In vitro correlates of the acute toxic syndrome induced by some monoclonal antibodies: a rationale for the design of predictive tests

• Published in: Toxicology (Amsterdam) Vol. 96; no. 1; pp. 51 - 58
• Main Authors: Revillard, J.P., Robinet, E., Goldman, M., Bazin, H., Latinne, D., Chatenoud, L.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 19.01.1995; Amsterdam Elsevier Science
• Subjects: Activation syndrome; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - toxicity; Biological and medical sciences; Biotechnology; Blood Platelets - drug effects; Blood Platelets - immunology; Drug toxicity and drugs side effects treatment; Endothelium - cytology; Humans; Lymphocyte Activation - drug effects; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Monoclonal antibodies; Monocytes - drug effects; Monocytes - immunology; Pharmacology. Drug treatments; Predictive tests; Syndrome; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumor Necrosis Factor-alpha - metabolism; Monoclonal antibodies; Predictive tests; Activation syndrome; Human; Drug; Biotechnology; Toxicity; Prediction; Monoclonal antibody; In vitro; Symptomatology; Antigenicity; Investigation method; Test; Animal; Recombinant protein; Mechanism of action
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/0300-483X(94)02975-Z

Monoclonal antibodies (mAbs) and proteins produced by recombinant DNA technology are not only powerful tools for biomedical research but many of them are already used in human clinical applications. For instance, the CD3 mAb OKT3, secreted by a murine hybridoma cell line, is a powerful immunosuppressive agent currently used in the treatment of acute graft versus host disease after bone marrow transplantation and acute rejection of transplanted organs. Many other mAbs have been subjected to controlled or open clinical trials. For instance mAbs specific for the alpha chain of the interleukin-(IL-)2 receptor, CD25, have been used in renal and liver transplantation and a mAb which reacts with the integrin CD11a/CD18 on leukocyte membranes was shown to markedly improve the rate of success of non-HLA-compatible bone marrow transplantation in children. This paper will address the following issues: (1) is it possible to delineate a common pattern of clinical side-effects among those reported in patients treated with these products? (2) can we identify on the basis of clinical and experimental data some key mediators which may play a central role in the generation of the adverse reactions; (3) is it feasible to design in vitro toxicity assays that could predict these adverse reactions at an early stage of the preclinical development of a monoclonal antibody? (4) what should be the guidelines recommended for evaluating such tests?