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Archives for: August 2008

27/08/08

Permalink 02:47:13 pm, by Tom, 1094 words, 3442 views   English (UK)
Categories: Information

The long road to Lucentis

Patients in England suffering from wet form of age related macular degeneration (AMD), a leading cause of blindness, received some good news this week when the National Institute for Health and Clinical Excellence (NICE) announced that they should get access to the drug Lucentis on the NHS thanks to a deal struck with drug's manufacturer, Novartis. A key feature of wet AMD is the excessive growth of blood vessels which tend to leak and damage the tissues of the eye.

http://news.bbc.co.uk/1/hi/health/7582242.stm.

This is excellent news since Lucentis has been shown to be highly effective in slowing the progression of wet AMD and preventing blindness. Lucentis is a mouse monoclonal antibody fragment that binds to and inhibits a chemical messenger called vascular endothelial growth factor A (VEGF-A) that is required for the growth of blood vessels, and by doing so prevents the growth of blood vessels that is responsible for the damage seen in wet AMD.

This is perhaps an opportune moment to look at the basic animal research that eventually lead to the development of Lucentis. Doctors and scientists have been interested in the role of blood vessel proliferation, or angiogenesis, in disease for a long time, but in the early days they were mostly interested whether it played a role in cancer. Studies done on rats by Warren Lewis at the Johns Hopkins University in the mid 1920's showed that the growth of blood vessels varied between different tumour types. Shortly after that J. Sandison introduced a key invention, a transparent chamber that could be inserted into an animal tissue and allowed microscopic observation of living tissues underneath a glass coverslip. With this chamber scientists could study the growth of tumours and their effect on the surrounding tissue in living animals. In 1939 Gordon Ide at Rochester University demonstrated that tumours transplanted into rabbits only grew if blood vessels proliferated around the tumour site, a result that was subsequently verified and advanced by Glenn Algire and colleagues at the National Cancer Institute who studied the ability of transplanted tumours to grow in mice and hypothesized that the ability to promote blood vessel growth was a crucial property of aggressive tumours (1). The next major development came in 1968 when two groups, Melvin Greenblatt and Philippe Shubik at Chicago Medical School, and Robert Ehrmann and Mogens Knoth at Harvard Medical School, showed that cancer cells transplanted into hamster cheek pouches promoted blood-vessel proliferation even when a filter was placed between the tumour and the host, demonstrating that a diffusible factor (or factors) was responsible for promoting angiogenesis. Now the search was on to identify those factors.

In 1971 Judah Folkman and colleagues published a paper (2) describing how a factor they named tumour angiogenesis factor (TAF) could be isolated from animal and human tumours and promoted blood vessel growth when injected into rats. Judah Folkman later went on to develop sensitive in vitro assays for angiogenesis, but the rat assay was vital to his early work and angiogenesis and to evaluation of the later in vitro assays. In the decades the discovery of TAF several other angiogenesis factors were identified.

The discovery of VEGF happened when a group of scientists lead by Harold Dvorak noticed that the blood vessels surrounding tumours in guniea pigs were unusually permeable, or leaky, and that that permeability was important to tomour growth(3). They proceeded to isolate a factor, initially named vascular permeability factor (VPF), that was responsible for this increased permeability (4). In 1989 researchers lead by Napoleone Ferrara identified a protein secreted by bovine pituitary cells that promoted angiogenesis and which they named vascular endothelial growth factor (VEGF) (1) . Subsequent gene sequencing demonstrated that VPF and VEGF were the same protein, a key regulator of angiogenesis during both tumour growth and normal processes such as wound healing and embryonic development. The next step was to examine whether it was possible to safely block the activity of VEGF, and in 1993 scientists at Genentech Inc. demonstrated that a monoclonal antibody that bound to VEGF could greatly reduce the growth of tumours that had been implanted in mice by preventing blood vessel proliferation, even though it had no effect on the same tumour cells in vitro(5).

The discovery that by blocking VEGF you could potentially treat cancer lead to the development of drugs such as Genentech's Avastin, but that is perhaps a story for another day. It was known that proliferation of leaky blood vessels was a major factor in wet AMD, and that patients with the disease had high levels of VEGF in their eyes, so VEGF was a tempting target for inhibition. A study published in 2002 demonstrated that a mouse monoclonal antibody fragment, subsequently named Ranibizumab/Lucentis, developed by Genentech could prevent experimental induction of blood vessel formation in the eyes of monkeys (6). Other studies with monkeys were performed to discover the amount of Lucentis that needed to be injected into the eye so that it remained in the retina and vitreous of the eye in sufficient concentrations for long enough to effectively block VEGF (7), and these showed that the amount required was acceptable for trials in humans. They also demonstrated that level of Lucentis subsequently detected in the blood was very low as it was cleared quite rapidly, which was good news given the potential of an anti-VEGF drug to interfere with normal processes such as wound healing. These important results provided the information needed to design clinical trails in human patients.

The process leading to the development of Lucentis is an excellent example of how basic research into "interesting" biological processes leads to medical advances.

Cheers

Paul

1) Ferrara N. "VEGF and the quest for tumour angiogenesis factors." Nat Rev Cancer. Volume 2(10), pages 795-803 (2002).
2) Folkman J.et al. "Isolation of a tumour factor responsible for angiogenesis" J Exp Med. Volume133(2), pages 275–288 (1971).
3) Dvorak H.F. et al."Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression." J Natl Cancer Inst. Volume 62(6), pages1459-1472 (1979).
4) Senger D.R. et al. "Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid." Science Volume 219(4587), pages 983-985 (1983).
5) Kim K.J. et al. "Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo" Nature Volume 362(6423), pages 841-844.
6) Krzystolik M.G. et al. "Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment." Arch Ophthalmol. Volume120(3), pages 338-346 (2002).
7) Gaudreault J. "Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration" Invest Ophthalmol Vis Sci. Volume 46(2), pages 726-33 (2005)

25/08/08

Permalink 01:18:44 pm, by Tom, 716 words, 2150 views   English (UK)
Categories: Information

Taking a BiTE out of non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma (NHL) is a diverse family of cancers that affect a part of the body's immune system known as the lymphatic system. In NHL white blood cells become cancerous and develop into tumours at key points in the lymphatic system known as the lymph nodes, before spreading to other tissues. About 50,000 Americans develop NHL every year, and while effective treatments such as Rituximab are available they don't work for all patients and every year NHL kills nearly 20,000 people in the USA.

So it's not surprising that the news that Blinatumomab, a novel treatment developed by the German firm Micromet, has performed very well in early clinical trials has been greeted with enthusiasm by cancer research charities and the stock market alike.

In the trials (1) published this week in the prestigious journal Science Blinatumomab was given to 38 NHL patients who had not responded to other treatments. In 7 of these patients tumours were found to have shrunk dramatically while in 4 patients the tumours disappeared completely. Blinatumomab is the first BiTE antibody to enter clinical trials, and its innovative design combines a portion of an antibody, a protein produced by the immune system that binds to foreign material in the body, that targets the cancer cell with a portion of an antibody that binds to the T-cells of the immune system. The BiTE antibody directs the T-cell to the cancer cell, which the T-cell then destroys. Blinatumomab was developed after earlier studies using animal models of NHL had shown that antibodies could direct T-cells to target cancer cells, and it was hoped that the BiTE antibodies would do this more effectively. Of course before it was assessed in human clinical trials the BiTE antibody Blinatumomab was studied in mouse models of NHL, since it was important to determine that they could target circulating immune cells to the tumours (2).

The contribution of animal research to the development of Blinatumomab was not limited to the evaluation of anti-cancer activity and pre-clinical safety, it was also crucial to manufacturing Blinatumomab itself*. BiTE antibodies are produced by heavily modifying a type of antibody known as a monoclonal antibody that binds very specifically to a particular target in the body. The first step of monoclonal antibody production is the immunization of an animal, usually a rodent, with the protein such as a cancer cell protein to which you wish the antibody to bind. Animals are required for this step because an immune system is needed to produce the immune cells that recognize the target protein, and humans cannot be used for this process both because they cannot be injected with a disease-bearing agent in order to make antibodies, and because the human body does not produce antibodies to the human proteins that researchers often wish to target. Blood samples containing cells that produce antibodies against the foreign protein are then taken from the animal. These antibody producing cells are fused with a special cancer cell to produce a hybrid cell, or hybridoma, which can be grown almost indefinitely in the petri dish and produce a large supply of monoclonal antibodies. These monoclonal antibodies can then in their turn be modified to produce antibody derived drugs such as Rituximab and Blinatumomab.

We hope that larger trials of Blinatumomab against NHL confirm the results of this early trial, and that it will go on to be a valuable addition to the range of treatments available to fight this deadly disease.

* While hybridoma based monoclonal antibody production methods have been very successful, and are vital to current efforts to develop antibody based medicines, replacement technologies that require far fewer animals are currently being developed. In the coming decades it is hoped that hybridoma based methods will increasingly be replaced by rapidly improving in vitro technologies, for example antibody phage libraries that display vast numbers of human or animal antibody fragments and can be used to identify antibodies specific for a particular target.

Paul Browne

1) Bargou R. et al. "Tumor regression in cancer patients by very low doses of a T cell-engaging antibody." Science Volume 321(5891), pages 974-977 (2008).

2) Dreier T. et al. "T cell costimulus-independent and very efficacious inhibition of tumor growth in mice bearing subcutaneous or leukemic human B cell lymphoma xenografts by a CD19-/CD3- bispecific single-chain antibody construct." J. Immunol. Volume 170(8), pages 4397-4402 (2003)

11/08/08

Permalink 03:31:28 pm, by Tom, 451 words, 2861 views   English (UK)
Categories: Information

A new malaria vaccine from Oxford

Scientists at the Jenner Institute in Oxford are at the forefront of efforts to develop vaccines against Malaria, and this week the BBC reports that they have developed a new vaccine that they hope will protect against malaria. You can read the BBC report.

Malaria kills over a million people each year, mostly in developing nations, and even when it doesn't kill it places an enormous burden on already very stretched public health systems. A vaccine that prevents it or helps sufferers to recover more quickly is much needed, and developing one is seen as a priority by organizations such as the Bill & Melinda Gates Foundation http://www.gatesfoundation.org/default.htm.

The malaria is parasite is transmitted to humans by the mosquito, and once in the bloodstream they travel to the liver where they multiply for several days before rupturing the liver cells and infecting red blood cells. Once in the blood cells the parasites begin a cycle of infection, multiplication and rupture that is responsible for the fever and leads to the other deadly effects of malaria. The only vaccine that has been successful in human clinical trials is the RTS,S vaccine that prompts the immune system to attack the malaria parasite while it is in the liver, but scientists also wish to develop a vaccine that targets the parasite while it is in the blood stage of its life cycle.

The new vaccine developed by Dr. Simon Draper and his colleagues (1) is based on genetically modified viruses which present fragments of protein from the malaria parasite to the cells of the immune system, and stimulates the immune system of mice to destroy the blood stage malaria parasite. While mice do not normally suffer from the malaria parasite species that infect humans they were able to show that this method protected mice from infection by a lethal strain of Plasmodium yoelii, a species of malaria parasite that infects mice. Subsequently they found that when they immunized mice with a vaccine made from protein fragments from Plasmodium falciparum, the most dangerous human malaria parasite, the mice produced antibodies that could prevent the growth of P.falciparum/ in vitro/. These results provide strong evidence that this vaccine strategy will also protect against the malaria species that infect humans. Following the success of the animal tests human trials are expected to start next year, beginning with small scale trials to see if it can protect against laboratory strains of the malaria parasite and if those are successful moving on to larger field trials in countries where malaria is endemic.

Cheers

Paul

1) Draper S.J et al. "Effective induction of high-titer antibodies by viral vector vaccines" Nature Medicine Vol. 14(8), pages 819-821 (2008)

05/08/08

Permalink 06:18:35 pm, by Tom, 1262 words, 2077 views   English (UK)
Categories: Information

Scientists 1: Animal Rights Extremists 0 (A new proof that mice and other mammals are good experimental models to understand human biology)

The architecture of haematopoiesis – which is the process by which all blood cells originate – is essentially the same throughout the mammal world, report scientists in the Proceedings of the Royal Society (1). This is an unexpected result considering the thousands of mammals’ species with a myriad of habitats and lifestyles, as so well demonstrated when comparing the 30 mm flying bumblebee bat and the 30 metre-long aquatic blue whale both mammals. But the work now published shows that the variations in the blood system - necessary to adapt to the evolutionary changes found within the mammals’ world - can be explained quantitatively (for example by producing more cells or having the cells dividing faster), and are directly correlated to the animals’ body mass and do not require any fundamental alteration in the haematopoietic process.

This unified view of haematopoiesis - where both its architecture and function is maintained throughout a group as important as the mammals - have many and important implications. For a start it gives support to the view that mice and other small mammals are good experimental models to understand humans’ physiology as well as to develop new treatments to human diseases. And used directly in humans these results can help improve things as diverse as bone marrow transplants or leukaemia’s treatments just to mention a few examples

The amazing complexity of the biological world can be explained (and predicted) mathematically and formulas that relate different biological functions, anticipating how a system will perform, are major tools to understand living organisms. One such example is allometric scaling a mathematical technique that describes the relationships between the rate of some biological variables (for example the number of cell divisions per time) and the organism’s body mass. In biology size is crucial as all body functions are related to the animal’s metabolism, and this is linked to its body mass. So, in fact, many biological variables can be directly correlated to mass. Allometric scaling formulas describe these relationships and are used to understand and even predict the behaviour of the body.

And a phenomenon that recently has been linked to mass via allometric models is haematopoiesis - the process by which all blood cells are formed, from platelets (crucial to blood coagulation) to white blood cells (the basis of the immune response) and red blood cells ( responsible for carrying oxygen throughout the body to all cells).

Scientists know that the haematopoietic process is organised as a tree where hematopoietic stem cells (HSC) - which have the ability to differentiate into all the different blood cells - represent the trunk from which a multitude of branches comes out, each dividing again and again, until in the end a type of blood cell is generated. It is also known that HSC are divided into two groups, quiescent HSC - which serve as a reserve pool - and active HSC - those that divide and differentiate into the many blood cells. Although the basis of the whole process is relatively well known, the possible differences between very different animals - for example humans and insects or even the bumblebee bat and the blue whale - are much less clear

And, as HSC are the root of the whole haematopoietic process, to understand better their behaviour in different animals has been seen as a way to get closer to the real nature of haematopoiesis changes throughout the different animals.

And in fact, recent research is beginning to give us some clues on what can be going on. For a start, through mathematical reasoning it has been shown in several mammals how HSC proliferation is related to the animal’s body mass, with these cells dividing faster in smaller organisms. These results, obtained by mathematical deduction, were supported by experimental work (so done in a laboratory) in non-human primates that revealed that the smaller the primates, the faster was their HSC proliferation. Finally it was also shown that active HSC from different organisms when grown in laboratory– so out of the body– divided at very similar rates, a result strikingly different from what was seen when their division was measured inside the animal. This last result further supported the idea that the organisms’ metabolism affected HSC division explaining the different division rates found in different sized animals.

All these observations led David Dingli, a haematologist from the Mayo Clinic in Minnesota USA, together with two theoretical physicists, Arne Traulsen and Jorge M. Pacheco respectively from the Mayo Clinic in Minnesota USA, the Max Planck Institute for Evolutionary Biology in Germany and the Department of Physics at Lisbon University in Portugal, to decide to use allometric tools to understand HSC behaviour and the possible haematopoiesis changes throughout mammal’s evolution.

Their first results predicted that HSC replicate faster in a mouse than in a cat than in a human and they were even able to calculate the approximate HSC divisions’ rate in each of these species. Both results were supported by experimental data from other researchers, showing the validity of the allometric scaling approach used by Dingli, Traulsen and Pacheco.

Their second prediction involved the number of divisions that any given HSC goes during its life time, which they concluded was constant among mammals, something that has been proposed before but never proved. Dingli, Traulsen and Pacheco, however, could explain this allometrically since, even if smaller animals have faster HSC divisions, bigger animals with slower HSC rates compensate this by having a longer life expectancy.

To further confirm their model the researchers calculated the daily bone marrow production of HSC in several mammals to find that the number of cells found by them were compatible with those obtained by directly working in animals, with the number of cells produced by a mouse during its lifetime (around 2 years) similar to the ones produced by humans in one day, and cats in a week. These results supported the validity of the scientists’ first two findings and their model. It also revealed how the haematopoietic demands of different animals is so very different.

Dingli, Traulsen and Pacheco’s results, together with experimental data by others, strongly support the idea of a common hematopoietic process, at least among mammals, despite the changes that appeared throughout evolution within this group. Adaptation to the different needs of different mammals is simply a question of quantity - different HSC numbers or division rates - directly related to the animal’s body mass and without affecting the basic architecture and functions of the haematopoietic process. In this way smaller animals, like mice, as they need less active HSC differentiating, may simply have a bigger HSC quiescent compartment After all, the main principle of evolutionary biology is “maintain what is effective, adapting in simple ways to higher complexities when necessary”.

Dingli, Traulsen and Pacheco’s work clearly shows how mathematical modelling – so many time ignored by pure biologists - can help understand complex biological systems. The model here described can now, for example, help to predict the minimum number of cells necessary for an optimum bone marrow transplant, or bone marrow dynamics both in health or disease or even how to better extrapolate to humans, experimental results found when studying HSC in animal models. And it is, no doubt, an important support for the validity of using of animal models to understand the biology of humans, contrary to the opinion of so many animal rights groups.

By

Catarina Amorim


1) Dingli D., Traulsen A., Pacheco J.M. “Dynamics of haemopoiesis across mammals” Proceedings of the Royal Society - advance online publication – http://journals.royalsociety.org/content/w253174843634560/

02/08/08

Permalink 05:47:55 am, by Tom, 1099 words, 8793 views   English (UK)
Categories: Information

Attacking Alzheimer's disease from every angle

Alzheimer’s disease is the most common form of dementia in Britain, and affects over 25 million people worldwide. The proportion of the population at risk of the disease is expected to rise as the populations in industrialized countries age. The characteristic feature of Alzheimers’s disease is the presence in the brain of two different kinds of abnormal protein structures, the amyloid plaques that are formed from the amyloid beta peptide along the outside of the nerve cells, and the neurofibrillary tangles (NFTs) that are formed by the tau protein inside the nerve cells. As the disease progresses the NFTs become progressively more widespread, leading to nerve cell death, loss of cognitive function and ultimately severe dementia. The Alzheimers Association provides an excellent "brain tour" introduction to the biology of the disease http://www.alz.org/alzheimers_disease_4719.asp. Unfortunately there are at present few effective treatments available, and while drugs such as Aricept (donepezil) can improve the quality of life of sufferers they appear to have little impact on overall disease progression. New drugs that can slow down, halt or even reverse disease progression are urgently needed, so the news this week that three drugs which work in different ways have performed well in early clinical trials is very welcome.

The first trial was a Phase II clinical trial of the drug PBT2 in 78 patients suffering from mild to moderate Alzheimer’s disease, and targeted the amyloid plaques that form early in the course of the disease. The trial results showed that those taking PBT2 showed improvements in cognitive function over the duration of the trial when compared to both their own performance at the outset of the trial and that of those taking a placebo. http://esciencenews.com/articles/2008/07/29/alzheimers.disease.patients.show.improvement.trial.new.drug
PBT2 acts by moving zinc and copper ions from outside to inside the nerve cells, and since the amyloid plaques form outside the nerve cells and require zinc and copper ions to form this inhibits the development of the plaques. The development of PBT2 was greatly assisted by the availability of transgenic mice which have mutations in the gene that encodes the amyloid beta peptide precursor and develop many of the symptoms of Alzheimer’s disease (1). Using these mouse models of Alzheimer’s disease Dr. Ashley Bush and colleagues at the University of Melbourne and Prana Biotechnology Ltd were able to show that PBT2 was more effective at blocking amyloid plaque formation and cognitive decline than earlier drugs that they had been studying, and these promising results lead to the trial whose results were announced this week.

The second trial targeted the other type of abnormal protein structure associated with Alzheimer’s disease, the neurofibrillary tangle, and again in a Phase II trial Alzheimer’s disease patients taking drug Rember showed dramatic improvement over those taking a placebo pill http://www.guardian.co.uk/science/2008/jul/30/medicalresearch.health. Rember is a curious drug, it’s actually a chemical called Methylthioninium chloride that has been used medically in the past for a range of conditions, and 20 years ago Professor Claude Wischnik accidently discovered that it could disentangle the bundles of tau proteins in NFTs in vitro. A team of scientists at TauRX Therapeutics Ltd lead by Professor Wischik developed mouse models of Alzheimers to evaluate whether this in vitro observation could translate into a drug that could stop the progression of Alzheimer’s disease http://www.taurx.com/science_aggregation_hypothesis.aspx

These two trials go some way to finally resolving a debate that has divided the Alzheimer’s disease for decades, namely whether amyloid plaques or NFTs are primarily responsible for causing nerve cell death in Alzheimer’s disease. Since the mid 1990’s a series of transgenic mouse models of Alzheimer’s disease have been developed, and have taught researchers a lot about how the disease progresses. In particular the transgenic mouse models have demonstrated that while amyloid plaque formation can trigger and accelerate the development of Alzheimer’s disease the formation of NFTs is required for nerve cell death to occur and the full clinical symptoms to be displayed (2). As a consequence over the past decade many researchers have begun to study treatments that target NFT formation as well as those that target amyloid plaques. It seems that both sides of the debate were at least half right!

The final trial to report is once again a phase II trail, this time of an antihistmine that was approved in Russia a couple of decades ago but has since been replaced by newer drugs. In a phase II trial of 183 patients with mild to moderate Alzheimer’s disease Dimebon was found to improve cognitive ability wwithout causing any serious side effects http://news.bbc.co.uk/1/hi/health/7511949.stm.
The team undertaking this work do not yet know how Dimebon combats Alzheimer’s disease, but suspect that it may act by preserving the function of energy producing subcellular organelles called mitochondria and thereby preventing nerve cell death. The decision to undertake clinical trials of Dimebon in Alzheimer’s disease was prompted by a study published in 2000 showing that it had neuroprotective properties in a rat model of Alzheimer’s disease (3).

These three clinical trials all illustrate how important animal research is to the development of treatments for Alzheimer’s disease, by contributing to our understanding of how the disease develops and by providing us with disease models that we can use to evaluate potential treatments. It’s worth remembering though that these are Phase II trials, and as Tom mentioned in his last post adverse effects are often not identified until the drugs are tested on thousands of patients in Phase III trials. It’s possible, even probable, that not all these drugs will be approved by the FDA and go into clinical use, and if they do it will be in four or five years time. This caveat shouldn’t however diminish our optimism at the end of what has been a very exciting week for Alzheimer’s disease research, for the first time we have clinical trial evidence that Alzheimer’s can be stopped in its tracks.

Cheers
Paul

1) Adlard P.A. et al. “Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta” Neuron. Volume 59(1), Pages 43-55 (2008).

2) McGowan E. et al. “A decade of modeling Alzheimer’s disease in transgenic mice.” Trends Genet. Volume 22(5), pages 281-289 (2006).

3) Lermontova N.N. et al. “Dimebon improves learning in animals with experimental Alzheimer’s disease.” Bull Exp Biol Med. Volume 129(6), Pages 544-546 (2000).

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