Immunology and Biotherapies
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Targeting the IL-6/JAK/STAT3 signalling axis in cancer

Targeting the IL-6/JAK/STAT3 signalling axis in cancer | Immunology and Biotherapies | Scoop.it

Review


The IL-6/JAK/STAT3 pathway is aberrantly hyperactivated in many types of cancer, and such hyperactivation is generally associated with a poor clinical prognosis. In the tumour microenvironment, IL-6/JAK/STAT3 signalling acts to drive the proliferation, survival, invasiveness, and metastasis of tumour cells, while strongly suppressing the antitumour immune response. Thus, treatments that target the IL-6/JAK/STAT3 pathway in patients with cancer are poised to provide therapeutic benefit by directly inhibiting tumour cell growth and by stimulating antitumour immunity. Agents targeting IL-6, the IL-6 receptor, or JAKs have already received FDA approval for the treatment of inflammatory conditions or myeloproliferative neoplasms and for the management of certain adverse effects of chimeric antigen receptor T cells, and are being further evaluated in patients with haematopoietic malignancies and in those with solid tumours. Novel inhibitors of the IL-6/JAK/STAT3 pathway, including STAT3-selective inhibitors, are currently in development. Herein, we review the role of IL-6/JAK/STAT3 signalling in the tumour microenvironment and the status of preclinical and clinical investigations of agents targeting this pathway. We also discuss the potential of combining IL-6/JAK/STAT3 inhibitors with currently approved therapeutic agents directed against immune-checkpoint inhibitors.


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Immunology and Biotherapies
Page Ressources et Actualités du DIU immunologie et biothérapies
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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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Eltrombopag is an effective and safe therapy for refractory thrombocytopenia after haploidentical hematopoietic stem cell transplantation

Eltrombopag is an effective and safe therapy for refractory thrombocytopenia after haploidentical hematopoietic stem cell transplantation | Immunology and Biotherapies | Scoop.it
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Incidence and risk factors for life-threatening bleeding after allogeneic stem cell transplant [...] Risk factors and impact of secondary failure of platelet recovery after allogeneic stem cell transplantation [.

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70 year olds in Jersey being urged to get shingles vaccine | Channel

70 year olds in Jersey being urged to get shingles vaccine | Channel | Immunology and Biotherapies | Scoop.it
Read the latest Channel stories, 70 year olds in Jersey being urged to get shingles vaccine on ITV News, videos, stories and all the latest Channel news...
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Infectious Disease Transmission in Solid Organ Transplantation: Donor Evaluation, Recipient Risk, and Outcomes of Transmission. - PubMed - NCBI

Transplant Direct. 2018 Dec 20;5(1):e416. doi: 10.1097/TXD.0000000000000852. eCollection 2019 Jan.
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Translation control of the immune checkpoint in cancer and its therapeutic targeting

Translation control of the immune checkpoint in cancer and its therapeutic targeting | Immunology and Biotherapies | Scoop.it
Abstract
Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5′ untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.

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Research reveals mechanism for leukaemia cell growth, prompting new treatment hopes. ecancer - News

Research reveals mechanism for leukaemia cell growth, prompting new treatment hopes. ecancer - News | Immunology and Biotherapies | Scoop.it
Research reveals mechanism for leukaemia cell growth, prompting new treatment hopes 17 Jan 2019 A mechanism which drives leukaemia cell growth has been discovered by researchers at the University of Sussex, who believe their findings could help to inform new strategies when it comes to treating the cancer. Acute myeloid leukaemia (AML) is a devastating blood cancer with around 3,000 new cases annually in the UK. Despite considerable improvement in patient survival over the last 50 years, the prognosis remains poor for many subsets of adults and children who suffer from the disease. Current chemotherapies are highly toxic, and often fail to induce a long-term cure resulting in an urgent clinical need for the design of better tolerated and highly targeted therapies that induce durable remissions. Leukaemia cells are known to have an overactive level of a protein called β-catenin, which can drive cancer development. Once this protein moves into the nucleus of cells, where DNA is stored, it can assist the activation of genes important for leukaemia development. The activity of β-catenin is highly dependent upon the interactions it forms with other proteins in the cell. Up until now, the movement of β-catenin into the nucleus of leukaemia cells has been a poorly understood process in blood cells. But researchers from the University of Sussex, Bristol and Cardiff using funding from the Kay Kendall Leukaemia Fund (KKLF) and Bloodwise have now discovered a protein partner that promotes this process and therefore helps leukaemia cells to grow. Their findings could lead to the development of new therapeutic strategies to treat AML. In a paper published in the journal Haematologica, Dr Rhys Morgan, Lecturer in Biomedical Science, observed that protein LEF-1 can actively control the level of β-catenin in the nucleus of myeloid leukaemia cells. This is the first study to reveal such a mechanism is active in leukaemia cells, and also the first to reveal β-catenin's interaction partners in blood cells. Dr Rhys Morgan, from the University of Sussex, said: "Whilst scientists have long been aware of the involvement of β-catenin in cancer progression, drugs directly targeting the protein or its partners haven't yet reached the clinic. From our research findings we'd suggest that pharmacological targeting of β-catenin's movement into the nucleus, through a partner like LEF-1, could be a viable treatment strategy in leukaemia." He explained further: "This research is at a very early stage and targeting the activity of β-catenin won't be a solution for all leukaemia cases and subtypes. "However data suggests that anywhere between 20-80% of AML cases display elevated levels of this molecule which justifies further investigation in this setting." Dr Morgan and his team are now working to further understand the biological significance of many of the new interacting proteins discovered in the study, with the belief that others could be worth targeting to inhibit β-catenin level and activity in leukaemia. Source: University of Sussex
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Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantation

Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantation | Immunology and Biotherapies | Scoop.it
Cytomegalovirus (CMV) infection and reactivation are common and potentially fatal complications after bone marrow or hematopoietic stem cell transplantation (BMT). Martins et al. developed faithful preclinical murine models of CMV reactivation following BMT and found that humoral immunity can prevent this process (see the Perspective by Alegre). After BMT, antiviral antibodies that would have kept CMV at bay dwindle because host plasma cells are ablated and the donor B cell pool reconstitutes poorly. CMV reactivation was prevented by transferring antibody-containing immune serum. Such a therapeutic strategy would avoid some limitations of cellular therapies for BMT patients.

Science , this issue p. [288][1]; see also p. [232][2]

Cytomegalovirus infection is a frequent and life-threatening complication that significantly limits positive transplantation outcomes. We developed preclinical mouse models of cytomegalovirus reactivation after transplantation and found that humoral immunity is essential for preventing viral recrudescence. Preexisting antiviral antibodies decreased after transplant in the presence of graft-versus-host disease and were not replaced, owing to poor reconstitution of donor B cells and elimination of recipient plasma cells. Viral reactivation was prevented by the transfer of immune serum, without a need to identify and target specific antigenic determinants. Notably, serotherapy afforded complete protection, provided that the serum was matched to the infecting viral strain. Thus, we define the mechanisms for cytomegalovirus reactivation after transplantation and identify a readily translatable strategy of exceptional potency, which avoids the constraints of cellular therapies.

[1]: /lookup/doi/10.1126/science.aat0066
[2]: /lookup/doi/10.1126/science.aav9867
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Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells - ScienceDirect

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells - ScienceDirect | Immunology and Biotherapies | Scoop.it
An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strate…
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Anti-vaxxers are among the WHO’s top 10 global health threats, and Ebola fake news is killing people » Nieman Journalism Lab

Anti-vaxxers are among the WHO’s top 10 global health threats, and Ebola fake news is killing people » Nieman Journalism Lab | Immunology and Biotherapies | Scoop.it
During an outbreak in the Democratic Republic of Congo, "as rumors surface, communications experts rebut them with accurate information via WhatsApp or local radio."...
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A Science Supplement: Novel Trends In immuno-oncology Research: Advanced Cell Analysis for immunotherapeutic Applications

A Science Supplement: Novel Trends In immuno-oncology Research: Advanced Cell Analysis for immunotherapeutic Applications | Immunology and Biotherapies | Scoop.it
This supplement introduces the latest groundbreaking research in immuno-oncology and provides a peek into some of the latest cell analysis tools that are unlocking the secret to immune cell interactions, potentially enabling future breakthroughs in immune-based therapies.
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Leukocytoclastic vasculitis with purpura and renal failure induced by the anti-epidermal growth factor receptor antibody panitumumab: a case report | Journal of Medical Case Reports | Full Text

Leukocytoclastic vasculitis with purpura and renal failure induced by the anti-epidermal growth factor receptor antibody panitumumab: a case report | Journal of Medical Case Reports | Full Text | Immunology and Biotherapies | Scoop.it
Panitumumab is the first human combinatorial antibody for the treatment of metastatic colorectal carcinoma. Dermatologic toxicity of all grades occurs in more than 90% of patients. However, there are few reports of purpura induced by anti-epidermal growth factor receptor antibody.
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Developing A Treatment | ASGCT - American Society of Gene & Cell Therapy

Developing A Treatment | ASGCT - American Society of Gene & Cell Therapy | Immunology and Biotherapies | Scoop.it
Developing A Treatment New therapies spend a lot of time being tested in labs and animals in preclinical studies before making it to patients. By the time the therapy enters human clinical trials, it is better understood and ready for further development. Learn more information about the process of developing a treatment. FDA Efforts Between preclinical study and clinical trials, the process can take many years to conclude. Clinical trials alone sometimes can take eight years or more. There are many variables that go into that duration including study planning, authorization to run a trial, ethics review, funding, research materials such as patient information, consent forms and monitoring systems. However, the U.S. Food and Drug Administration (FDA) is putting an effort into various expedited pathways to accelerate the process while still maintaining safety. Sometimes the typically described three phases of a clinical trial are combined to make the evaluation process more efficient. For serious and rare diseases where there is a clear unmet medical need and very few patients, the treatment may be made available more quickly. It’s worth noting that there are challenges associated with streamlining the clinical trial process. Researchers need to ensure that they avoid exposing multiple patients to suboptimal or toxic doses. Or, they need enough time to properly interpret the outcomes of a trial. It all goes back to making sure that the treatment is well understood, safe and effective enough to be approved for market. Speeding up the availability of drugs that treat serious diseases is in everyone’s interest. That’s why the FDA has created five different approaches to accelerating the development of treatment, they're called "expidited pathways." Some of these approaches can be combined to make the development of treatment even more efficient. However, the names of these different approaches all sound, well, fast. So what is the difference between them? Expedited Pathways Accelerated Approval SHOW ANSWER Breakthrough Therapy SHOW ANSWER Fast Track SHOW ANSWER RMAT Designation SHOW ANSWER Priority Review SHOW ANSWER Not all research transpires in the United States, so there are global approval bodies similar to the FDA. National governments are responsible for establishing strong national medicines regulatory authorities, also known as MRAs. You may also see the phases of clinical trial referred to as early, late and pivotal stages of development. Patient Access Once a treatment successfully passes through clinical trials and is approved by the FDA, then what happens? How can patients access the treatments? There were three gene therapies approved in 2017, so we’ll use those as our starting point - Luxturna, Yescarta and Kymriah. These therapies are offered at a limited number of sites, currently only at specialized academic medical centers. Although patients can reach out directly to a treatment center that offers the therapy, it’s important to inform their primary medical practitioner of the decision. Most times a clinician that knows the individual best will help in determining if the treatment is applicable and then may set up the referral. This primary clinician can also be involved in post-procedure care and answering questions along the way. The currently available gene therapies are covered by many health insurance options, including Medicare. Interested patients should contact their health insurance provider to determine its coverage, as well as what to expect as far as out-of-pocket costs. Manufacturers of the gene therapies often offer patient support services to assist in navigating the process. One of the most important components to moving along research and development of these therapies are the many volunteers that participate in clinical trials every year. Thanks to the volunteers, more people are living longer, healthier lives. Participating in clinical trials is a way to receive an investigational treatment at no cost, while benefiting the medical community, and others who have the same disease or condition. According to a study from CISCRP, 94 percent of people who have participated in a clinical trial of some type would be willing to participate again or would recommend others to participate. Finding a Clinical Trial Patients can access gene or cell therapy treatment by participating in a clinical trial. Not only can you potentially receive treatment for a disease, you can also help the greater good by assisting researchers in their studies. Talk to your Doctor: even if you find a clinical trial on your own, it is still important to speak with your doctor about it. Visit ClinicalTrials.gov: this clinical trial navigation service is a national database of treatment trials from different sponsors. Sign Up for a Patient Registry: patient registries are a collection of information about patients who share a condition or experience. Their goal is to help medical researchers better understand how diseases develop and progress over time. Some registries invite people to sign up to be contacted about participating in clinical research. Here’s a helpful list of patient registries from the National Institutes of Health (NIH).  Patient Advocacy Organizations: these organizations are hard at work to support rare genetic diseases and can be a great way to get involved and advocate for a disease. It is also a valuable source for emotional support, advice, and to learn others’ experiences with clinical trials. Download as PDF
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Gene Therapy Basics | Education | ASGCT American Society of Gene & Cell Therapy | ASGCT - American Society of Gene & Cell Therapy

Gene Therapy Basics | Education | ASGCT American Society of Gene & Cell Therapy | ASGCT - American Society of Gene & Cell Therapy | Immunology and Biotherapies | Scoop.it
Gene therapy has been studied for more than 40 years and can help stop or slow the effects of disease on the most basic level of the human body—our genes. And to understand how it works, ASGCT starts at the basics.
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EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL)

EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL) | Immunology and Biotherapies | Scoop.it
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 Allogeneic hematopoietic stem cell transplantation for T-prolymphocytic leukemia: a report from the French society for stem cell transplantation (SFGM-TC) [...] The PARP inhibitor olaparib induces significant killing of ATM-deficient

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A single administration of human adipose tissue‐derived mesenchymal stromal cells (MSC) induces durable and sustained long‐term regulation of inflammatory response in experimental colitis - Alves -...

Current therapies for Inflammatory Bowel Diseases (IBD) are aimed at controlling the exacerbated response in the gut, but no treatment is fully effective for several refractory patients. Mesenchymal stromal cells (MSC) are multipotent cells with regulatory immunosuppressive activity that may control inflammatory diseases. Then, here we investigated the short and specially the long‐term protective effects of MSC on experimental colitis. We showed that MSC elicited protection to acute intestinal inflammation with gain of weight, improvement in the clinical disease score and expressive reduction in the mortality rate of treated mice. MSC changed the population of neutrophils, eosinophils and augmented the frequency of CD4 T lymphocytes in the gut draining lymph nodes, together with reduced accumulation of these cells in colon intraepithelial compartment. Interestingly, there were increased levels of PD‐1 and GITR in the spleen regulatory T cells of mice that received MSC treatment, which also presented a reversal in the pattern of immune response in the gut, with diminished inflammatory, Th1 and Th17 profile, in contrast to augmented Th2 responses. Most strikingly, this balanced response elicited by a single administration of MSC during the acute colitis persisted at long‐term, with restored goblet cells, eosinophils and maintenance of elevated gut IL‐4, besides increased CD4+CD25+PD‐1+ cells in the spleen and reduced Th17 response in MLN of treated mice, on day 60. Taken together, our findings provided a significant contribution to translational immunology by pointing human adipose tissue‐derived MSC as a novel therapeutic approach with long‐term beneficial regulatory effects in experimental colitis. This article is protected by copyright. All rights reserved.
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Tuberculosis following PD-1 blockade for cancer immunotherapy. - PubMed - NCBI

Tuberculosis following PD-1 blockade for cancer immunotherapy. - PubMed - NCBI | Immunology and Biotherapies | Scoop.it
Sci Transl Med. 2019 Jan 16;11(475). pii: eaat2702. doi: 10.1126/scitranslmed.aat2702.
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Toxins | Free Full-Text | Toxin Neutralization Using Alternative Binding Proteins | HTML

Toxins | Free Full-Text | Toxin Neutralization Using Alternative Binding Proteins | HTML | Immunology and Biotherapies | Scoop.it
Animal toxins present a major threat to human health worldwide, predominantly through snakebite envenomings, which are responsible for over 100,000 deaths each year. To date, the only available treatment against snakebite envenoming is plasma-derived antivenom.
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Expressional activation and functional roles of human endogenous retroviruses in cancers - Zhang - - Reviews in Medical Virology - Wiley Online Library

Summary

Human endogenous retroviruses (HERVs) are widely believed to be remnants of ancestral germ line infections by exogenous retroviruses. Although HERVs are deemed as “nonfunctional DNAs” due to loss of most of their viral protein coding capacity during evolution as part of the human genome, cumulative evidences are showing the expressional activation and potential roles of HERVs in diseases especially cancers. Work by other researchers and us has observed the dysregulation of HERVs in cancers, identified new HERV‐related genes, and revealed their potential importance in cancer development. Here, we summarized the current knowledge on the mechanisms of the expressional activation and functional roles of HERVs, with a focus on the H family HERV (HERV‐H), in carcinogenesis. HERV expression is regulated by external chemical or physical substances and exogenous virus infection, as well as host factors such as epigenetic DNA methylation, transcription factors, cytokines, and small RNAs. Diverse roles of HERVs have been proposed by acting in the forms of noncoding RNAs, proteins, and transcriptional regulators during carcinogenesis. However, much remains to be learnt about the contributions of HERVs to human cancers. More investigation is warranted to elucidate the functions of these “fossil remnants” yet important viral DNAs in the human genome.

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Adventitious Viral Genomes in Vaccines but Not in Vaccinees - Volume 7, Number 1—February 2001 - Emerging Infectious Diseases journal - CDC

Adventitious Viral Genomes in Vaccines but Not in Vaccinees - Volume 7, Number 1—February 2001 - Emerging Infectious Diseases journal - CDC | Immunology and Biotherapies | Scoop.it
Adventitious Viral Genomes in Vaccines but Not in Vaccinees...
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Human blood vessel organoids as a model of diabetic vasculopathy

Human blood vessel organoids as a model of diabetic vasculopathy | Immunology and Biotherapies | Scoop.it
Organoids derived from human stem cells recapitulate the structure and functions of human blood vessels, and can be used to model and identify regulators of diabetic vasculopathy.
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Scientists design protein that prods cancer-fighting T-cells: New protein mimics interleukin-2 without toxic effects and works against cancer in an animal model

Scientists design protein that prods cancer-fighting T-cells: New protein mimics interleukin-2 without toxic effects and works against cancer in an animal model | Immunology and Biotherapies | Scoop.it
Scientists have created a new protein that mimics a key immune regulatory protein, interleukin 2 (IL-2). IL-2 is a potent anticancer drug, but with toxic side effects. The researchers report using computer programs to design a protein that they have shown in animal models to have the same ability...
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False-Positive Light Chain Clonal Restriction by Flow Cytometry in Patients Treated With Alemtuzumab | American Journal of Clinical Pathology | Oxford Academic

False-Positive Light Chain Clonal Restriction by Flow Cytometry in Patients Treated With Alemtuzumab | American Journal of Clinical Pathology | Oxford Academic | Immunology and Biotherapies | Scoop.it
AbstractObjectives. To increase awareness of potential diagnostic test interference associated with alemtuzumab, which is a therapeutic immunoglobulin G1 κ mon
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Approaches to treat immune hot, altered and cold tumours with combination immunotherapies

Approaches to treat immune hot, altered and cold tumours with combination immunotherapies | Immunology and Biotherapies | Scoop.it
Immunoscore classifies cancers according to their immune infiltration. In this Review, Galon and Bruni provide a panel of therapeutic strategies to use, combine and develop to treat hot, altered and cold tumours.
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Cell therapy bioprocessing: Moving toward commercial scale and efficiency - WHITEPAPER

Cell therapy bioprocessing: Moving toward commercial scale and efficiency - WHITEPAPER | Immunology and Biotherapies | Scoop.it
At the time of writing there are 672 cell and gene therapy companies worldwide and 20 products approved by the food and drug administration (FDA). Dendreon’s Provenge autologous cell therapy although approved by the FDA ultimately failed commercially due to a manufacturing and distribution model that was not efficient. Cost of Goods (CoGs), manufacturing process and logistics are critical to the success of cell therapy commercialisation and these need to be considered from the inception of a cell therapy company in addition to the clinical science. Three key enablers for success are manufacturing automation/ single use technologies, a diverse pipeline in modularised facilities, and sophisticated data acquisition/ logistics. This whitepaper explores the ways that progress towards commercial scale and efficiency in cell therapy bioprocessing is happening. To download the whitepaper simply log in or register for a KNect365 account, which will give you access to all our exclusive premium content.
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A Complete Workflow Solution for Intact Monoclonal Antibody Characterization Using a New High-Performance Benchtop Quadrupole-Orbitrap LC-MS/MS

A Complete Workflow Solution for Intact Monoclonal Antibody Characterization Using a New High-Performance Benchtop Quadrupole-Orbitrap LC-MS/MS | Immunology and Biotherapies | Scoop.it
Purpose: A LC/MS-based workflow solution was developed for robust, accurate and comprehensive intact monoclonal antibody (mAb) characterization.
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New hope for stem cell approach to treating diabetes –

New hope for stem cell approach to treating diabetes – | Immunology and Biotherapies | Scoop.it
Insulin-producing cells more responsive to fluctuating glucose levels...
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