The Biologics Revolution and Endotoxin Test Concerns
ABSTRACT: The advent of “at will” production of biologics in lieu of harvesting animal proteins (i.e. insulin) or human cadaver proteins (i.e. growth hormone) has revolutionized the treatment of disease. While the fruits of the biotechnology revolution are widely acknowledged, the realization of the differences in the means of production and changes in the manner of control of potential impurities and contaminants in regard to the new versus the old are less widely appreciated. This chapter is an overview of the biologics revolution in terms of the rigors of manufacturing required to produce them, their mechanism of action, and caveats of endotoxin control. It is a continulation of the previous chapter that established a basic background knowledge of adaptive immune principles necessary to understand the mode of action of both disease causation and biologics therapeutic treatment via immune modulation.
Project description:The biologics used in transplantation clinical practice include several monoclonal and polyclonal antibodies aimed at specific cellular receptors. The effect of their mechanisms of action includes depleting or blocking specific cell subpopulations, complement system, or removing circulating preformed antibodies and blocking their production. They are used in induction, desensitization ABO-incompatible renal transplantation, rescue therapy of steroid-resistant acute rejection, treatment of posttransplant recurrence of primary disease such as nephrotic syndrome or atypical hemolytic-uremic syndrome, and in late humoral rejection. There are various indications for the use of biologic agents before and early or late after renal transplantation in both high- and low-risk recipients. In the latter situation, the biologics-based induction is used to further minimize immunosuppression maintenance. The targets of several biologic agents are present across a variety of cells, and manipulation of the immune system with biologics may be associated with significant risk of acute and late-onset adverse events; therefore, clinical risk-versus-benefit ratio must be carefully balanced in every case. Several trials on novel biologics are reported in adults but not in the pediatric population.
Project description:Skin and subcutaneous diseases affect millions of people worldwide, causing significant morbidity. Biologics are becoming increasingly useful for the treatment of many skin diseases, particularly as alternatives for patients who have failed to tolerate or respond to conventional systemic therapies. Biological therapies provide a targeted approach to treatment through interaction with specific components of the underlying immune and inflammatory disease processes. This review article examines the increasing evidence base for biologics in dermatology, including well-established treatments and novel agents.
Project description:Background:The aim of our study was to synthesize evidence on the occurrence of malignancy in spondyloarthritis (SpA), from randomized controlled trials (RCTs) comparing biologics with non-biologics and biologics to each other. Methods:We systematically searched Medline, Cochrane Library, EMBASE, Scopus and ClinicalTrials.gov from inception until 31 October 2018. RCTs with ?24-week follow-up were included. We extracted data using standardized forms and assessed the risk of bias using the Cochrane Risk of Bias Tool. We performed pair-wise meta-analyses and network meta-analyses to compare the risk of malignancy for each biologics class and SpA type. We reported the Peto odds ratio (OR) of any malignancy along with 95% confidence intervals (95% CI). Bayesian posterior probabilities comparing risk of malignancy of each biologic class with non-biologics were computed as supplementary measures. Results:Fifty-four trials were included; most (44/54) had follow-up?<1?year. Among 14,245 patients, 63 developed a malignancy. While most Peto ORs were >1, they had wide 95% CI and p?>0.05. The overall Peto OR comparing biologics with non-biologics was 1.42 (95% CI 0.80-2.53). Only interleukin-17 inhibitors in peripheral SpA had p?<0.05 (Peto OR 2.77, 95% CI 1.07-7.13); the posterior probability that the risk was higher than non-biologics was 98%. Stratified analyses revealed no consistent trend by prior exposure to biologics, duration of follow-up, study quality, study-arm crossover, analytical approaches and type of malignancy. Conclusions:Our findings indicate no overall elevated risk of malignancy with biologics in SpA. As our meta-analyses are unable to conclude on the long-term risk, long-term pharmacovigilance of biologics in SpA may still be warranted.
Project description:The Chinese Communist Revolution that culminated in the 1949 founding of the People's Republic of China fundamentally transformed class relations in China. With data from a nationally representative, longitudinal survey between 2010 and 2016, this study documents the long-term impact of the Communist Revolution on the social stratification order in today's China, more than 6 decades after the revolution. True to its stated ideological missions, the revolution resulted in promoting the social status of children of the peasant, worker, and revolutionary cadre classes and disadvantaging those who were from privileged classes at the time of the revolution. Although there was a tendency toward "reversion" mitigating the revolution's effects in the third generation toward the grandparents' generation in social status, the overall impact of reversion was small. The revolution effects were most pronounced for the birth cohorts immediately following the revolution, attenuating for recently born cohorts.
Project description:The aim of this study was to compare the clinical characteristics of pneumocystis pneumonia (PCP) between patients with rheumatoid arthritis (RA) being treated with biologics and those being treated without biologics.From 8,630 patients with RA in our institution, we enrolled 24 patients who had developed PCP during the course of their treatment. They were divided into two groups according to the treatment they were receiving for RA: the biologics group (n = 12) and the nonbiologics group (n = 12). Clinical characteristics of PCP were compared between the two groups.At PCP diagnosis, the biologics group showed significantly lower serum levels of β-D-glucan and C-reactive protein than the nonbiologics group, while the biologics group had significantly higher lymphocyte counts than the nonbiologics group. In the nonbiologics group, lower lymphocyte counts were associated with higher β-D-glucan levels; however, this was not observed in the biologics group.The finding that RA patients being treated with biologics developed PCP with relatively normal lymphocyte counts and lower β-D-glucan levels suggests that the pathophysiology of PCP in those patients is different from that in patients being treated with other antirheumatic drugs.
Project description:Patients with severe uncontrolled asthma have disproportionally high morbidity and healthcare utilization as compared with their peers with well-controlled disease. Although treatment options for these patients were previously limited, with unacceptable side effects, the emergence of biologic therapies for the treatment of asthma has provided promising targeted therapy for these patients. Biologic therapies target specific inflammatory pathways involved in the pathogenesis of asthma, particularly in patients with an endotype driven by type 2 (T2) inflammation. In addition to anti-IgE therapy that has improved outcomes in allergic asthma for more than a decade, three anti-IL-5 biologics and one anti-IL-4R biologic have recently emerged as promising treatments for T2 asthma. These targeted therapies have been shown to reduce asthma exacerbations, improve lung function, reduce oral corticosteroid use, and improve quality of life in appropriately selected patients. In addition to the currently approved biologic agents, several biologics targeting upstream inflammatory mediators are in clinical trials, with possible approval on the horizon. This article reviews the mechanism of action, indications, expected benefits, and side effects of each of the currently approved biologics for severe uncontrolled asthma and discusses promising therapeutic targets for the future.
Project description:The ubiquitous biological nanomotors were classified into two categories in the past: linear and rotation motors. In 2013, a third type of biomotor, revolution without rotation (http://rnanano.osu.edu/movie.html), was discovered and found to be widespread among bacteria, eukaryotic viruses, and double-stranded DNA (dsDNA) bacteriophages. This review focuses on recent findings about various aspects of motors, including chirality, stoichiometry, channel size, entropy, conformational change, and energy usage rate, in a variety of well-studied motors, including FoF1 ATPase, helicases, viral dsDNA-packaging motors, bacterial chromosome translocases, myosin, kinesin, and dynein. In particular, dsDNA translocases are used to illustrate how these features relate to the motion mechanism and how nature elegantly evolved a revolution mechanism to avoid coiling and tangling during lengthy dsDNA genome transportation in cell division. Motor chirality and channel size are two factors that distinguish rotation motors from revolution motors. Rotation motors use right-handed channels to drive the right-handed dsDNA, similar to the way a nut drives the bolt with threads in same orientation; revolution motors use left-handed motor channels to revolve the right-handed dsDNA. Rotation motors use small channels (<2 nm in diameter) for the close contact of the channel wall with single-stranded DNA (ssDNA) or the 2-nm dsDNA bolt; revolution motors use larger channels (>3 nm) with room for the bolt to revolve. Binding and hydrolysis of ATP are linked to different conformational entropy changes in the motor that lead to altered affinity for the substrate and allow work to be done, for example, helicase unwinding of DNA or translocase directional movement of DNA.
Project description:Immunomodulatory biologics, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions--including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity--pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics.
Project description:Biological medicinal products (biologics) are subject to specific pharmacovigilance requirements to ensure that biologics are identifiable by brand name and batch number in adverse drug reaction (ADR) reports. Since Member States collect ADR data at the national level before the data is aggregated at the European Union (EU) level, it is important that an unambiguous understanding of which medicinal products belong to the biological product category exists. This study aimed to identify the level of consistency between Member States regarding the classification of biologics by national authorities responsible for ADR reporting.A sample list of recombinant biologics from the European Medicines Agency database of European Public Assessment Reports was created to analyze five Member States (Belgium, the Netherlands, Spain, Sweden, and the UK) according to which products were classified as biologics by each Member State. We calculated the Fleiss kappa value to analyze interrater reliability.A considerable divergence was identified regarding the classification of the 146 recombinant biologics from the sample list: one Member State classified 100 % of the recombinant biologics from the sample list as biologics, whereas the classification rates in the remaining four Member States ranged between 70 and 88 % for products available on the national market. The interrater reliability for 87 products available on the market in all five Member States was considered poor.Discrepancies exist between Member States in the classification of biologics; less divergence exists for common well-known biologics. These findings highlight the need to think about the best approaches to translate EU legislation into national practices. Additionally, we recommend a publicly available and frequently updated list of centrally authorized biologics.
Project description:Advancements in science enable researchers to constantly innovate and create novel biologics. However, the use of non-human animal models during the development of biologics impedes identification of precise in vivo interactions between the human immune system and treatments. Due to lack of this understanding, adverse effects are frequently observed in healthy volunteers and patients exposed to potential biologics during clinical trials. In this study, we evaluated and compared the effects of known immunotoxic biologics, Proleukin®/IL-2 and OKT3 in humanized mice (reconstituted with human fetal cells) to published clinical outcomes. We demonstrated that humanized mice were able to recapitulate in vivo pathological changes and human-specific immune responses, such as elevated cytokine levels and modulated lymphocytes and myeloid subsets. Given the high similarities of immunological side effects observed between humanized mice and clinical studies, this model could be used to assess immunotoxicity of biologics at a pre-clinical stage, without placing research participants and/or patients at risk.