̽��ֱ�� of Cambridge - Bill and Melinda Gates Foundation

Monoclonal antibodies offer hope for tackling antimicrobial resistance

cjb250 — Mon, 16 Sep 2024 10:31:11 +0000

A team lead by researchers at the ̽��ֱ�� of Cambridge has developed a monoclonal antibody drug, using a technique involving genetically engineered mice, that may help prevent infection from Acinetobacter baumannii, a bacteria associated with hospital-acquired infections, which is particularly common in Asia.

A. baumannii bacteria can cause life-threatening respiratory illness and sepsis in vulnerable individuals, particularly in newborn babies whose immune systems have not fully developed. It is usually spread through contaminated surfaces, medical equipment and via contact with others. In recent years infections with strains of this bacteria that are resistant to almost every antibiotic available have become common.

Professor Stephen Baker from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the ̽��ֱ�� of Cambridge said “A. baumannii is good at sticking to medical equipment, and if people are vulnerable or don't have a particularly well-developed immune system, they can succumb to this infection and get aggressive pneumonia requiring ventilation – and in many cases, the patients can acquire the infection from the ventilation itself.

“ ̽��ֱ��bacteria are naturally resistant to many antimicrobials, but as they’re now found in hospitals, they’ve acquired resistance to almost everything we can use. In some hospitals in Asia, where the infections are most common, there isn't a single antibiotic that will work against them. They’ve become impossible to treat.”

In a study published today in Nature Communications, the team produced monoclonal antibodies using transgenic mice – mice that have been genetically-engineered to have a human-like immune system, producing human antibodies instead of mouse antibodies. They went on to show that these monoclonal antibodies were able prevent infection with A. baumannii derived from clinical samples.

Monoclonal antibodies are a growing area of medicine, commonly used to treat conditions including cancer (for example, Herceptin for treating some breast cancers) and autoimmune disease (for example, Humira for treating rheumatoid arthritis, psoriasis, Crohn's disease, and ulcerative colitis).

Usually, monoclonal antibodies are developed from the antibodies of patients who have recovered from an infection, or they are designed to recognise and target a particular antigen. For example, monoclonal antibodies targeting the ‘spike protein’ of the SARS-CoV-2 coronavirus were explored as a way of treating COVID-19.

In the approach taken by the Cambridge team, however, transgenic mice were exposed to the outer membrane of A. baumannii bacteria, triggering an immune response. ̽��ֱ��researchers then isolated almost 300 different antibodies and tested which of these was the most effective at recognising live bacteria, identifying the single monoclonal antibody mAb1416 as the best.

Professor Baker said: “Using this method, we don't infect the mice with the live bacteria, but we instead immunise them using multiple different elements and let the mouse’s immune system work out which ones to develop antibodies against. Because these mice have ‘humanised’ immune systems, we wouldn’t then need to reengineer the antibodies to work in humans.”

̽��ֱ��team treated mice with mAb1416, and 24 hours later exposed them to A. baumannii isolated from a child with sepsis in an intensive care unit. They found that those mice treated with the drug saw a significant reduction in bacterial load in their lungs a further 24 hours later, compared to mice that were not treated.

All of the isolates used to produce and test the monoclonal antibodies were from patients in Ho Chi Minh City, Vietnam, but the isolate used to test mAb1416 was taken from a patient ten years later than the other isolates. This is important because it shows that mAb1416 was protective against A. baumannii bacteria that may have evolved over time.

Professor Baker said: “Using this technique, you can take any bacterial antigen or cocktail of antigens, rather than waiting for somebody that's recovered from a particular infection – who you assume has developed an appropriate antibody response – give it to the mice and extract the antibodies you think are the most important.”

More work is now needed to understand the mechanism by which mAb1416 protects against infection, as this could allow the team to develop an even more effective treatment. Any potential new drug will then need to be tested in safety trials in animals before being trialled in patients.

Professor Baker added: “We know that monoclonal antibodies are safe and that they work, and the technology exists to produce them – what we have done is identify how to hit bacteria with them. Apart from the cost effectiveness, there's no reason why this couldn’t become a medicine within a few years. Given the emergency presented by antimicrobial resistance, this could become a powerful new weapon to fight back.”

̽��ֱ��research was funded by the Bill & Melinda Gates Foundation, the UK Medical Research Council Newton Fund, the Viet Nam Ministry of Science and Technology, and Wellcome.

Professor Baker is a fellow at Wolfson College, Cambridge.

Reference
Baker, S, Krishna, A & Higham, S. Exploiting human immune repertoire transgenic mice to identify protective monoclonal antibodies against an extensively antimicrobial resistant nosocomial bacterial pathogen. Nat Comms; 12 Sept 2024; DOI: 10.1038/s41467-024-52357-8

Monoclonal antibodies – treatments developed by cloning a cell that makes an antibody – could help provide an answer to the growing problem of antimicrobial resistance, say scientists.

We know that monoclonal antibodies are safe and that they work, and the technology exists to produce them – what we have done is identify how to hit bacteria with them

Stephen Baker

TopMicrobialStock (Getty Images)

A Petri dish with a culture of the Superbug Acinetobacter baumannii next to antibiotics

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Gates Cambridge: Class of 2022

mjg209 — Thu, 21 Apr 2022 10:30:21 +0000

Meet some of this year’s 79 new scholars from 30 countries – including Sanjiv Ranchod from South Africa who will be starting a PhD in Computer Science in October.

Key mutations in Alpha variant enable SARS-CoV-2 to overcome evolutionary weak points

cjb250 — Tue, 29 Jun 2021 07:00:14 +0000

SARS-CoV-2 is a coronavirus, so named because spike proteins on its surface give it the appearance of a crown (‘corona’). ̽��ֱ��spike proteins bind to ACE2, a protein receptor found on the surface of cells in our body. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. ̽��ֱ��virus manipulates the host cell’s machinery to allow the virus to replicate and spread.

As SARS-CoV-2 divides and replicates, errors in its genetic makeup cause it to mutate. Some mutations make the virus more transmissible or more infectious, some help it evade the immune response, potentially making vaccines less effective, while others have little effect.

Towards the end of 2020, Cambridge scientists observed SARS-CoV-2 mutating in the case of an immunocompromised patient treated with convalescent plasma. In particular, they saw the emergence of a key mutation - the deletion of two amino acids, H69/V70, in the spike protein. This deletion was later found in B1.1.7, the variant that led to the UK being forced once again into strict lockdown in December (now referred to as the ‘Alpha variant’).

Now, in research published in the journal Cell Reports, researchers show that the deletion H69/V70 is present in more than 600,000 SARS-CoV-2 genome sequences worldwide, and has seen global expansion, particularly across much of Europe, Africa and Asia.

̽��ֱ��research was led by scientists at the ̽��ֱ�� of Cambridge, MRC- ̽��ֱ�� of Glasgow Centre for Virus Research, ̽��ֱ��Pirbright Institute, MRC Laboratory of Molecular Biology, and Vir Biotechnology.

Professor Ravi Gupta from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the ̽��ֱ�� of Cambridge, the study’s senior author, said: “Although we first saw this mutation in an immunocompromised patient and then in the Kent – now ‘Alpha’ – variant, when we looked at samples from around the world, we saw that this mutation has occurred and spread multiple times independently.”

Working under secure conditions, Professor Gupta and colleagues used a harmless form of the virus that displays SARS-CoV-2 spike proteins with the H69/V70 deletion to understand how the spike protein interacts with host cells and what makes this mutation so important.

When they tested this virus against blood sera taken from fifteen individuals who had recovered from infection, they found that the deletion did not allow the virus to ‘escape’ neutralising antibodies made after being vaccinated or after previous infection. Instead, the team found that the deletion makes the virus twice as infective – that is, at breaking into the host’s cells – as a virus that dominated global infections during the latter half of 2020. This was because virus particles carrying the deletion had a greater number of mature spike proteins on their surface. This allows the virus to then replicate efficiently even when it has other mutations that might otherwise hinder the virus.

“When viruses replicate, any mutations they acquire can act as a double-edged sword: a mutation that enables the virus to evade the immune system might, for example, affect how well it is able to replicate,” said Professor Gupta.

“What we saw with the H69/V70 deletion was that in some cases, the deletion helped the virus compensate for the negative effects that came with other mutations which allowed the virus to escape the immune response. In other words, the deletion allowed these variants to have their cake and eat it – they were both better at escaping immunity and more infectious.”

Dr Dalan Bailey from ̽��ֱ��Pirbright Institute, who co-led the research, added: “In evolutionary terms, when a virus develops a weakness, it can lead to its demise, but the H69/V70 deletion means that the virus is able to mutate further than it otherwise would. This is likely to explain why these deletions are now so widespread.”

Bo Meng from the Department of Medicine at the ̽��ֱ�� of Cambridge, first author on the paper, said: “Understanding the significance of key mutations is important because it enables us to predict how a new variant might behave in humans when it is first identified. This means we can implement public health and containment strategies early on.”

̽��ֱ��research was supported by Wellcome, the Medical Research Council, the Bill & Melinda Gates Foundation and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

Reference
Meng, B, Kemp, SA, Papa, G, Datir R, Ferreira, IATM et al. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role 1 in the Alpha variant B.1.1.7. Cell Reports; 8 June 2021; DOI: 10.1016/j.celrep.2021.109292

One of the key mutations seen in the ‘Alpha variant’ of SARS-CoV-2 – the deletion of two amino acids, H69/V70 – enables the virus to overcome cracks in its armour as it evolves, say an international team of scientists.

Understanding the significance of key mutations is important because it enables us to predict how a new variant might behave in humans when it is first identified. This means we can implement public health and containment strategies early on

Bo Meng

Kevin Grieve

Man walking past Stay Alert/Save Lives artwork

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Public Domain

Gates Cambridge class of 2021

mjg209 — Wed, 14 Apr 2021 09:39:01 +0000

Gates Cambridge, Cambridge's leading international postgraduate scholarship programme, announces its Class of 2021: 74 new Gates Cambridge Scholars-Elect will take up their postgraduate studies in October.

Study highlights risk of new SARS-CoV-2 mutations emerging during chronic infection

cjb250 — Fri, 05 Feb 2021 16:00:48 +0000

Writing in Nature, a team led by Cambridge researchers report how they were able to observe SARS-CoV-2 mutating in the case of an immunocompromised patient treated with convalescent plasma. In particular, they saw the emergence of a key mutation also seen in the new variant that led to the UK being forced once again into strict lockdown, though there is no suggestion that the variant originated from this patient.

Using a synthetic version of the virus Spike protein created in the lab, the team showed that specific changes to its genetic code – the mutation seen in the B1.1.7 variant – made the virus twice as infectious on cells as the more common strain.

SARS-CoV-2, the virus that causes COVID-19, is a betacoronavirus. Its RNA – its genetic code – is comprised of a series of nucleotides (chemical structures represented by the letters A, C, G and U). As the virus replicates itself, this code can be mis-transcribed, leading to errors, known as mutations. Coronaviruses have a relatively modest mutation rate at around 23 nucleotide substitutions per year.

Of particular concern are mutations that might change the structure of the ‘spike protein’, which sits on the surface of the virus, giving it its characteristic crown-like shape. ̽��ֱ��virus uses this protein to attach to the ACE2 receptor on the surface of the host’s cells, allowing it entry into the cells where it hijacks their machinery to allow it to replicate and spread throughout the body. Most of the current vaccines in use or being trialled target the spike protein and there is concern that mutations may affect the efficacy of these vaccines.

UK researchers within the Cambridge-led COVID-19 Genomics UK (COG-UK) Consortium have identified a particular variant of the virus that includes important changes that appear to make it more infectious: the ΔH69/ΔV70 amino acid deletion in part of the spike protein is one of the key changes in this variant.

Although the ΔH69/ΔV70 deletion has been detected multiple times, until now, scientists had not seen them emerge within an individual. However, in a study published today in Nature, Cambridge researchers document how these mutations appeared in a COVID-19 patient admitted to Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust.

̽��ֱ��individual concerned was a man in his seventies who had previously been diagnosed with marginal B cell lymphoma and had recently received chemotherapy, meaning that that his immune system was seriously compromised. After admission, the patient was provided with a number of treatments, including the antiviral drug remdesivir and convalescent plasma – that is, plasma containing antibodies taken from the blood of a patient who had successfully cleared the virus from their system. Despite his condition initially stabilising, he later began to deteriorate. He was admitted to the intensive care unit and received further treatment, but later died.

During the patient’s stay, 23 viral samples were available for analysis, the majority from his nose and throat. These were sequenced as part of COG-UK. It was in these sequences that the researchers observed the virus’s genome mutating.

Between days 66 and 82, following the first two administrations of convalescent sera, the team observed a dramatic shift in the virus population, with a variant bearing ΔH69/ΔV70 deletions, alongside a mutation in the spike protein known as D796H, becoming dominant. Although this variant initially appeared to die away, it re-emerged again when the third course of remdesivir and convalescent plasma therapy were administered.

Professor Ravi Gupta from the Cambridge Institute of Therapeutic Immunology & Infectious Disease, who led the research, said: “What we were seeing was essentially a competition between different variants of the virus, and we think it was driven by the convalescent plasma therapy.

“ ̽��ֱ��virus that eventually won out – which had the D796H mutation and ΔH69/ΔV70 deletions – initially gained the upper hand during convalescent plasma therapy before being overtaken by other strains, but re-emerged when the therapy was resumed. One of the mutations is in the new UK variant, though there is no suggestion that our patient was where they first arose.”

Under strictly-controlled conditions, the researchers created and tested a synthetic version of the virus with the ΔH69/ΔV70 deletions and D796H mutations both individually and together. ̽��ֱ��combined mutations made the virus less sensitive to neutralisation by convalescent plasma, though it appears that the D796H mutation alone was responsible for the reduction in susceptibility to the antibodies in the plasma. ̽��ֱ��D796H mutation alone led to a loss of infection in absence of plasma, typical of mutations that viruses acquire in order to escape from immune pressure.

̽��ֱ��researchers found that the ΔH69/ΔV70 deletion by itself made the virus twice as infectious as the previously dominant variant. ̽��ֱ��researchers believe the role of the deletion was to compensate for the loss of infectiousness due to the D796H mutation. This paradigm is classic for viruses, whereby escape mutations are followed by or accompanied by compensatory mutations.

“Given that both vaccines and therapeutics are aimed at the spike protein, which we saw mutate in our patient, our study raises the worrying possibility that the virus could mutate to outwit our vaccines,” added Professor Gupta.

“This effect is unlikely to occur in patients with functioning immune systems, where viral diversity is likely to be lower due to better immune control. But it highlights the care we need to take when treating immunocompromised patients, where prolonged viral replication can occur, giving greater opportunity for the virus to mutate.”

̽��ֱ��research was largely supported by Wellcome, the Medical Research Council, the National Institute of Health Research, and the Bill and Melinda Gates Foundation.

Reference
Kemp, SA et al. SARS-CoV-2 evolution during treatment of chronic infection. Nature; 5 Feb; DOI: 10.1038/s41586-021-03291-y

SARS-CoV-2 mutations similar to those in the B1.1.7 UK variant could arise in cases of chronic infection, where treatment over an extended period can provide the virus multiple opportunities to evolve, say scientists.

Given that both vaccines and therapeutics are aimed at the spike protein, which we saw mutate in our patient, our study raises the worrying possibility that the virus could mutate to outwit our vaccines

Ravi Gupta

NIAID

3D print of Spike protein

Yes

Licence type:

Attribution

Technique to regenerate the optic nerve offers hope for future glaucoma treatment

cjb250 — Thu, 05 Nov 2020 10:00:30 +0000

Axons – nerve fibres – in the adult central nervous system (CNS) do not normally regenerate after injury and disease, meaning that damage is often irreversible. However, over the past decade there have been a number of discoveries that suggest it may be possible to stimulate regeneration.

In a study published today in Nature Communications, scientists tested whether the gene responsible for the production of a protein known as Protrudin could stimulate the regeneration of nerve cells and protect them from cell death after an injury.

̽��ֱ��team, led by Dr Richard Eva, Professor Keith Martin and Professor James Fawcett from the John van Geest Centre for Brain Repair at the ̽��ֱ�� of Cambridge, used a cell culture system to grow brain cells in a dish. They then injured their axons using a laser and analysed the response to this injury using live-cell microscopy. ̽��ֱ��researchers found that increasing the amount or activity of Protrudin in these nerve cells vastly increased their ability to regenerate.

Nerve cells in the retina, known as retinal ganglion cells, extend their axons from the eye to the brain through the optic nerve in order to relay and process visual information. To investigate whether Protrudin might stimulate repair in the injured CNS in an intact organism, the researchers used a gene therapy technique to increase the amount and activity of Protrudin in the eye and optic nerve. When they measured the amount of regeneration a few weeks after a crush injury to the optic nerve, the team found that Protrudin had enabled the axons to regenerate over large distances. They also found that the retinal ganglion cells were protected from cell death.

̽��ֱ��researchers showed that this technique may help protect against glaucoma, a common eye condition. In glaucoma, the optic nerve that connects the eye to the brain is progressively damaged, often in association with elevated pressure inside the eye. If not diagnosed early enough, glaucoma can lead to loss of vision. In the UK, round one in 50 people over the age of 40, and one in ten people over the age of 75 is affected by glaucoma.

To demonstrate this protective effect of Protrudin against glaucoma, the researchers used a whole retina from a mouse eye and grew it in a cell-culture dish. Usually around a half of retinal neurons die within three days of retinal removal, but the researchers found that increasing or activating Protrudin led to almost complete protection of retinal neurons.

Dr Veselina Petrova from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, the study’s first author, said: “Glaucoma is one of leading causes of blindness worldwide. ̽��ֱ��causes of glaucoma are not completely understood, but there is currently a large focus on identifying new treatments by preventing nerve cells in the retina from dying, as well as trying to repair vision loss through the regeneration of diseased axons through the optic nerve.

“Our strategy relies on using gene therapy – an approach already in clinical use – to deliver Protrudin into the eye. It’s possible our treatment could be further developed as a way of protecting retinal neurons from death, as well as stimulating their axons to regrow. It’s important to point out that these findings would need further research to see if they could be developed into effective treatments for humans.”

Protrudin normally resides within the endoplasmic reticulum, tiny structures within our cells. In this study, the team showed that the endoplasmic reticulum found in axons appears to provide materials and other cellular structures important for growth and survival in order to support the process of regeneration after injury. Protrudin stimulates transport of these materials to the site of injury.

Dr Petrova added: “Nerve cells in the central nervous system lose the ability to regenerate their axons as they mature, so have very limited capacity for regrowth. This means that injuries to the brain, spinal cord and optic nerve have life-altering consequences.

“ ̽��ֱ��optic nerve injury model is often used to investigate new treatments for stimulating CNS axon regeneration, and treatments identified this way often show promise in the injured spinal cord. It’s possible that increased or activated Protrudin might be used to boost regeneration in the injured spinal cord.”

̽��ֱ��research was supported by the Medical Research Council, Fight for Sight, the Bill and Melinda Gates Foundation, Cambridge Eye Trust and the National Eye Research Council.

Reference
Petrova, V et al. Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat Comms; 5 Nov 2020; DOI: 10.1038/s41467-020-19436-y

Scientists have used gene therapy to regenerate damaged nerve fibres in the eye, in a discovery that could aid the development of new treatments for glaucoma, one of the leading causes of blindness worldwide.

It’s possible our treatment could be further developed as a way of protecting retinal neurons from death, as well as stimulating their axons to regrow

Veselina Petrova

TobiasD

Eye

Yes

Licence type:

Public Domain

Gates Cambridge

cg605 — Wed, 12 Sep 2018 13:32:50 +0000