Immunology and Biotherapies
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Biosimilars Savings: “...the Substance of Things Hoped For”

Biosimilars Savings: “...the Substance of Things Hoped For” | Immunology and Biotherapies | Scoop.it
Healio Rheumatology | In 2006, the European Medicines Agency approved Omnitrope, a biosimilar recombinant human growth hormone, as the first biosimilar. Over the subsequent decade, the EMA has approved additional biosimilars and, as of December 2017, 33 biosimilars were marketed in the European Union to treat a variety of conditions.Market competition in many European Economic Area countries has resulted in
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Resources for DIU Immunologie et Biothérapies

DIU Immunologie et Biotherapies is a french diploma associating many french universities and immunology laboratories. It is dedicated to the involvement of immunology in new biotherapies, either molecular or cellular

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in Immunology also use http://www.scoop.it/t/immunology

in Mucosal Immunity http://www.scoop.it/t/mucosal-immunity

in Flow Cytometry and Cytomics http://www.scoop.it/t/from-flow-cytometry-to-cytomics

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in Autoimmunity http://www.scoop.it/t/autoimmunity

 

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by MdC

 

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Pitfalls of immunotherapy: lessons from a patient with CTLA-4 haploinsufficiency | Allergy, Asthma & Clinical Immunology | Full Text

Pitfalls of immunotherapy: lessons from a patient with CTLA-4 haploinsufficiency | Allergy, Asthma & Clinical Immunology | Full Text | Immunology and Biotherapies | Scoop.it
Daclizumab is a humanized monoclonal antibody that blocks CD25, the high affinity alpha subunit of the interleukin-2 receptor. Daclizumab therapy targets T regulatory cell and activated effector T cell proliferation to suppress autoimmune disease activity, in inflammatory conditions like relapsing...
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Toxin or treatment? Peanut allergy

Toxin or treatment? Peanut allergy | Immunology and Biotherapies | Scoop.it
Ingesting small doses of peanut products guards against allergic reactions—but an undercurrent of anxiety persists.

![Figure][1]

Jacob Kingsley, 12, visits a bakery that was off-limits before he began oral immunotherapy for a peanut allergy.

PHOTO: MADDIE MCGARVEY

Jacob Kingsley was 9 years old when he was handed the poison he'd shunned since before he could walk and told to swallow it as medicine. Obediently, he gulped down a few micrograms of peanut flour—less than 1/1000 of a peanut—diluted in grape Kool-Aid. His mother and a nurse hovered, ready to inject him with epinephrine if an itchy throat and wheezing struck.

Jacob's mother, Jennifer Kingsley, had driven him 2 hours from their home in Columbus to this doctor's office in Cincinnati, Ohio, for the first of dozens of sessions of peanut immunotherapy. Giving Jacob gradually increasing doses of peanuts, she hoped, would desensitize his immune system.

It's a strategy Kingsley hadn't pursued until she reached her breaking point. A year earlier, Jacob had swallowed a handful of popcorn that, unbeknownst to him, was laced with peanut product. He suffered a particularly frightening reaction: two bouts of intense symptoms about 6 hours apart. The incident marked his second peanut-related trip to the emergency room, and Kingsley was terrified that the next encounter could be fatal. “I decided, ‘I can't live like this,’” she says. “I was desperate.”

As Jacob sat through the hourslong appointment in Cincinnati, playing video games and swigging increasing doses of peanut-spiked Kool-Aid, he joined legions of children writing food allergy's next chapter. Today, more than 3000 people worldwide, most of them children, have undergone peanut immunotherapy, with the goal of protecting them if they accidentally encounter the food. Other children are trying immunotherapy for allergies to milk, eggs, and tree nuts. Some, like Jacob, get treatment in allergists' offices, where doctors share protocols informally and in published papers. Other children have enrolled in clinical trials, including those run by two companies racing to introduce a peanut-based capsule or skin patch. Both plan to apply for approval from the Food and Drug Administration (FDA) this year. The agency's blessing would dramatically boost immunotherapy's credibility and reach.

In a field that for decades has had nothing to offer patients beyond avoidance, immunotherapy marks a seismic shift. As it edges closer to mainstream, “There's mixed feelings, with a whole range of enthusiasm,” says Corinne Keet, a pediatric allergist-immunologist at Johns Hopkins Medicine in Baltimore, Maryland. Fear that it might cause harm is mingling with euphoria that children living constrained lives could be set free. Doctors who offer immunotherapy describe families eating in Chinese restaurants for the first time and home-schooled children rejoining their peers.

Like many medical firsts, the therapy is not perfect. “This is version 1.0,” says Brian Vickery, a pediatric allergist-immunologist at Emory University in Atlanta. He has conducted peanut immunotherapy trials and worked for 2 years at Aimmune Therapeutics, headquartered in Brisbane, California, one of the companies whose products are nearing approval. Physicians fret about oral immunotherapy's rigors—treatment must continue indefinitely—and its risks, which include the same allergic reactions it aims to prevent. Last year in Japan, a child suffered brain damage during a trial of immunotherapy for milk allergies.

Meanwhile, physicians on the front lines are navigating hazy science. No one knows exactly how immunotherapy works or who's most likely to be helped or hurt by it. “For me,” Keet says, “it's really not clear for an average child with peanut allergy whether it will make sense to do oral immunotherapy or not.”

LIKE MANY WHO STUDY food allergies, Keet was enticed by their mystery. Animal models are poor. The intensity of allergic reactions varies unpredictably, even in the same person over time. Why one child outgrows an allergy and another doesn't is unknown.

“This was something we didn't cover much in medical school” in the 1990s, says Matthew Greenhawt, a pediatric allergist-immunologist at Children's Hospital Colorado in Denver. Greenhawt's career trajectory tracks with a surge in food allergies, and these days, he can barely keep up with the stream of affected children who visit his hospital. Today, between 1% and 2% of people in the United States, the United Kingdom, and several other countries are allergic to peanuts—a rate that has roughly tripled since the mid-1990s. Other food allergies, such as those to tree nuts, are also on the rise. What's causing the increase is not well understood.

Despite rising caseloads, deaths from food allergies remain rare. Precise numbers are hard to come by, and estimates range from fewer than 10 to more than 150 a year in the United States. But even though an affected child is more likely to be struck by lightning than to die of a food allergy, the risk can feel ever-present. Parents never know when their children will happen upon culprit foods and how they'll be affected if they do. “We live in a complex world—people move food all over the place,” says David Bunning, a businessman whose two sons, now adults, have multiple food allergies. “The impact on children in terms of their confidence to explore their environment can be extreme.” Bunning's family almost never traveled or ate out. At their grandparents' house, the boys were usually confined to one room where food wasn't allowed.

Bunning now chairs the board of directors at Food Allergy Research & Education (FARE), an advocacy group in McLean, Virginia. Families like his, and the doctors who cared for their children, began to agitate for new treatments about a decade ago. Immunotherapy was the obvious candidate: Injections that desensitize the immune system to pollen, grass, pet dander, and bee venom have been around for decades.

Whether for an allergy to cats or pistachios, immunotherapy aims to disrupt the cells that swing out of control when faced with an allergen. When a child who is allergic to a food eats it, food proteins cross from the digestive tract into the bloodstream. An antibody called immunoglobulin E (IgE), which is bound to white blood cells called mast cells in tissues, recognizes the culprits. IgE activates the mast cells, which release histamine and other chemicals. In the skin, that response can lead to hives; in the respiratory tract, wheezing; and in the gut, vomiting. The most serious symptoms, such as a swollen throat or a reaction throughout the body, mark anaphylaxis, which is what families fear the most. Allergy shots blunt production of IgE, in part, researchers believe, by boosting levels of certain T cells that prompt a cascade of immune changes.

![Figure][1]

Fighting fire with fire
Eating gradually increasing doses of a food allergen seems to desensitize the immune system over time. Thousands of children have tried oral immunotherapy, and a capsule to treat peanut allergies might be approved by regulators next year. But there's anxiety about the strategy's risks and unknowns.

GRAPHIC: C. BICKEL/ SCIENCE

Brief testing decades ago indicated that shots for food allergies weren't safe. So around the mid-2000s, scientists began to feed children the allergen instead. One watershed moment came in 2005, when the National Institutes of Health formed a consortium for food allergy clinical trials. A second was in 2011, when advocates sponsored a symposium at Harvard Medical School in Boston to standardize goals and strategy for the pioneering immunotherapy efforts. About 60 people attended. “The patients were very clear,” says Carla McGuire Davis, a pediatric allergist-immunologist at Texas Children's Hospital in Houston. They didn't care about eating a peanut butter sandwich; they wanted protection if they accidentally encountered one. Trialists set their end dose at a couple of peanuts and pressed ahead.

The results of early clinical trials were promising, says Hugh Sampson, a pediatric allergist-immunologist at the Icahn School of Medicine at Mount Sinai in New York City, who has studied immunotherapy in food allergies for many years. After 6 to 12 months of treatment, he says, about 70% to 80% of patients could handle higher doses of the food than before. Lab data were encouraging, too: Ingesting allergens over time seems to make mast cells less reactive, inhibiting their release of harmful chemicals. The therapy also produces other immunoglobulins: IgG4, which further inhibits mast cell activity, and IgA, which helps keep food allergens from escaping the gut (see graphic, p. 280).

The 2011 conference inspired the founding of the company now called Aimmune, fueled by more than $3.5 million from FARE. A second company, DBV Technologies, based in Montrouge, France, and New York City, expanded a few years later. Aimmune began to develop an oral product, essentially a capsule of powder derived from peanut flour with proteins held to consistent levels. In February, the company announced in a press release the results of a phase III trial involving 496 children and teenagers, with a regimen stepping up every 2 weeks through 11 dose levels. Among the 372 people in the treatment group, about 20% dropped out for various reasons, including side effects. After about a year, 96% of people who completed treatment could consume one peanut with no more than mild symptoms, 84% could tolerate two, and 63% could tolerate at least three.

DBV's skin patch represents a more conservative strategy: It delivers tiny amounts of peanut protein, the equivalent of one peanut over 3 years. Last year, DBV announced that in its phase III trial of almost 400 patients, after a year, those using the patch could, on average, eat three peanuts over the course of several hours before experiencing clinical symptoms such as vomiting or hives; before the trial, the average was just under one peanut. Outcomes varied substantially from person to person.

If one or both products are approved by FDA in the coming months, expectations are high that they'll be welcomed: Aimmune is now worth about $1.5 billion on the U.S. stock exchange. In 2016, FARE sold its share in Aimmune for $47 million.

MEANWHILE, SOME DOCTORS embrace another route: offering peanut immunotherapy in their practices. “I can treat 20 patients with $5.95 of peanut flour,” says Richard L. Wasserman, a pediatric allergist-immunologist in Dallas, Texas.

Wasserman ventured into food allergy immunotherapy 11 years ago. He developed a protocol based partly on published case reports and protocols for allergy shots, and he put IVs into his first five peanut allergy patients in case he had only seconds to rescue them from severe anaphylaxis. “When they all sailed through the first day, we stopped doing IVs,” he says. “But that's a measure of how concerned I was.”

Wasserman has since treated more than 300 children with peanut allergies and more than 400 with other food allergies. Other practitioners are joining in, among them the Cincinnati allergist whom the Kingsley family sought out: Justin Greiwe at Bernstein Allergy Group. Greiwe joined the practice in 2014, straight out of medical training. “It was a little nerve-wracking at the beginning,” he says, because no officially sanctioned oral immunotherapy protocol existed. He took precautionary measures, such as lung testing before every treatment, to help ensure patient safety.

Some clinicians—and executives at the companies developing products—aren't happy about the doctor's office treatments. “That gives a lot of us pause,” says Sampson, who in addition to his academic post is chief scientific officer of DBV. “We're very afraid that if this goes on enough, somebody is going to have an accident or a fatal reaction, and that's really going to change the FDA's viewpoint” about the products in development, he says.

Wasserman agrees about the need for caution. “Not every practicing allergist should be doing oral immunotherapy,” he says. Greiwe suggests the treatment requires a dedicated staff, and he gives every immunotherapy family his cellphone number.

Jacob was one of Greiwe's first immunotherapy patients. His mother remembers Jacob's ears burning—a minor reaction that subsided on its own. “Or he said he hated peanuts and wanted to quit,” she says. Worst was about 6 months in, when Kingsley discovered that for 2 weeks, Jacob had hidden his dose to avoid eating it. That was “the only time we ever felt danger,” she says. Stopping treatment can quickly alter the immune system, says Cecilia Berin, an immunologist at Mount Sinai, because immunotherapy requires constant exposure. When Jacob squirreled away his daily dose, the changes induced in his immune system almost certainly started to fade out, putting him at risk. Greiwe restarted him on a lower dose and, his mother says, “We got through it.”

EVEN CHILDREN WHO faithfully follow instructions face risks. The immune system can react to even subtle pressures, and the list of what can provoke a reaction to treatment is long. Exercising within a couple of hours of the dose can do it; so can a cold, a stomach virus, menstruation, or a hot shower. An asthma attack can trigger a reaction—many children with allergies have asthma as well—and so can stress. “We had a patient who had just played the violin on a stage, came down, and about 15 minutes later … took the dose and had a reaction,” Davis says.

Berin posits that external pressures such as physical activity or illness make the gut more permeable, pushing more of the immunotherapy dose into the bloodstream. But that remains hypothesis. Regardless, it's becoming clear that “there are people who react years down the road to a maintenance dose,” Keet says. For Jacob, such a moment came 9 months in. One evening while watching a movie, he downed his peanut M&M's and later ran outside with his cousins to dance in a rainstorm. He broke out in hives head to toe. Kingsley dialed Greiwe's number, and Jacob got a double dose of an allergy medication.

![Figure][1]

Food allergies are becoming more common, and a handful of foods accounts for the vast majority of allergies. But small doses of the foods can blunt allergic reactions.

PHOTO: SCIENCE PHOTO LIBRARY/SCIENCE SOURCE

The most tragic data point to date is the case in Japan. A child had enrolled in a trial of immunotherapy for milk allergies at the Kanagawa Children's Medical Center in Yokohama. He'd raised what he could ingest from less than 8 milliliters to 135 milliliters—about half a glass of milk. After 3 months on that maintenance dose, he swallowed it and soon complained of pain. Within minutes, he had stopped breathing. His heartbeat was later restored in the emergency room, but he'd gone too long without it and sustained severe brain damage, according to a statement from the hospital's president, Sumimasa Yamashita, in November 2017. Kanagawa Children's Medical Center declined to comment, saying only that the incident remains under investigation.

In its statement, the hospital noted the boy had suffered an asthma attack the day before the catastrophic dose. He also was on a protocol that aimed to rapidly escalate the volume of milk he could drink over less than 3 weeks. But why the child reacted so disastrously to that glass of milk is unknown.

“What people don't understand is this level of protection fluctuates,” says Mimi Tang, a pediatric allergist-immunologist at Murdoch Children's Research Institute in Melbourne, Australia. “It is not guaranteed, nor is it constant.”

One of the few long-term analyses was published in 2013 in The Journal of Allergy and Clinical Immunology . Keet, pediatric allergist-immunologist Robert Wood at Johns Hopkins Medicine, and their colleagues sought out 32 children who'd been in a milk immunotherapy trial. Three to 5 years later, “The results were surprising in a sobering kind of way,” Wood says. Only about a quarter “were doing great … tolerating unlimited quantities of milk without side effects.” Another quarter had abandoned the protocol and returned to strict avoidance. The rest were eating dairy products inconsistently, with intermittent or even frequent allergic reactions. “It's hard to know which comes first, whether they got complacent” about ingesting it “or backed off because [they were] having too many symptoms,” Wood says.

MORE AND MORE families are willing to live with those uncertainties because the alternative is greater anxiety. “We were scared senseless,” says Divya Balachandar, whose daughter Leena Wong, now 7 years old, had her first episode of anaphylaxis at age 4 after being touched by a cashew. Testing revealed Leena also was allergic to sesame, eggs, milk, other tree nuts, and peanuts. Balachandar, a pediatric pulmonologist in New York City, and her husband enrolled Leena in a federally funded oral immunotherapy trial for peanut allergy in 2015. “It made me nervous, really nervous, to put something in my daughter's mouth that she was allergic to,” Balachandar says. She gravitated toward a trial over treatment with a local allergist because, she says, “there were no rules” about how to treat in private practice. By this spring, Leena could eat two spoonfuls of peanut butter—about 25 peanuts—without a problem. She started second grade sitting with her classmates at lunchtime, liberated from a separate nut-free table.

Both companies developing peanut-based treatments say they had more volunteers for their trials than they could accommodate. Private practitioners usually have a waiting list; Greiwe's runs more than 4 months. At Stanford University in Palo Alto, California, which has a large food allergy research program, more than 2000 patients are waitlisted to enroll in the university's clinical trials, says Sharon Chinthrajah, an allergist-immunologist there.

More treatments are on the horizon. In Australia, Tang is working with a company that's testing an approach she pioneered, a combination of a probiotic and oral peanut immunotherapy. The probiotic should tilt the body toward producing the subset of T cells that tolerate the allergen and away from making cells that attack it, she says. Chinthrajah and others are enthusiastic about combining oral immunotherapy with a monoclonal antibody called omalizumab, which is FDA approved to treat allergic asthma. Clinical trials are also gearing up to test other monoclonal antibodies that target molecules involved in allergic inflammation.

Jacob's and Leena's families are eager to see what comes next. Jacob is also allergic to pistachios and cashews, but because he finds those foods easier to avoid than peanuts, the family has rejected immunotherapy that targets them. Leena's family is the opposite. With her older sister and her parents, Leena attends Indian functions regularly, where tree nuts are a common ingredient in sauces. In August, another episode of anaphylaxis landed her in the emergency room: She began to vomit and suffered chest tightness and eye swelling after eating Indian food her parents suspect contained cashews—despite having triple-checked with the restaurant that it did not. “I would love to do tree nuts,” Balachandar says, once immunotherapy “becomes more available and better understood.”

Physicians with deep roots in food allergy immunotherapy hope those new to it tread carefully. Doctors who offer such treatments “have to know the data cold,” including published results and side effects that may crop up, Greenhawt says. Still, he's thrilled that peanut immunotherapy treatments may soon be approved. The other day, talking with a peanut-allergic 4-year-old and his mother, Greenhawt shared what the next year might bring. “I said, ‘I'm going to see you a year from now; hopefully, we will have two products that are approved, and we can talk about which one might be best for you.’” The mother looked startled and delighted, Greenhawt says. “I've never seen somebody smile as brightly as that.”

[1]: pending:yes
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Anti-CD19 CAR-T Preclinical in vivo Assay - Creative Biolabs

Anti-CD19 CAR-T Preclinical in vivo Assay - Creative Biolabs | Immunology and Biotherapies | Scoop.it
Creative Biolabs provides GLP-compliant in vivo test services for anti-CD19 CAR-T cell therapy in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and many non-Hodgkin lymphoma (NHL).
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Adipose stem cells enhance excisional wound healing in a porcine model

Adipose stem cells enhance excisional wound healing in a porcine model | Immunology and Biotherapies | Scoop.it
Adipose-derived stem cells (ASCs) are capable of secreting regenerative growth factors
and replacing multiple tissue types. Although current literature suggests that ASCs accelerate wound healing and reduce scarring, the dose-response relationship has not been adequately investigated in large...
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A Comparison of the Conditioning Regimens BEAM and FEAM for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma: An Observational Study on 1038 Patients From Fondazione Italiana Linfomi

A Comparison of the Conditioning Regimens BEAM and FEAM for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma: An Observational Study on 1038 Patients From Fondazione Italiana Linfomi | Immunology and Biotherapies | Scoop.it
The first series of patients transplanted with autologous marrow for lymphomas was
reported in 1978, using the BACT (carmustine [bis-chloroethylnitrosourea (BCNU)]-cytarabine-cyclophosphamide-thioguanine)
regimen [1].
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Regulatory T cells in the treatment of disease

Regulatory T cells in the treatment of disease | Immunology and Biotherapies | Scoop.it
Abstract
Regulatory T (Treg) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, Treg cells are compromised. Approaches to strengthen Treg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing Treg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, Treg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of Treg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating Treg cells in autoimmune disorders, transplantation and cancer.

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FDA approves first drug designed to prevent chronic migraines

FDA approves first drug designed to prevent chronic migraines | Immunology and Biotherapies | Scoop.it
The drug, Aimovig, is a monthly injection with a device similar to an insulin pen
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Putting Natural Killer Cells to the Test in Cancer Immunotherapy

Putting Natural Killer Cells to the Test in Cancer Immunotherapy | Immunology and Biotherapies | Scoop.it
NK cells are “first responders” that rapidly detect and attack virus-infected cells and tumor cells, and can also help prevent metastasis.
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Cell Therapies in Tendon, Ligament, and Musculoskeletal System Repair. - PubMed - NCBI

Cell Therapies in Tendon, Ligament, and Musculoskeletal System Repair. - PubMed - NCBI | Immunology and Biotherapies | Scoop.it
Sports Med Arthrosc Rev. 2018 Jun;26(2):48-58. doi: 10.1097/JSA.0000000000000192.Review...
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Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration

Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration | Immunology and Biotherapies | Scoop.it
Immunogenicity of AAV vectors renders repeated AAV dosing ineffective. Here the authors show that coadministration of nanoparticle-encapsulated rapamycin overcomes AAV immunogenicity through Treg induction, enabling efficient AAV redosing in mice and nonhuman primates.
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JCI Insight - Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy

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Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion

Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion | Immunology and Biotherapies | Scoop.it
HIV-1 Env undergoes conformational changes after binding to host receptor CD4 that
allow coreceptor binding, resulting in fusion between host and viral membranes. Wang,
Barnes et al. solved cryo-EM structures of CD4-bound Envs, revealing the order of changes involved in coreceptor binding-site...
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Next Generation of Biosimilars and Biobetters: Challenges and Opportunities

Next Generation of Biosimilars and Biobetters: Challenges and Opportunities | Immunology and Biotherapies | Scoop.it
Next Generation of Biosimilars and Biobetters: Challenges and Opportunities 5 hours 13 min agoComments by Editors, R&D Magazine Editor's Note: This technical paper is adapted from a webinar sponsored by Dassault Systèmes and presented by Advantage Business Marketing. The webinar featured Rakesh Dixit, PhD, as the speaker, who is an expert in the field of biologics from Medimmune and who presented his insights on the future of the transformative biologics market and helped navigate the webinar discussion. Laura Panjwani, the R&D Magazine Editor, served as the moderator.The full webcast can be viewed here: https://event.webcasts.com/starthere.jsp?ei=1192416&tp_key=1cd32f57f1 The biopharmaceutical market is a rapidly growing class of therapeutics, showing significant potential in oncology, diabetes and other disease areas. Unlike conventional chemically synthesized pharmaceuticals, biopharmaceuticals—also known as biologics—are derived from living organisms, typically using biotechnology. Examples of biologics include hormones, blood products, cytokines, monoclonal antibodies (mAbs), and vaccines, as well as gene transfer, cell therapy and tissue engineered products. There are more than 300 mAbs, more than 250 vaccines, and more than 100 other biologics— including cell and gene therapies—currently in clinical development. The global biologics market is expected to reach around $291 billion in 2020 and by 2022, 50 percent of the pharmaceutical market share is expected to be in biologics. But the future of biologics won’t be focused solely on the discovery of new therapeutics. There is also a significant market for biosimilars, biologic drugs that demonstrate high similarity to an already approved biologic reference drug, and can in turn serve as an alternative to it. Biosimilars are different than generics, which are synthetic chemical copies of their reference drugs and are identical in active ingredients, strength, dosage form and route of administration. Because biologics are made with living cells and no two molecules can be exactly the same, making a copy of a biologic is a much more involved and expensive process than creating a generic drug. There will always be very subtle differences between the biosimilar and its reference biologic. There are significant benefits to biosimilars. Biosimilars are a more cost effective way to manufacture biologics, increasing the affordability of life-saving biologics to patients. They could also increase worldwide regulatory approvals, including with the U.S. FDA. The Patient Protection and Affordable Care Act was signed into law by President Barack Obama on March 23, 2010, amending the Public Health Service Act to create an abbreviated approval pathway for biosimilars that are considered “highly similar” with an FDA-approved biological product. It is expected that by 2030 the biosimilar market will be a greater than a $240 billion opportunity, as patents on major biologics continue to expire. To be approved, biosimilars need to prove a high degree of similarity in biophysical properties, safety and effectiveness to the marketed reference product. The agent must demonstrate no meaningful difference in immunogenicity and pharmacokinetic/ pharmacodynamic (PK/PD) outcomes in a well-designed clinical trial. However, lower immunogenicity and better safety are acceptable. Sources: EvaluatePharma, Cortells Challenges facing the biosimilar market Despite its potential in cost savings, the biosimilar market still faces hurdles. There are gaps in knowledge and understanding of biosimilars among the public, and that can lead to challenges with physicians and patients’ perception of the safety and efficacy of the product. Worldwide there is also a high variability in regulations regarding the approval of biosimilars. In Europe, the regulatory pathway and litigation procedures are much clearer and more defined. In the U.S., however, there are very broad IP and patent laws, which can make patent infringements a major obstacle in effective marketing. This can impact patient access and increase cost. Health plans and pharmacy benefit managers (PBMs) can also contribute to increased costs, as some require high rebates that block biosimilar access and uptake. Finally, multiple companies also often compete to make the same biosimilar of a biological drug that has recently come off patent, causing stiff competition across the market. Overcoming these obstacles To stand out from the competition, companies that make biosimilar products can consider lowering prices or offering high rebates to PBMs. However, this approach is best suited in developing countries with high price sensitivity. In more established markets for biologics, such as the U.S., Europe and Japan, pricing alone isn’t sufficient, as there typically isn’t significant price variety among similar therapeutics. It is also possible to attempt to differentiate the molecule itself by providing better tolerability. However, regulatory agencies will not typically allow bio superiority to be claimed on a label on a biosimilar product. One potentially effective way to differentiate a biosimilar is through a novel delivery device or container closure system, which improves convenience, ease of use or patient acceptability of the therapeutic from its reference product. Some design differences in the delivery device or container closure system used with the proposed biosimilar product also may be acceptable for regulatory approval of a biosimilar. For a proposed biosimilar product in a different delivery device or container closure system, the presentation must be shown to be compatible for use with the final formulation of the biological product through appropriate studies including, for example, extractable/leachable studies and stability studies. For certain design differences in the delivery device or container closure system, performance testing and a human factors study may be needed. “Biobetters” Enhancing a biosimilar with an improved or more convenient delivery system is not the only way to differentiate a product. Highly differentiated biosuperior drugs, known as “Me-Betters” (after the term “Me-Too” drugs used to describe two highly similar therapeutics) are needed to serve patients who have increasingly become resistant to current therapies/standard of care. These “Me-Betters” or “biobetters,” are new biologics based on an existing approved biologic. Biobetters can deliver the mechanism of action of potency improvements, enhanced half-life, better safety and immunogenicity, and better and broader efficacy. These biobetters may serve high unmet medical needs more rapidly than a novel therapeutic, as they often receive shorter review and more rapid approval with better reimbursement. There are numerous biosimilars and biobetters in development today. Biobetter strategy Biopharmaceutical companies have focused on several strategies to develop biobetters. They are only working with molecules that have mechanisms of action (MOA) that are clinically proven or have a proof-of-efficacy that has been established and where addition values can be gained. They are focusing on areas where there are unmet medical needs within a known class of agents, where current drugs or their biosimilars do not already serve well. They aim to create biobetters where current agents are inadequate to treat refractory patients, relapsed patients, or those that have inconvenient dosing systems or safety concerns. To do this, they are focusing on application of best science and antibody technologies to create highly differentiated and potent biologics within the same general MOA as already established agents. Pros and cons of developing biobetters There are several positive outcomes from creating a highly differentiated biosuperior drug. Unlike with a biosimilar, there is generally no need to wait for patents to expire because all biobetters are treated as new molecular entries from a regulatory perspective. Despite these benefits, developing biobetters does come with challenges. As compared to biosimilars, the regulatory process will be longer and more expensive, as the agent is treated as an entirely new entry. As a result, clinical development cost may not be too dissimilar to innovative drug development. Biobetters also face fierce challenges for demonstrating superiority in efficacy or safety against established biologics and market leaders, and unless the benefits are superior to biosimilars, the higher costs of biobetters may be questioned. It can be complex to establish biosuperority, and not every attempt at doing so will be successful. Credit: Medimmune Credit: Medimmune One example of an extremely successful biobetter is Humira (adalimumab), an immunosuppressive drug used to treat arthritis, plaque psoriasis, ankylosing spondylitis, Crohn’s disease, and ulcerative colitis and other diseases. Humira works by binding to tumor necrosis factor-alpha (TNFα), which normally binds to TNFα receptors, leading to the inflammatory response of autoimmune diseases. Humira was the third TNF inhibitor, after infliximab and etanercept, to be approved in the U.S. A “biobetter” of the two agents, it was constructed from a fully human monoclonal antibody, which was an improvement over infliximab, a mouse-human chimeric antibody, and etanercept, a TNF receptor- IgG fusion protein. Humira resulted from collaboration between BASF Bioresearch Corporation and Cambridge Antibody Technology (CAT), which became MedImmune in 2007. The key to Humira’s discovery was the “phage display” method discovered at MedImmune. As of 2017, the drug has made more than 18 billion in the U.S.   Credit: Medimmune Conclusion Biosimilars have tremendous potential to reduce the high cost of biologics and increase the affordability of biologics medicines. However, there are still barriers to the market’s success on the large scale, including patent limitations and legal challenges, a fractionated market, high discount expectations from PBMs and physician and patient acceptance. For innovation companies, highly differentiated and technologically advanced biobetters offer the greatest potential to mitigate the risks associated with the introduction of biosimilars, as they can be approved before the patent expires and have blockbuster potential. However, strategy is key, as long development time, high cost, and uncertainty in biosuperiority over existing drugs can hinder the success of a biobetter agent. RELATED READS
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Advances in Blockchain Enabling Advances in Medicine

Advances in Blockchain Enabling Advances in Medicine | Immunology and Biotherapies | Scoop.it
Since stem cells have the ability to turn into various other types of cells, scientists believe that they can be useful for treating and understanding Since stem cells have the ability to turn into various other types of cells, scientists believe that they can be useful for treating and...
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T cell bispecific antibody for the immune-mediated killing of HER2+ breast cancer cells

T cell bispecific antibody for the immune-mediated killing of HER2+ breast cancer cells | Immunology and Biotherapies | Scoop.it
Researchers show that the p95HER2-T cell bispecific antibody (TCB) can successfully guide immune cells, known as lymphocytes, directly to cancerous ones for their targeted killing. This direct delivery is achieved thanks to the p95HER2 protein, which is only located in tumor cells.
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Response to therapeutic monoclonal antibodies for multiple myeloma in African Americans versus whites - Chehab - - Cancer - Wiley Online Library

Background Myeloma occurs disproportionately in African Americans, with disparities in outcomes potentially caused by access to care, cytogenetics, and immunity. A gap in knowledge of immune function dissimilarities between African Americans and whites exists. Data for other diseases suggest innate differences in immunity and inflammatory markers, with potential implications for therapeutic monoclonal antibodies reliant on secondary immune activation for activity. Methods Patients receiving daratumumab or elotuzumab, lenalidomide, and dexamethasone were retrospectively studied with a primary endpoint of response at 2 (daratumumab) or 4 months (elotuzumab). Secondary endpoints included stable disease or better at the same points, treatment duration, time to best response, and adverse events. Results Eighty patients were included; baseline characteristics were balanced with the exception of the stage at diagnosis, which was more advanced in African Americans. No statistically significant difference in response was seen: 37.9% in whites versus 11.8% in African Americans with daratumumab (P = .090) and 60% in whites versus 44% in African Americans with elotuzumab (P = .462). There were no differences in the duration of treatment, the time to best response, or adverse events. Common potential immune‐related adverse events in both arms were fatigue (39%), back pain (30%), and infusion reactions (40%). Anemia was significantly associated with a response to daratumumab (P = .02); no patients without anemia responded at 2 months, whereas 34.4% of patients with anemia did. Conclusions No significant difference in response, duration of treatment, or time to response was seen by race, although a trend toward greater early response rates in whites was observed. In these cohorts, as in other analyses, African American patients tended to present with later stage disease.
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PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells

PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells | Immunology and Biotherapies | Scoop.it
Author Summary Congenital infection by human cytomegalovirus (HCMV) might result in permanent neurological sequelae, including sensorineural deafness, cerebral palsies or devastating neurodevelopmental abnormalities.
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Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques

Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques | Immunology and Biotherapies | Scoop.it
Author summary Tuberculosis (TB), a lung disease caused by the bacterial pathogen Mycobacterium tuberculosis, is endemic in many developing countries. This infection is transmitted from a person with active tuberculosis through coughing, talking, and singing. Exposure to this bacterium can result in a spectrum of infection outcomes, including in the majority of persons asymptomatic infection, known as latent TB. However, re-exposure to those with active disease occurs frequently, particularly in crowded conditions. Here we demonstrate that ongoing Mtb infection in a non-human primate model provides robust protection against reinfection and disease. This has important implications for vaccine development against this infection.
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CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells

CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells | Immunology and Biotherapies | Scoop.it
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Mechanisms of molecular resistance and predictors of response to biological therapy in inflammatory bowel disease

Biological therapy has led to marked improvements in treatment of patients with inflammatory
bowel disease, and an increasing number of drugs has been approved for treatment. However, only a subgroup of patients responds to therapy, highlighting the need to identify biomarkers for therapeutic...
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[Academic] Public Knowledge and Perceptions of Monoclonal Antibodies Survey [18+] : datascience

[Academic] Public Knowledge and Perceptions of Monoclonal Antibodies Survey [18+] : datascience | Immunology and Biotherapies | Scoop.it
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Science + Science Writing: The Wild West of stem cell therapy | ScienceWriters2018

Science + Science Writing: The Wild West of stem cell therapy | ScienceWriters2018 | Immunology and Biotherapies | Scoop.it
Twenty years ago, in November 1998, human embryonic stem (ES) cells were introduced to the world. Derived in a nondescript laboratory at the University of Wisconsin, the master cells of human development sparked immediate hope for an inexhaustible supply of cells for therapy to potentially treat conditions such as Parkinson’s, diabetes, heart disease, spinal cord injury, and other disorders. ES cells are now widely used in research and for industrial applications such as drug screening. Their use in the clinic has lagged, but as of late 2017 at least 18 clinical trials in six countries have been launched to test the therapeutic efficacy of ES cells. In the meantime, the advent of induced pluripotent stem cells, where skin and other adult cells are genetically reprogrammed to behave like stem cells, coupled with a dearth of regulation, has enabled unproven treatments to come to market, in some cases with tragic consequences. This session will explore the Wild West landscape of stem cell therapy and how to separate legitimate science from snake oil. Social media hashtag: #WildWestStemCells
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Feasibility of desensitizing children highly allergic to peanut by high‐dose oral immunotherapy - Reier‐Nilsen - - Allergy - Wiley Online Library

1 Background There are limited data on the feasibility, efficacy and safety of high‐dose oral immunotherapy (OIT) in children highly allergic to peanuts. 2 Objective In children highly allergic to peanut, we primarily aimed to determine the feasibility of reaching the maximum maintenance dose (MMD) of 5000 mg peanut protein or, alternatively, a lower individual maintenance dose (IMD), by OIT up‐dosing. Secondarily, we aimed to identify adverse events (AEs) and determine factors associated with reaching a maintenance dose. 3 Methods The TAKE‐AWAY peanut OIT trial enrolled 77 children 5‐15 years old, with a positive oral peanut challenge. Fifty‐seven were randomized to OIT with biweekly dose step‐up until reaching MMD or IMD and 20 to observation only. Demographic and biological characteristics, AEs, medication and protocol deviations were explored for associations with reaching maintenance dose. 4 Results All children had anaphylaxis defined by objective symptoms in minimum two organ systems during baseline challenge. The MMD was reached by 21.1%, while 54.4% reached an IMD of median (minimum, maximum) 2700 (250, 4000) mg peanut protein, whereas 24.5% discontinued OIT. During up‐dosing, 19.4% experienced anaphylaxis. Not reaching the MMD was caused by distaste for peanuts (66.7%), unacceptable AEs (26.7%) and social reasons (6.7%). Increased peanut s‐IgG4/s‐IgE ratio (OR [95% CI]: 1.02 [1.00, 1.04]) was associated with reaching MMD. 5 Conclusion Although 75.5% of children with peanut anaphylaxis reached a maintenance dose of 0.25‐5 g, only 21.1% reached the MMD. Distaste for peanuts and AEs, including high risk of anaphylaxis, limited the feasibility of reaching MMD.
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Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis.

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis. | Immunology and Biotherapies | Scoop.it
A new interesting article has been published in Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.and titled: Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: …...
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Allogeneic BK Virus–Specific T Cells for Progressive Multifocal Leukoencephalopathy | NEJM

Allogeneic BK Virus–Specific T Cells for Progressive Multifocal Leukoencephalopathy | NEJM | Immunology and Biotherapies | Scoop.it
Summary
JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo–expanded, partially HLA-matched, third-party–produced, cryopreserved BK virus–specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord-blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T-cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor-derived T cells were detected in the CSF after infusion. (Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; ClinicalTrials.gov number, NCT02479698.)
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