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3D models as tools for inhaled drug development
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Sally-Ann Cryan, Jennifer Lorigan, Cian O’Leary
Immunological differences between species are perhaps of even more significance. Novel treatments for asthma that showed promise in animal studies, for example, have failed when brought forward to clinical trials. For example, extreme systemic inflammatory responses occurred in human volunteers to novel agents when they were originally safe in animals, in the tragic case of the phase I trial of TGN1412. This discordance between inflammatory pathways and the immune system between rodents and humans is clearly evident in the lack of a model that efficiently demonstrates the respiratory pathophysiology of respiratory diseases such as asthma and cystic fibrosis. The shortcomings in these models are reflected in the attrition rate of candidate drugs proposed for clinical use, with only 7.5% of investigational new drugs obtaining approval after Phase III clinical trials (46). It is clear that there is an unmet need for improved tools for the clinical and commercial translation of inhaled medicines. The need for improved models therefore is driven by (1) the desire for reduction, refinement, and replacement of animal models in research; and (2) the need to establish improved IVIVCs for inhalation toxicology to provide more complete and/or effective preclinical assessment.
Medical research
Published in Marc Stauch, Kay Wheat, Text, Cases and Materials on Medical Law and Ethics, 2018
Non-therapeutic research can take place in the context of all forms of medical treatments, but it is in the field of clinical drug trials that the most risk lies and which can give rise to considerable controversy. Trials of new drugs are divided into a number of phases. Prior to human testing, drugs are tested on animals to ascertain minimum safety levels. Although this gives rise to considerable emotional responses and protestation, this chapter is not concerned with non-human aspects of research. The first phase for our purposes is the ‘first in human’ phase, where the new drug is tested on healthy volunteers. This phase of a clinical trial has been highlighted in the UK by the tragic events that occurred at Northwick Park Hospital, London, in 2006. The drug concerned, TGN1412, was an anti-inflammatory drug developed at a German university, which had set up a biotechnology company, TeGenero, to develop it, and this company contracted with Parexel to conduct the clinical trial on this drug in the UK. Parexel carries out a number of functions with regard to servicing the pharmaceutical industry. This structure is described in detail because TeGenero subsequently became insolvent. Questions arise as to liability and ability to pay compensation for injury, and this will be discussed further at 10.5 below.
Medical progress and human costs
Published in Philip Cheung, Public Trust in Medical Research?, 2018
While we can celebrate the success of medical science, should we not also critically examine some of these developments against specific criteria or principles and in the light of public opinion? One of the questions that needs addressing is whether there are human costs associated with medical advancements. Consider for example, the first-in-man clinical trials1 carried out by Parexel, a contract research organisation, in March 2006. (The term ‘first-in-man trials’, ‘first-in-man studies’, ‘first-in-man clinical trials’ and ‘Phase One clinical trials’ of high-risk medicines are used by the Expert Scientific Group on Phase One Clinical Trials, interchangeably.) Eight healthy volunteers were used for the trial. Six of them were given the untested drug TGN1412, which is a monoclonal antibody developed for the treatment of chronic inflammatory or immune conditions such as rheumatoid arthritis and leukaemia.1 Within minutes of the drug administration, a violent allergic reaction, referred to scientifically as a cytokine release, occurred and the six healthy volunteers were left fighting for their lives.
Factors Affecting the Cancer Immunotherapeutic Efficacy of T Cell Bispecific Antibodies and Strategies for Improvement
Published in Immunological Investigations, 2022
Meixiao Long, Alice S. Mims, Zihai Li
T-BsAbs do not provide costimulatory signals (“signal 2”) for T-cells on their own, and the target cells usually express no or low levels of costimulatory molecules. Thus, providing additional signal 2 via agonist antibodies for costimulatory molecules is another intriguing approach to enhance the efficacy of T-BsAbs. However, this is a concern due to side effects and toxicities, especially cytokine release syndrome. A CD28 agonist is well known to cause a dangerous cytokine storm as learned from the disastrous TGN1412 trial (Suntharalingam et al. 2006). High-affinity agonist antibody for 4-1BB has demonstrated single-agent clinical efficacy in multiple types of solid tumors. However, it also comes with the risk of fatal liver toxicity (Bartkowiak et al. 2018). To mitigate excessive toxicity, researchers have focused on bispecific strategies. Agonist antibodies to costimulatory molecules such as CD28 and 4-1BB have been constructed into a bispecific platform along with the target (e.g., CD20) binding arm for targeted delivery to tumor sites. These costimulatory BsAbs have been tested along with T-BsAbs in preclinical studies and have demonstrated enhanced efficacy as well as promising safety profiles (Claus et al. 2019; Moore et al. 2021 Skokos et al. 2020). Some costimulatory BsAbs have been put into clinical trials, although most of them are still in the early phase, and the data regarding efficacy and safety are still pending (Ku et al. 2020; Muik et al. 2022; Zhang et al. 2021).
The annoying flaws of gerontological research
Published in Drug Metabolism Reviews, 2022
Magomed Khaidakov, Valeria Troshina, Dmitry Menglet, Yusef Yusef, Alexander Plotkin
One of the reasons is a lack of certainty that human toxicity profile will be in line with predictions based on experimental findings. The analysis based on a data set of 2366 drugs has shown extreme variability of likelihood ratios followed by a conclusion that ‘the absence of toxicity in the animal provides little or virtually no evidential weight that adverse drug reactions will also be absent in humans’ (Bailey et al. 2014). In one of the more dramatic examples, an anti-inflammatory drug, TGN1412, was comprehensively tested in two species before going to a preclinical trial stage. However, the volunteers injected with this drug suffered from catastrophic failures of multiple organs within minutes after injection (Attarwala 2010). Another reason is translational failure, which may be partially explained by flaws in experimental design, and certain disconnect between animal models and target diseases (van der Worp et al. 2010). Finally, there is a troubling phenomenon of appallingly low reproducibility of biomedical research (Begley and Ioannidis 2015; An 2018).
Highly sensitive in vitro cytokine release assay incorporating high-density preculture
Published in Journal of Immunotoxicology, 2021
Shiho Ito, Kyoko Miwa, Chiharu Hattori, Tetsuo Aida, Yoshimi Tsuchiya, Kazuhiko Mori
Cytokine release syndrome (CRS), which occurred in the Phase-I clinical trial of the anti-CD28 super-agonist (SA) monoclonal antibody (mAb) TGN1412, is one of the most serious adverse effects associated with parenteral administration of therapeutic mAb (Suntharalingam et al. 2006). CRS is typically characterized by the release of pro-inflammatory cytokines including interleukins (IL), interferon (IFN)-γ, and tumor necrosis factor (TNF)-α into the blood, resulting in fever, chills, hypotension, and multiple organ failure immediately after treatment with a therapeutic mAb (Finco et al. 2014). The cytokine release caused by therapeutic mAb is considered to be mediated by two mechanisms: the binding of the fragment antigen-binding region (Fab) of mAb to the cell surface target on immune cells and the binding of the fragment crystallizable region (Fc) of mAb to Fcγ receptors (FcγR) on effector cells (Wing et al. 1996). The former (i.e., binding of Fab) is primarily associated with CRS associated with T-cell agonists such as OKT3 [an anti-CD3 mAb] and TGN1412; the latter (i.e., binding of Fc) is mainly associated with CRS that arises with alemtuzumab, trastuzumab, and rituximab and is due to antibody-dependent cellular cytotoxicity (ADCC) activity (Kirton et al. 2011; Paul and Cartron 2019).