Therapeutic antibody targeting of individual Notch receptors

This recent paper, published in Nature, follows the ideas covered in Ronald Levy's lecture of using antibodies to target proteins related to cancer (although in this case, the cancer in question is not B Cell Lymphoma). Receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. The researchers have found that using antibodies to selectively block the Notch1 receptor successfully inhibits tumor growth in pre-clinical models.

http://www.nature.com/nature/journal/v464/n7291/full/nature08878.html

Immune Signatures to Predict Successful Kidney Transplants

More than half of kidney transplants from deceased donors fail within 10 years, requiring the recipient to go on dialysis or get another transplant. These failures are usually the result of immune rejection, a return of the original kidney disease, or even the effect of drugs used for immunosuppression. However, there are some recipients who, even after stopping their medications, never reject the donated kidney. Why?

Recent evidence suggests that there might be biological markers, or more critically genetic signatures, that enable some people to be less susceptible to transplant rejection. Blood tests have shown that these patients make more B cells and are more likely to have activated versions of three genes on their B cells. In addition, almost all of them lacked antibodies specifically aimed against the donated kidney. Other researchers are trying to use kidney biopsies to assess rejection risk and to develop of risk-scoring formula based on genetic features found to predict transplant failure. Thus far, their predictions have been fairly accurate.

Such immune signatures are beginning to emerge and be recognized by researchers in the lab. Slowly the predictions are becoming more accurate for who will and who won't reject a kidney transplant. The next step is to figure out a way to make such predictive information more accessible and useful to clinics to help determine which patients could be taken off their harsh immunosuppressive drugs without high risk of losing the organ.

Breast Cancer Vaccine Successful in Mice

Scientists at Ohio's Cleveland Clinic have a new vaccine in the works that they hope will prove capable of preventing breast cancer. The vaccine introduces a protein found in most breast cancers but not in healthy women, except during lactation. As is the goal of vaccines, the introduction of this protein will allow the body's immune system to recognize and target cells expressing the protein. This would allow cancerous tissue to be destroyed without damaging surrounding healthy breast tissue.

As of yet, the vaccine has only been tested in mice--the FDA will require much more rigorous testing before trials can begin in humans. However, the vaccine was able to significantly prevent the occurrence of breast cancer in the mice. Further experiments need to be done, but the hope is that one day this vaccine can be offered to women at higher risk for breast cancer, namely women over 40 and those with a genetic predisposition or family history. Dr. Vincent Tuohy, the study's principal investigator and an immunologist at the Cleveland Clinic's Lerner Research Institute believes it will take at least 10 years before the vaccine is approved, probably even more.

Influenza Vaccine for Egg-Allergic Patients-- What's safe?

The journal Pediatrics published their report entitled "Safety of Influenza Vaccine Administration in Egg-Allergic Patients." As influenza vaccine manufacturers (except for cell-culture processed vaccine manufacturers such as Novartis) use eggs to to culture the inactive virus, influenza prophylaxis is a concern for individuals with egg allergies. Current guidelines recommend that all people with egg allergies receive a skin test before getting the vaccine; as only 20-30% of the population receives the vaccine as it is, this rate is much lower for people with egg allergies with this additional requirement.

The authors of this article questioned if the current guidelines for egg-allergic people could be loosened, increasing their vaccine utilization. To do this, they conducted a retrospective chart-review study of egg-allergic patients who did receive the skin test or a two dose graded vaccine (which the authors argue can be an alternative option). They found that of the patients who first received the skin test, 95% went on to tolerate the vaccine without serious side effects. Of the 115 patients who did not receive the skin test, 97% tolerated the vaccine without serious side effects. The authors argue that this data suggests that patients with food-allergies (as long as they are without anaphylaxis to egg) can safely receive the two-dose, graded vaccine without the skin test

Do you think these findings support alteration of the current guidelines, in order to increase the rate of vaccination in this population?

Image source: http://discovermagazine.com/2009/jul-aug/27-vaccine-production-horribly-outdated-3-ways-fix-it/vaccine_egg.jpg

Article source: http://pediatrics.aappublications.org/cgi/content/full/125/5/e1024

Probiotic Cheese Boosts Immune System in Elderly

Why We Should all Start Eating More Cheese

According to a study in theFEMS Immunology & Medical Microbiology, eating probiotic cheese on a daily basis can help preserve and enhance the immune system. Because it is a carrier for probiotic bacteria, a population of elderly showed increase immunity to disease.

In the study, three different trials were run: phase I (two weeks, 15g/day) was breakfast consumption of a control cheese, phase II (four weeks 15g/day) was the intervention and participants consumed a similar cheese containing Danisco probiotics (109 CFU/dose), and phase III (four weeks) control cheese again.

The HOWARU® Rhamnosus (Lactobacillus rhamnosus HN001) and HOWARU® Dophilus (Lactobacillus acidophilus NCFM), enhanced cheese from the second phase increased phagocytic and Natural Killer cell activity and blood indicators of immune activity. This observation relates to the observed benefits of yogurt on immunity, vitamin D, and the bad effects of fatty foods that weaken the immune system.

http://www.foodproductdesign.com/news/2010/05/probiotic-cheese-boosts-immune-systems-in-elderly.aspx

Universal Flu Vaccine

Researchers at Mt. Sinai Medical School are looking into creating a universal influenza vaccine. A "headless" form of the vaccine has been tested in mince and has proven to prevent against influenzas that killed other mice. They say that with more development this technology will be applicable to humans.

Flu vaccines today allow the body to create antibodies against the "heads" of the virus as seen in the picture above. That portion of the virus is very specific and changes rapidly- which is why we get a new vaccine every year as the prevalent strain changes. The new vaccines allow the body to create vaccines against the lower portion of the hemaglutinin, which does not change as often.

"Through further development and testing, we predict that a single immunization with a headless HA vaccine will offer effective protection through several influenza epidemics," Peter Palese of Mt. Sinai Medical School stated.

The hope is that the possibility of a universal flu vaccine could open the door to other types of universal vaccines.

Read More http://www.wired.com/wiredscience/2010/05/universal-flu-vaccine/#ixzz0p3YTmVmF

New Therapeutic Target for Diabetes

Dysfunction of beta cells in the pancreas underlies diabetes onset; this dysfunction is in part initiated by inflammation mediated by cytokines. Previously, there has been a call for more research on the mechanism by which beta cells respond to cytokines if protective therapies were available.

Researchers at the Indiana University School of Medicine have done just this, identifying the role of a particular protein-- eIF5A. By depleting this specific protein, preventing it from becoming active, and blocking its modification to contain hypsusine, mice were protected from developing diabetes. The researchers, under Dr. Raghavendra G. Mirmira, found that eIF5A was involved in the production of pro-inflammatory cytokines that leads to islet dysfunction and thus diabetes onset. They propose that a new form of therapy should capitalize on these mice trials that show that eIF5A depletion and hypusination inhibition protects against glucose intolerance .

Article Source: http://www.jci.org/articles/view/38924?key=b2bc783a7aa254cd4fbd and http://www.jci.org/articles/view/38924?key=b2bc783a7aa254cd4fbd

Image Source: http://www.babble.com/CS/blogs/strollerderby/2009/02/diabetes_0.jpg

Antibacterials, Immunology and Allergies

Why Have Peanut Allergies Tripled in a Decade?

The rate of childhood peanut allergies has more than tripled from 1997 to 2008 (nationwide survey in Journal of Allergy and Clinical Immunology). Other research concluded that more than three million Americans report peanut and/or tree nut allergies; these high rates suggest a significant health burden to the population that requires attention and a response from the public health field.

The main theory for this spike in food allergies is attributed to the overly sterile environments of many households today. Schools have become flooded with anti-bacterial hand lotions and in turn banned peanuts from lunchboxes. According to Dr. Delespesse, a professor at the Université de Montréal Faculty of Medicine, “There is an inverse relationship between the level of hygiene and the incidence of allergies and autoimmune diseases. The more sterile the environment a child lives in, the higher the risk he or she will develop allergies or an immune problem in their lifetime.”

Overwhelming our bodies with germ killing agents and antibacterials leaves our immune system in a vulnerable state to substances that were previously harmless in pollen, food, and animal dander. Normally the development of the immune system is spurred by bacteria and viruses; By removing the bacteria and viruses that previously entered the body through dirt, our immune system cannot develop properly.

The new public health debate is engaged trying to pick apart the apparent trade off between sterile environemnt which have clear implications for decreasing some diseases and the seemingly related increase in autoimmune diseases.

http://www.care2.com/greenliving/why-have-peanut-allergies-tripled-in-a-decade.html?page=2

IDEC-C2B8 (Rituximab) Shows Promise for Treatment of Low-Grade NHL

Treating cancer always involves trade-offs. Although many are treated using the shotgun approach with chemotherapy, the side effects resulting from such treatments can be just as awful as the disease itself. Furthermore, since chemotherapy doesn't discriminate between cancerous and noncancerous cells, a patient's immune system is compromised, leaving this person vulnerable to deadly infections. Fortunately new, more targeted treatments that avoid some of these pitfalls are being developed.

Non-Hodgkin's Lymphoma (NHL), a cancer affecting B lymphocytes, has been particularly difficult to treat since most patients undergo a series of treatments with chemotherapy, each with increasing toxicity and decreasing bone marrow reserves, until they eventually die either from the disease or from an opportunistic infection. The Levy Lab at Stanford has been conducting studies with a monoclonal antibody called IDEC-C2B8 (Rituximab) that targets CD20, an antigen specific to the B cells, and, thus far, it seems to show great promise. IDEC-C2B8 is a chimera of murine (mouse) variable regions with human IgG1 and κ constant regions. This hybrid allows researchers to use a NHL mouse model while preventing rejection by patients.

In a somewhat recent (2007) study, patients were given 4 infusions peripherally with IDEC-C2B8 MoAbs and complete or partial clinical responses were observed in 37% of these patients. Since CD20 is not expressed on differentiated ab secreting plasma cells, IgG, IgA, and IgM antibody levels experienced only transient decreases, if at all. Though some side-effects were reported, most were mild. The median time to progression for the clinical responders was 10.2 months, with 5patients exceeding 20 months and 2 patients exceeding 30 months. Future research hopes to test extended and repeated dosing times and combination with or after standard chemotherapy. Already CD20 antibodies armed with small radioactive particles that deliver radiation directly to non-Hodgkin’s lymphoma cells have been used as well. Obviously there are huge upsides to this type of treatment and the future certainly looks bright.

Prothymosin-alpha: CD8+ T cells Blocking HIV

For several years, researchers at Duke University Medical School and Mount Sinai School of Medicine have been trying to understand the role that prothymosin-alpha, a molecule generated by CD8+ T cells, plays in blocking HIV viral replication in virally-infected cells. They've just published a new paper revealing what they believe is the mechanism by which prothymosin-alpha accomplishes this anti-HIV response.

CD8+ T cells, which can have potent anti-HIV activity, produce prothymosin-alpha which then binds to TLR4, a common pattern recognition receptor found on the surface of numerous immune cells and is typically associated with lipopolysaccharide (LPS) recognition to initiate immune responses against gram-negative bacteria. Binding of prothymosin-alpha to TLR4 in macrophages induces production of type I interferons, cytokines famous for their anti-viral capacities.

Such research is interesting for two main reasons. Firstly, we see a novel mechanism by which cells of the adaptive immune system, CD8+ T cells, can induce an anti-viral response via interaction with the innate immune system, i.e. the TLR4 signaling and production of interferons in macrophages. Secondly, this indicates to us that there are naturally occurring molecules produced by immune cells in the body that have anti-HIV activity, and such a discovery could potentially lead to very beneficial therapeutic research.

Biosimilars: An Obstacle to Innovation and Safety

I respectively disagree about the field of biosimilars. Sure, they might create a more competitive market for many biologics, but at what cost? Not only does Pfizer plan to heavily invest in the market of biologics, Merck, another very large pharmaceutical company has announced that it also plans to completely shift its focus to biosimilars. This shift of priorities means that there will be a global decrease in resources used to pursue novel drugs, and less incentive to do so for companies still trying to develop new biotechnological therapeutics. On average, the development of a novel drug costs 1.2 billion dollars and takes about 12 to 15 years. By shortening the patent life on biologics and decreasing the potential profit of developing a novel drug to make room for biosimilars, it is no longer in a company’s best interest to do novel research.

Aside from stunting new biotechnological research, biosimilars also pose many safety concerns that have not yet been addressed by the FDA. Although biosimilars may treat similar diseases, their safety profiles will not be identical. The immunogenicity of the drugs can widely vary with only a subtle change in the manufacturing process. Pharmacovigilance should be absolutely mandatory, but will be very difficult if manufacturer’s products are not clearly distinguished. This problem will be especially difficult if biosimilars have the same international non-proprietary name (INN) as the inventor. Uncontrolled substitution of biosimilars will greatly confound accurate pharmacovigilance because as stated previously, biosimilars are not identical. If a pharmacist chooses a biosimilar from the same INN class as the drug prescribed, or if a doctor simply prescribes an INN class and the pharmacist is forced to choose a manufacturer, the safety of the therapeutic will be greatly decreased.

Biosimilars will unquestionably become a very important part of the future healthcare landscape, we will just have to wait and see whether the effects are positive or negative.

Sources:
Nowicki, Michal. Kidney Blood Press Res. 2007, 30, 267–272.

http://www.pharmalot.com/2008/12/merck-wants-to-develop-follow-on-biologics/

http://www.america.gov/st/econ-english/2008/April/20080429230904myleen0.5233981.html

http://www.arena-international.com/pharma/biosimilars/