of partial failure of immune tolerance and thus show existing high levels of auto-antibodies, they they would be at greater risk of severe coronavirus infection. How many such people are there, and how many of them are currently unrecognized?

Beyond that, theres the possibility that some of the autoimmune effects are being actually brought on by the infection. We already know about some of the larger, more obvious examples of this sort of thing (such as Guillain-Barr and others), but profiling via an assay like REAP could help to shed more light. There are already several mechanisms known for such tolerance failures, but its for sure that theres a lot more to learn, and I would think that a good-sized longitudinal study might have a lot to tell us. (Of course, Im not the person who has to go out and get funding for it, so thats easy for me to say!)

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Autoantibody Problems | In the Pipeline - Science Magazine

Immunology

Frontier and AbbVie to develop therapies targeting ‘undruggable’ proteins – pharmaceutical-technology.com

Precision medicine-focused Frontier Medicines has signed a multi-year collaboration with AbbVie to discover, develop and commercialise multiple small molecule therapeutics against difficult-to-drug protein targets.

The collaboration will focus on developing an undisclosed number of therapeutics against validated, but previously inaccessible, E3 ligase, immunology and oncology targets.

In return for the use of its proprietary chemoproteomics platform, Frontier will be eligible for an upfront cash payment of $55m, as well as additional milestone payments that could exceed $1bn and royalty payments on any commercial sales. AbbVie will also reimburse Frontiers pre-clinical research and development costs.

Frontier co-founder, CEO and chairman Chris Varma explains the $55m upfront payment will support the independent advancement of the companys own pipeline of high-value targets. These internal programmes are not part of this latest collaboration with AbbVie.

Varma notes that

Approximately 90% of human proteins could not be targeted by small-molecule drugs because there was no known or accessible binding site on the surface of the protein, adds Varma. However, proteins are dynamic and when they function in a cellular context and interact with other cellular members, the movement and bending creates temporary pockets to which a drug can bind.

Frontiers chemoproteomics approach allows the company to exploit these binding pockets using covalent drug discovery and by leveraging a curated and diverse chemical library, a proprietary hotspot database and machine learning approaches, according to Varma.

Varma argues that Frontiers platform enables a paradigm shift in drug discovery by allowing previously undruggable proteins to now be accessible to therapeutic intervention. It allows for a precision medicine discovery approach that can identify unique, even disease-specific pockets for a given protein, with laser precision, pointing our teams to the highest quality sites for ligandability and to increase the probability of success.

In a release, AbbVie vice-president of discovery Jose-Carlos Gutirrez-Ramos commented: AbbVie is focused on making investments in promising new technologies that assist us in our mission to develop innovative medicines.

One of our key strategic focus areas is targeted protein degradation and chemoproteomics, and this collaboration with Frontier will be highly synergistic and complementary to our ongoing efforts.

Varma echoes this sentiment, stating: AbbVies commitment to explore clinically meaningful yet extremely challenging targets is aligned with Frontiers focus and expertise.

They are embracing innovative approaches to discovering new therapies such as with our chemoproteomics platform which ensures that these programs will be appropriately prioritised.

In addition, Varma notes that AbbVie has significant useful expertise in global research, development and commercialisation of drugs, and it can provide the necessary know-how and resources to maximise on the potential of transforming these promising targets into therapies benefiting patients.

Importantly, by partnering with AbbVie, Frontier is able to advance more targets than it could on its own. Some of the immunology and oncology targets that the pair are focused on are exciting, but not part of Frontiers internal focus.

Laboratory Testing and Project Management for Clinical Trials

28 Aug 2020

Handling / Packaging Machines for the Pharmaceutical Industry

28 Aug 2020

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Frontier and AbbVie to develop therapies targeting 'undruggable' proteins - pharmaceutical-technology.com

Immunology

Research Could Offer Novel Way to Restore Lung Function to COVID-19 Patients – Stony Brook News

December 14, 2020 3 minutes

Targeting endothelial cells cells that comprise the blood vessel wall which regulate oxygen exchange between airways and the bloodstream may be a novel approach restoring normal lung function to Covid-19 patients with serious lung disease.

This hypothesis stems from a study by researchers in the Department of Microbiology and Immunology in the Renaissance School of Medicine at Stony Brook University and published inmBio, the leading journal for the American Society for Microbiology.

SARS-CoV-2 causes Covid-19, characterized by pulmonary edema, viral pneumonia, coagulopathy, inflammation and other physiological abnormalities. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) receptors to infect and damage ciliated epithelial vascular cells in the upper respiratory tract. Yet how SARS2 dysregulates vascular functions causing an acute respiratory distress syndrome (ARDS) in Covid-19 patients remains an enigma.

Led byErich Mackow, PhD, a Professor of Microbiology and Immunology, the team of scientists sought to unravel this mechanism by investigating SARS-CoV-2 infection of human endothelial cells from the lung, brain, heart and kidney that are impacted in COVID-19 patients.

Claims that endothelial cells are infectedby SARS-CoV-2 through ACE2 receptors have never been assessed directly, Mackow said. Our research revealed that endothelial cellslack ACE2 receptors and that endothelial cells were only SARS-CoV-2 infected after expressing ACE2 receptors in them. Since endothelial cell functions are dysregualted by SARS-CoV-2, these findings suggest a novel mechanism of regulation that does not require viral infection. Instead it suggests the indirect activation of the endothelium, potentially resulting from surrounding tissue damage, that could be the basis for further research to therapeutically target and restore normal endothelial cell responses.

Mackow adds that their work centers on both endothelial cells and ACE2 functions in Covid-19 disease to identify mechanisms of capillary inflammation and aberrant clotting within vessels. He explains that the research reveals a novel mechanism of clotting and endothelial inflammation observed in the lung and heart of COVID-19 patients.

A transformative change in the mechanism of endothelial cell dysfunction, not the infection of the cells themselves, changes the way in which disease is initiated and rationales for therapeutic targeting. If endothelial cells are not infected or directly damaged, they can still direct inflammation and clotting by just being activated, he concludes from the research findings.

The team is working on how endothelial cells can be activated by the virus or in response to other SARS-CoV-2 infected lung cells that express ACE2.

The research suggests the potential to therapeutically target activation, rather than infection of the endothelium, as a strategy for resolving coagulation and inflammatory Covid-19 symptoms.

Mackow emphasizes that additional research of endothelial cells and down-regulated ACE2 functions following SARS-CoV-2 infection are necessary to determine targets that could lead to a reduction in respiratory distress and symptoms of Covid-19 patients.

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Research Could Offer Novel Way to Restore Lung Function to COVID-19 Patients - Stony Brook News

Immunology

SIMON The Machine Learning Platform Paving the Future of Vaccine Development – News-Medical.Net

This article was written in correspondence with Adriana Tomic, Ph.D., of the Oxford Vaccine Group.

The Oxford Vaccine Group is in high demand at the moment as they make huge progress in their goal to finalize a vaccine for COVID-19. However, elsewhere in the group, other work is going on that also has wide implications for COVID-19 and the future of vaccine development.

Adriana Tomic, co-developer of SIMON, an open-source platform for applying machine learning to biomedical data, has given News-Medical insight into this groundbreaking research on flu vaccine responses.

Image Credit: People Image Studio / Shutterstock.com

Millions of people are infected with the influenza virus, commonly known as flu, every year, and whilst for most, suffering is short-term, what many do not realize is that for some people, it can be fatal. It is estimated that every year flu kills up to 0.5 million people worldwide, and especially vulnerable are elderly and young children.

Due to a high mutational rate, new flu strains appear regularly, making the development of a vaccine particularly challenging. Each year, we have to develop flu vaccines to provide protection against the circulating viral strains otherwise there is a risk of a global pandemic. Therefore, to prevent future pandemics, it is of critical importance to understand how seasonal vaccines provide protection against flu.

Tomic describes SIMON, or Sequential Iterative Modeling OverNight, as an open-source software for the application of machine learning to biomedical data.

The Oxford Vaccine Group set about with the goal of improving the vaccines effectiveness by determining who was likely to respond positively to it.

The major aims of our project are to understand why some individuals who receive the vaccine are protected against flu while others get infected and to predict if an individual will respond appropriately to the vaccine.

Adriana Tomic, Ph.D., Oxford Vaccine Group

Using SIMON to understand these challenges involved a lot of time-consuming work, processing and standardizing all the clinical data before the analysis. However, the results have proved it was worth it.

SIMON was able to identify immune cell subsets that were present in those who would respond well to the vaccine, described in one of the most-read publications of 2019 and 2020 as rated by the American Association of Immunologists. These results came from FluPRINT, a project in collaboration with Stanford University that analyzed five flu clinical studies from 2007-2015.

SIMON can be used to predict if the individual can respond appropriately to a vaccine based on a set of immune system parameters. By using SIMON, we identified subsets of immune cells not previously described to provide protection against the virus.

These results are important for the development of the next generation of vaccines and have the capacity to fundamentally change vaccinology by application of computational discovery algorithms to speed up the discovery of the biomedical patterns.

Adriana Tomic, Ph.D., Oxford Vaccine Group

The theory behind this discovery for improving the flu vaccine is that the cell types that are responding well in some individuals could be ameliorated in those who are not responding well. This offers huge potential in improving the effectiveness of the flu vaccine.

SIMON - the open-source platform for applying machine learning to biomedical data. Image Credit: Adriana Tomic

SIMON was downloaded more than 3,000 times and it is widely used by immunology and vaccinology specialists across the University of Oxford, Stanford University, including also researchers at the Walter and Eliza Hall Institute for Medical Research in Melbourne. The software is open-source and free to download, as Tomic and the other developers believe it should be accessible to all in order to have the best impact.

Currently, SIMON is being used to investigate the flu vaccine which is given to children and understand whether re-immunization reduces protection. If this is proved true, it will greatly affect when flu vaccines should be given.

Vaccines for other diseases are also being examined. The Oxford Vaccine Group is also looking into meningococcal vaccine given to infants and vaccines against Salmonella typhi.

Adriana Tomic is part of the team developing a potential vaccine for COVID-19, which is well on its way to approval.

Our work with SIMON and systems immunology approach might be crucial for understanding SARS-CoV2 and the development of the vaccine to stop COVID-19 pandemics.

Adriana Tomic, Ph.D., Oxford Vaccine Group

SIMON could be a key factor in supporting this vaccine by applying machine learning to the immunological data being gathered around the world. It may help to develop more targeted and efficient therapies for COVID-19.

Another important aspect is an open-access FluPRINT database which we generated from multiple clinical trials on flu vaccines performed at the Stanford University, Tomic writes. Generating similar datasets from ongoing clinical trials on SARS-CoV2 will be critical for understanding this virus and generating an efficient vaccine.

Beyond the current vaccine, this research could have larger implications, as it may be used in vaccine development for all sorts of diseases. This is a promising prospect, given the likelihood of increasing numbers of new diseases in our future and hence the potential for pandemics to become more common.

To view the SIMON website, click here (genular.org).

The entire FluPRINT project is described in detail on the following website: http://www.fluprint.com

The publication on SIMON is available at:https://www.jimmunol.org/content/jimmunol/early/2019/06/13/jimmunol.1900033.full.pdf

Access Adriana Tomics review of how the dataset was generated here: https://researchdata.springernature.com/channels/1455-behind-the-paper/posts/53950-unifying-clinical-data-to-reveal-influenza-imprint-on-immune-system.

The publication for the open-access FluPRINT database is available at: https://www.nature.com/articles/s41597-019-0213-4.

Adriana Tomic, Ph.D. is a Marie Curie Fellow working at the Oxford Vaccine Group where she leads a systems immunology research aimed at applying machine learning to understand how vaccines work. During her postdoctoral training with Dr. Mark M. Davis at Stanford University she developed a computational tool for the application of machine learning to clinical datasets.

As a Ph.D. student at the Hannover Medical School, Germany, Adriana generated a novel cytomegalovirus vaccine and for this work, she received the award for the best Ph.D. work.

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SIMON The Machine Learning Platform Paving the Future of Vaccine Development - News-Medical.Net

Immunology

Therapeutic Hopes: Meet the Minds Behind Trinity’s COVID-19 Research Hub – The University Times

When the coronavirus pandemic struck Ireland and the world, it sent most people into a panic. But not the immunology researchers at the Trinity Biomedical Sciences Institute (TBSI) and Trinity Translational Medicine Institute (TTMI).

Once coronavirus reached Ireland, TBSI Director Prof Kingston Mills along with TTMI Director Prof Aideen Long gathered 14 of Trinitys top scientists to form the COVID-19 Research Hub. Their goal is to leverage Trinitys expertise in immunology and infectious disease to answer the big immunological questions surrounding the virus and contribute to the global efforts developing treatments and vaccines.

There are not too many experts around the world on SARS viruses, but everybody has suddenly become an expert in COVID-19, remarked Mills. None of us obviously worked on SARS viruses before, so were adapting our expertise to cope with that.

Under the groups main 4.8 million grant from Science Foundation Ireland (SFI), individual researchers are exploring a number of areas, from anti-inflammatories to vaccine efficacy. Were bringing our own strengths, our own specific areas of interest to bear on COVID, says Prof Luke ONeill, the chair of Trinitys School of Biochemistry and Immunology.

None of us obviously worked on SARS viruses before, so were adapting our expertise to cope with that

ONeills current area of interest is on the role of inflammation in disease. Inflammation is part of the bodys natural response to clear an infection but can cause severe damage if it gets out of control. In coronavirus patients, overactive production of immune molecules called cytokines can produce a cytokine storm, overstimulating the inflammatory response and damaging the lungs and other tissues.

But most of the time, the immune system naturally regulates levels of inflammation. In 2018, ONeills lab published in Nature that a molecule called itaconate, produced as part of the bodys natural metabolism, creates some of these natural anti-inflammatory effects.

Although the discovery of the anti-inflammatory role of itaconate is exciting on its own, in 2019, a lab unrelated to ONeills group published in Immunity that itaconate also has antiviral effects against Zika virus in brain cells. Following those findings, ONeill was approached by a SARS virus expert to collaborate on testing itaconate against the coronavirus, with promising early results.

What were showing is that itaconate can block the virus, says ONeill. It could be antiviral directly in some way, and secondly, the anti-inflammatory bit might help because obviously it will limit inflammation when this becomes a severe disease.

ONeill explains that the coronavirus uses a spike protein to enter human cells, binding to a receptor called ACE2 found on many cell types including lung and heart cells. Itaconate appears to lower ACE2 expression, thus preventing the virus from entering cells. If this molecule can block ACE2 and be anti-inflammatory double whammy. Youre going to have a very interesting prospect there, says ONeill.

Although the initial data is intriguing, ONeill is quick to point out that it is early days, both in terms of how recently itaconate was discovered and in testing its effects against the coronavirus. ONeills lab has several parallel projects also focused on anti-inflammatory therapies, and he says: Any one of our projects could be made relevant and have an impact on COVID. So whatever we do is going to feed in ultimately. The whole lab is kind of working on COVID with some directly, some indirectly.

If this molecule can block ACE2 and be anti-inflammatory double whammy, youre going to have a very interesting prospect there

ONeills research covers just one of the four main areas being explored by the COVID-19 Research Hub. Mills and his lab are focusing on vaccines, but not in the way you might think.

We wont be developing a vaccine on our own, but weve been working with pharmaceutical companies to help them to improve the way that the vaccines work, explains Mills, and how they can induce more sustained immune responses. This is frequently done by testing different adjuvants, which are additions to a vaccine that help stimulate a stronger immune response.

Its still unclear exactly how long immunity to the coronavirus lasts after an infection or administration of the vaccine, but ONeill says the goal of a vaccination programme is to ideally create herd immunity and in the process, prevent fatal cases of the disease.

What has become increasingly clear about the coronavirus, however, is that people vary widely in their immune response to the infection. A further research area is examining why some people who are exposed to the virus do not get infected, and why some people who do get infected go on to develop a severe disease.

[We are] looking at patients that have been exposed, and yet, spontaneously clear the virus, says Long. What is it about their innate immune system that helps them to do that?, she asks, citing examples of partners of coronavirus patients who did not become sick after exposure to the virus.

We wont be developing a vaccine on our own, but weve been working with pharmaceutical companies to help them to improve the way that the vaccines work and how they can induce more sustained immune responses

Long theorises that these patients innate immune systems (the non-specific first line of defense of our immune systems) may have some unique features that make them especially effective. Determining what those features are could lead to a better understanding of how to protect people from the virus.

Around 15 per cent of coronavirus cases globally are classified as severe, and a further five per cent are classified as critical, according to the World Health Organisation, but scientists still dont know why some people are more susceptible to serious illness than others. Long says the group is exploring the effects of diabetes, obesity and age, factors which have already been shown to potentially link to coronavirus susceptibility. But the group is going beyond these factors, also looking at differences in infection between genders as well as socioeconomic status.

Long says she brings the patient-focused angle to the research hub via TTMI which is based in St Jamess Hospital, allowing for a close collaboration between the lab-based scientists of the TBSI and the clinicians based in St Jamess.

Its nice to have a situation where you have clinicians that are dealing with the patients, that are making clinical observations that we dont see that form scientific questions that then we can try and answer in the lab, says Long. I think thats a really nice dimension.

Underpinning all the work being done in the COVID-19 Research Hub is a continued focus on testing, an area that has improved dramatically since March and April when the research hub was formed but can be improved even further.

Its nice to have a situation where you have clinicians that are dealing with the patients, that are making clinical observations that we dont see that form scientific questions that then we can try and answer in the lab

What were developing is a high throughput assay that will be completed in two hours and doesnt require a swab, you only need saliva, says Mills. A faster, less invasive test like this could significantly improve testing capacity and shorten the current wait time to receive test results which is currently around two to three days, according to the HSE.

Antibody tests are also being developed, which can identify what percentage of the population has been exposed to and produced an immune response to the virus. Those who have antibodies against the coronavirus are less likely to become reinfected, says Mills.

All of these research areas complement the existing vaccine clinical trials that have resulted in the first non-trial patient in the UK receiving the Pfizer-BioNTech vaccine this past week. Pfizer and their competitor Moderna are both using mRNA-based vaccines, a technology never before approved for use as a drug.

The RNA vaccines are pretty interesting because they were seen as fringe in the vaccine world for a long time, commented ONeill. He said he and the whole scientific community are waiting to see more hard data as the vaccines are rolled out but there is no reason not to trust the results coming out so far.

As enthusiastic as these researchers are about the progress being made, Long acknowledges that these things dont happen overnight. These things are slow, and things are moving relatively quickly. Theyre not as quick as we would like, she says. But these are unprecedented times. I am optimistic. ONeill agrees: Ive no doubt at all, if we fast forward even three months from now, therell be progress thatll give us hope.

ONeill thinks one of the most critical parts of making progress over the next few months will be an effective information campaign from the government about what to expect from a coronavirus vaccination. He thinks letting people know that there may be mild side effects that can be managed with paracetamol, releasing all the efficacy data about the vaccines to the public and ensuring that taking the vaccine is voluntary will be essential.

The RNA vaccines are pretty interesting because they were seen as fringe in the vaccine world for a long time

You say look, if you take this vaccine, youre protecting the community its not about you, he said. Because remember, 97, 98 per cent of people get over this virus and wouldnt need a vaccine anyway. Its the three per cent you want to protect with the vaccination program. He hopes that this approach will inspire people to respond to the greater good and get vaccinated for the benefit of the community.

Buoyed by the SFI grant after an initial investment of 2.4 million from Allied Irish Banks, the COVID-19 Research Hub scientists are also involved in several international collaborations with labs in the US, the UK, the Netherlands and Hong Kong.

Ultimately, these researchers hope that the establishment of the COVID-19 Research Hub will not just help fight the current pandemic, but future diseases as well. Thats sort of the long-term aim: to be ready to deal with the next pandemic, which may not be a SARS virus. It could be something else we dont know thats coming down the line, says Mills.

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Therapeutic Hopes: Meet the Minds Behind Trinity's COVID-19 Research Hub - The University Times