Journal of Immunotoxicology, 2020
Collinge M, Schneider P, Li D, Parish S, Dumont C, Freebern W, Ghanime J, Guimont-Derochers F, Langenkamp A, Lebron J, Li N, Marban C, Plitnick L, Wheeler J
Nonclinical immunotoxicity evaluation is an important component of safety assessment for pharmaceuticals. One in vitro assay that can be applied in a weight of evidence assessment is the human lymphocyte activation (HuLA) assay, an antigen recall assay, similar in many respects to the in vivo T-cell-dependent antibody response (TDAR) in that cooperation of multiple immune cell types are needed to produce responses. This assay uses human cells and is more amenable than the TDAR to compound ranking and mechanistic studies.
Journal of Immunotoxicology, 2020
Kamperschroer C, Shenton J, Lebrec H, Leighton JK, Moore PA, Thomas O
Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity.
EMBO Molecular Medicine, 2020
Pettit SD, Jerome KR, Rouquie D, Mari B, Barbry P, Kanda Y, Matsumoto M, Hester S, Wehmas L, Botten JW, Bruce EA
Current demand for SARS‐CoV‐2 testing is straining material resource and labor capacity around the globe. As a result, the public health and clinical community are hindered in their ability to monitor and contain the spread of COVID‐19. Despite broad consensus that more testing is needed, pragmatic guidance towards realizing this objective has been limited. This paper addresses this limitation by proposing a novel and geographically agnostic framework (the 4Ps Framework) to guide multidisciplinary, scalable, resource‐efficient, and achievable efforts towards enhanced testing capacity. The 4Ps (Prioritize, Propagate, Partition, and Provide) are described in terms of specific opportunities to enhance the volume, diversity, characterization, and implementation of SARS‐CoV‐2 testing to benefit public health. Coordinated deployment of the strategic and tactical recommendations described in this framework have the potential to rapidly expand available testing capacity, improve public health decision‐making in response to the COVID‐19 pandemic, and/or to be applied in future emergent disease outbreaks.
Drug Metabolism and Disposition, 2020
Bueters R, Bael A, Gasthuys E, Chen C, Schreuder MF, Frazier KS
This review provides insight in cross-species developmental differences of absorption, distribution, metabolism, and excretion properties in the kidney, which should be considered in neonate/juvenile study interpretation, hypotheses generation, and experimental design.
Nature Scientific Reports, 2020
James Kramer, Herbert M. Himmel, Anders Lindqvist, Sonja Stoelzle-Feix, Khuram W. Chaudhary, Dingzhou Li, Georg Andrees Bohme, Matthew Bridgland-Taylor, Simon Hebeisen, Jingsong Fan, Muthukrishnan Renganathan, John Imredy, Edward S. A. Humphries, Nina Brinkwirth, Tim Strassmaier, Atsushi Ohtsuki, Timm Danker, Carlos Vanoye, Liudmila Polonchuk, Bernard Fermini, Jennifer Beck Pierson & Gary Gintant
Automated patch clamp (APC) instruments enable efficient evaluation of electrophysiologic effects of drugs on human cardiac currents in heterologous expression systems. Differences in experimental protocols, instruments, and dissimilar site procedures affect the variability of IC50 values characterizing drug block potency. This impacts the utility of APC platforms for assessing a drug’s cardiac safety margin. We determined variability of APC data from multiple sites that measured blocking potency of 12 blinded drugs (with different levels of proarrhythmic risk) against four human cardiac currents (hERG [IKr], hCav1.2 [L-Type ICa], peak hNav1.5, [Peak INa], late hNav1.5 [Late INa]) with recommended protocols (to minimize variance) using five APC platforms across 17 sites.
