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In October 2013, the International Life Sciences Institute - Health and Environmental Sciences Institute Immunotoxicology Technical Committee (ILSI-HESI ITC) held a one-day workshop entitled, “Workshop on Cytokine Release: State-of-the-Science, Current Challenges and Future Directions”. The workshop brought together scientists from pharmaceutical, academic, health authority, and contract research organizations to discuss novel approaches and current challenges for the use of in vitro cytokine release assays (CRAs) for the identification of cytokine release syndrome (CRS) potential of novel monoclonal antibody (mAb) therapeutics. Topics presented encompassed a regulatory perspective on cytokine release and assessment, case studies regarding the translatability of preclinical cytokine data to the clinic, and the latest state of the science of CRAs, including comparisons between mAb therapeutics within one platform and across several assay platforms, a novel physiological assay platform, and assay optimization approaches such as determination of FcR expression profiles and use of statistical tests. The data and approaches presented confirmed that multiple CRA platforms are in use for identification of CRS potential and that the choice of a particular CRA platform is highly dependent on the availability of resources for individual laboratories (e.g. positive and negative controls, number of human blood donors), the assay through-put required, and the mechanism-of-action of the therapeutic candidate to be tested. Workshop participants agreed that more data on the predictive performance of CRA platforms is needed, and current efforts to compare in vitro assay results with clinical cytokine assessments were discussed. In summary, many laboratories continue to focus research efforts on the improvement of the translatability of current CRA platforms as well explore novel approaches which may lead to more accurate, and potentially patient-specific, CRS prediction in the future. [ABSTRACT FROM AUTHOR]

Background: Insulin-like growth factor (IGF) signaling has been linked to tumor cell survival and tumorigenesis. The anti-IGF-1 receptor monoclonal antibody, figitumumab, has been developed as an anti-cancer therapeutic. As part of the safety evaluation, an embryo-fetal developmental toxicity study was conducted in the cynomolgus monkey., Methods: Figitumumab was administered once weekly intravenously at a dose of 5, 15, or 100 mg/kg during the period of major organogenesis (gestation days [GD] 20-48) with scheduled cesarean section around GD100. Maternal endpoints included clinical observations, food consumption, body weights, hematology, placental weights, toxicokinetics, and immunogenicity. Fetal evaluations included viability; body weights; external, visceral, and skeletal examination (and measurements); drug exposure; and immunogenicity., Results: There was a dose-dependent increase in embryo-fetal loss in the presence of decreased maternal food consumption and slight reduction in body weight. Figitumumab-related embryo-fetal developmental toxicity was observed as growth retardation exhibited by reduced fetal body weights at all doses with corresponding developmental delays in morphology. Treatment-related fetal structural malformations were also observed in the mid- and high-dose groups., Conclusions: Maternal figitumumab dosing only during the period of organogenesis was associated with pregnancy loss and fetal growth deficits; both considered consistent with inhibition of IGF signaling. Fetal malformations were also observed, and were considered secondary to altered placental function and/or reduced fetal growth; however, direct inhibition of IGF signaling in the conceptus cannot be ruled out. This appears to be the first report of treatment-related fetal anomalies with a monoclonal antibody when administered only during the period of major organogenesis., (Copyright 2010 Wiley-Liss, Inc.)