BIO News

C&I Issue 7, 2012

Worm pigment may aid organ transplants

A respiratory pigment from marine worms could hold the key to ‘at least doubling’ the time period over which organs donated for transplantation can be stored and used.

Getting donor organs to patients is a race against the clock and surgeons currently have just 12 hours or less in which to receive organs such as kidneys, hearts and lungs ready for transplantation before they run out of oxygen and start to degrade.

However, researchers at French biotech company Hemarina have discovered a new respiratory pigment that may allow organs to be stored for up to one week, according to chief scientific officer and founder Franck Zal – potentially saving thousands of valuable organs from being routinely discarded as waste.

Unlike human haemoglobin (Hb) and most other animal respiratory pigments, Zal explained that the annelid Hb occurs outside cells, and can be easily extracted free from contaminants that may cause complications or side effects. The big advantage is that it is universally compatible across all human blood types so there is no need for matching of different blood groups to prevent rejection, Zal said.

It also means that organs from rare matched tissue types could be flown across the world, as well as giving recipients more time to prepare for surgery.

‘Organs such as the kidneys and pancreas need oxygen to survive but the current option is just to store them in saline ready for transplantation, ‘ Zal explained. ‘We are the best option to keep organs alive for longer.’

Hemarina is currently filing the technology with French regulators and is hopeful it could be approved as early as the end of 2013.

Like human Hb, the pigment is composed of protein globin strands, but the annelid version has 156 of them – meaning that it can carry 156 molecules of oxygen compared with just four molecules for human Hb. Together with the possession of a potent free radical scavenger – the enzyme superoxide dismutase (SOD) – this allows the annelid to survive for many hours without oxygen between tides, he explained.

Hemarina is also exploring the potential of the annelid Hb as a much-needed oxygen carrier for use in emergency human transfusions, such as after a car crash, and to prevent further tissue injury following a stroke. It has already been successfully transfused in animal models and the company hopes to begin human trials from 2014.

Other potential applications are to speed cell growth, useful both in wound dressings and in commercial bioreactors. Oxygen stimulates the production or turnover of new cells, while the presence of SOD bolsters the body’s ability to combat infection, particularly by anaerobic bacteria, Zal said. In tests in bioreactors, the pigment has been reported to increase production yields by 30 to 80%, which would dramatically lower the costs of expensive cell cultures and medicines.

Kidney injury hope

Acute kidney injury (AKI), which occurs when the organs are damaged, can result in the need for dialysis, extended hospital stays and the development and exacerbation of chronic kidney disease, as well as an increased risk of mortality. Now, researchers at US biotech AlloCure have developed what could be the first effective therapy for AKI using stem cells derived from donated adult bone marrow – a claim backed up the granting of a fast-track designation for the therapy by US regulators in December 2012.

In a recent Phase 1 trial on 16 patients who had recently undergone heart bypass or valve surgery, the therapy lowered the risk of developing AKI – only two people or 12% developed AKI, compared with 30% from a cohort of matched historical controls, according to AlloCure ceo Robert Brenner, speaking at the BIO meeting in Boston in June. The study also found that the therapy reduced hospital length of stay and readmission rates compared with the historical cohort, Brenner added.

AlloCure recently closed its $25m Series B financing and expects to begin a Phase 2 trial of the therapy involving 200 patients at 22 centres in the US during July 2012.

UK ‘shock’ strategy results

A meeting with Pfizer at Number 10 Downing Street in late 2011, giving notice of the planned closure of the pharma giant’s R&D facility in Sandwich in Kent, was ‘a shock to British complacency’ and prompted the UK government’s new Strategy for UK Life Sciences, admitted David Willetts, minister for universities and science.

Speaking at the BIO meeting in Boston six months after the strategy was launched in December 2011, Willetts pointed to examples such as GSK’s £0.5m investment in Cumbria and the news that Pfizer itself is putting ‘new resources’ into Cambridge and Scotland as signs it is starting to generate results.

One of the strategy’s aims is to promote faster adoption of innovative drugs and technologies by the NHS – with penalties imposed from 2013 for those that fail to adapt.

‘The central message is we want to reduce the timeline and cost of development to get to clinic; we want to make the UK the place [pharma companies] should come,’ Willetts said.

Protein PEGylation pegged

Protein or biologic drugs are gaining popularity, but their complex structures often render them poorly soluble or unstable in body fluids such as blood plasma, hampering their usefulness in the clinic.

PEGylation or the attachment of poly(ethylene glycol) polymer can make proteins more soluble, as well as improving stability. However, recent research reveals that current PEGylation methods may also make the molecules easily detectable by the body’s immune system – a finding that could explain the rapid clearance of many PEGylated drugs from the body, sometimes within just hours after administration.

Now, researchers have developed a second generation PEGylation technology, which they claim is able to better evade immune detection and thus allows protein drugs to continue working in the body for much longer.

The new PharmaPEG technology not only means that the drugs can be administered less frequently, which should lower drug costs, but will also make them more convenient for patients, according to Merry Sherman, ceo of California-based Mountain View Pharmaceuticals, the company developing the technology.

For some proteins, PharmaPEG could open the door for repeated administration of the drug over a treatment course, which may not previously have been possible because of the presence of anti-PEG antibodies in the patient’s bloodstream after prior exposure to the same or another PEGylated drug.

Current methods of PEGylation involve the attachment of methoxy-PEG (MeO-PEG) molecules to proteins, Sherman explains; however, the Mountain View researchers have found evidence that it is these MeO groups at the ends of the attached polymer chains that are eliciting the body’s immune response. The trick has been to replace these immunogenic MeO groups with OH groups, which are ubiquitous in the watery environment inside the body and so not recognised by the immune system as foreign.

In tests in animals comparing several methoxy PEGylated drugs with their equivalent PharmaPEG counterparts, the latter showed reductions in immune responses ranging from three-fold to more than 1000-fold, Sherman and colleagues reported (Bioconjugate Chem., 2012, 23, 485).

A US patent on the PharmaPEG technology was granted in March 2012 and will run to 2028 because of a five-year extension owing to delays in processing the application. At the BIO meeting in Boston in June 2012, the company announced receipt of a European patent for the production of both MeO-PEG and PharmaPEG versions of the multiple sclerosis drug interferon-beta-1b, which could lead to less frequent and better tolerated dosing regimens.

There are currently at least 10 approved PEGylated proteins or polypeptides in the marketplace, including the top-selling therapy for Hepatitis C – Roche’s Pegasys – and drugs for leukaemia and SCID or ‘Boy in the Bubble‘ syndrome.

All of them involve methoxyPEG. Many more are in the development pipeline awaiting approval. ‘In 2011, sales of the major PEGylated proteins alone totalled about $7bn and PharmaPEG has the potential to increase this market significantly,’ Sherman commented.

The company is currently in talks with a number of major pharma companies about possible licence agreements to use the technology, which could lead to products in clinical trials within three or four years, following abbreviated safety studies, according to Sherman.

Acne therapy promise for late-stage MS

The bacterium that causes acne could have a redeeming quality, researchers have discovered: a peptide-based microparticle derived from the organism may be helpful in treating multiple sclerosis (MS). Unpublished data from ongoing clinical trials by New Zealand biotech company Innate Immunotherapeutics show that the microparticle may significantly improve disease symptoms for patients in the chronic later stages of MS, the company revealed at the BIO meeting in Boston in June 2012 – the first time a therapy has promised to treat this phase of the disease.

Worldwide, there are roughly 2.5m MS sufferers and around half will go on to develop the secondary progressive form of the disease, where patients are often in constant pain, have trouble walking and going to the bathroom, and experience serious memory lapses. Currently, there are no effective drugs available to treat this progressive phase of MS.

In an ongoing Phase 2a study, 10 MS patients were administered 500μg of the drug by intravenous injection weekly for three months. At least half showed a 30% improvement in physical health parameters as monitored by assessment tools including a health questionnaire, according to Innate ceo Simon Wilkinson. Strikingly, over half were reported to have a more than 50% improvement in cognitive function such as information-processing and memory.

‘While patient numbers are still small, this result could be a game-changer in secondary progressive disease,’ says Wilkinson. ‘Before this, the aim was simply to stop or slow down disease progression in these patients. This is the first time that a therapy has actually resulted in meaningful improvements in a range of MS related symptoms.’

Regulations in New Zealand have allowed the drug to be used on compassionate grounds by four patients, one of whom has received the treatment for more than three years without adverse effects, Wilkinson added.

The microparticle works via regulatory pathways of the innate immune system, by which certain immune cells know when to start or stop an attack. Innate immune cells recognise the microparticle as foreign and so ingest the molecule, whereupon it activates protein receptors involved in signalling pathways to control the body’s immune response, Wilkinson explains. In the case of MS, the damage is caused when the body’s immune system goes out of control and attacks the insulating sheath surrounding the body’s own nerve cells.

Once the current Phase 2a study is completed later in 2012, Innate hopes to start Phase 2b trials in Australia with at least 100 patients treated for at least a year starting in 2013. The company opened a new round of funding at BIO and aims to raise $15m to fund the study.

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