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.
Mine samples enriched for Thiobacillus ferrooxidans at 18, 12 and 6°C, after numerous transfers in medium 9K, yielded average generation times of 23, 44, and 103 hr, respectively. Temperature characterization of 'a natural isolate, over a range of 6 to 35°C, showed that growth occurred at the temperature extremes and that the optimum temperature for growth was 25 to 30°C. A stock culture (commercially available) chosen for comparison showed a similar optimum temperature for growth, but lower growth rates at the lower temperatures examined. Growth studies of the natural isolates in the range of 2 to 35°C revealed that growth rates decreased on either side of 25 to 30°C. This effect was most pronounced in the 2 to 12~C range. These studies revealed the psychrotrophic nature of the natural T, ferrooxidans isolates, and their better growth capabilities at lower temperatures than T. ferrooxidans ATCC 33020. These observations are discussed in the light of their importance in the uranium bioleaching process, as it is currently being used.The bacterial leaching of uranium from low-grade ores, for which it is not economically feasible to concentrate uranium by conventional means, is a notable contribution to energy production. Insoluble tetravalent uranium oxide (U02) is converted to the leachable hexavalent species (UO2S04) by ferric ions (Fe3+), according to the following equation:U0z + 2Fe3 + + 5042 -UO2SO4 + 2Fe2 +The bacterium Thiobacillus ferrooxidans generates the oxidant (Fe3+) required for this reaction by oxidizing the ferrous (Fe2+) iron which often accompanies uranium
Safety concerns surrounding the use of recombinant human erythropoietin (Epo) to treat anemia in cancer patients were raised after 2 recent clinical studies reported a worse survival outcome in patients who received epoetin a or epoetin b compared with patients who received placebo. Although those findings con- KEYWORDS: tumor, erythropoietin, receptor, proliferation, survival, angiogenesis, animal models, hypoxia.C oncerns that recombinant human erythropoietin (rHuEpo) may adversely affect the survival of cancer patients through promoting tumor growth recently were raised by 2 randomized clinical trials that used rHuEpo to prevent anemia in patients with breast or head and neck cancer. 1,2 In those trials, decreased survival and increased tumor progression were observed in patients who received epoetin a or epoetin b compared with patients who received placebo. These outcomes were in contrast to many clinical trials, which demonstrated that erythropoiesis-stimulating agents (ESAs) are safe and efficacious for the treatment of anemia in cancer patients. 3,4 These trials were criticized for poor study design and execution. 4 However, a number of hypotheses were proposed to explain the potential role of ESAs in promoting tumor proliferation and reduced survival including, stimulation of tumor expression of the erythropoietin (Epo) receptor (EpoR), tumor neovascularization, enhanced tumor oxygenation, and, most recently, the role of coadministered iron, 5 although that topic is not addressed herein.This review reflects conclusions from a comprehensive survey of the literature that investigated the expression and function of EpoR
Selection of a pharmacologically responsive species can represent a major challenge in designing nonclinical safety assessment programs for many biopharmaceuticals (eg, monoclonal antibodies (mAbs)). Frequently, the only relevant species for nonclinical testing of mAbs is the non-human primate (NHP). This situation, coupled with a rapidly increasing number of mAb drugs in development, has resulted in a significant increase in the number of NHPs used in nonclinical safety assessment. Apart from ethical considerations related to responsible animal use, there is a clear need for more efficient and innovative approaches to drug discovery and development; these factors drive the need to investigate alternative approaches and strategies for the safety assessment. This review summarizes important scientific and regulatory perspectives derived from presentations and audience discussions in an educational forum at the 2010 annual American College of Toxicology meeting regarding opportunities for employing alternative approaches to minimize NHP use in mAb drug development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.