Abstract
Monoclonal antibody (mAb) therapeutics have a promising outlook within the pharmaceutical industry having made positive strides in both research and development as well as commercialisation, however this development has been hampered by manufacturing failures and attrition. This study explores the applicability of traditional in vitro toxicity tests for detecting any off-target adverse effect elicited by mAbs on specific organ systems using hepatocarcinoma cell line (HepG2) and human dermal fibroblasts neonatal (HDFn), respectively. The mechanism of antibody dependent cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) via complement activation, and complement dependent cellular cytotoxicity (CDCC) were assessed. Major results: no apparent ADCC, CDCC, or CDC mediated decrease in cell viability was measured for HepG2 cells. For HDFn cells, though ADCC or CDCC mediated decreases in cell viability wasn’t detected, a CDC mediated decrease in cell viability was observed. Several considerations have been elucidated for development of in vitro assays better suited to detect off target toxicity of mAbs.
Highlights
Monoclonal antibody therapeutics currently dominate many therapeutic areas such as oncology and rheumatism
Effector functions of Monoclonal antibody (mAb) such as phagocytosis, antibody dependent cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) via complement activation, and complement dependent cellular cytotoxicity (CDCC) are regulated by the interaction between the Fc region of mAbs with the receptors on immune cells [2,3].This requires the co culture of target cells with immune responsive cells, such as Peripheral Blood Mononuclear Cells (PBMCs), to elicit the immune response pre requisite for causing adverse effects that could lead to off-target toxicity
The in vitro systems selected in this study were based on the two main adverse effects associated with based therapeutics: dermal
Summary
Monoclonal antibody (mAb) therapeutics currently dominate many therapeutic areas such as oncology and rheumatism. The non-clinical safety testing of mAbs are different and more complex when compared to small molecules owing to innate differences in structure, clearance, mechanism of action, and specificity of immune responses elicited [1]. The main considerations for development of non-clinical safety testing strategies for mAbs are: co-incubation of cell line of interest with immune responsive cells; optimisation of cell density and incubation times; and choice of off-target organ system and assay endpoint. Effector functions of mAbs such as phagocytosis, antibody dependent cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) via complement activation, and complement dependent cellular cytotoxicity (CDCC) are regulated by the interaction between the Fc region of mAbs with the receptors on immune cells [2,3].This requires the co culture of target cells with immune responsive cells, such as Peripheral Blood Mononuclear Cells (PBMCs), to elicit the immune response pre requisite for causing adverse effects that could lead to off-target toxicity. PBMCs comprise of B cells, T cells, Antibodies 2018, 7, 30; doi:10.3390/antib7030030 www.mdpi.com/journal/antibodies
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