From bench to bedside: discovering rules for antibody design, and improving serotherapy with monoclonal antibodies.
Anti-T-cell monoclonal antibodies (mAbs) form a unique class of therapeutic agent. Their precise specificity offers tremendous potential for the treatment of autoimmune and inflammatory diseases but also prevents meaningful preclinical animal studies. In particular, adverse reactions to therapy may be unanticipated, and the first administration of a novel T-cell mAb to a patient thus marks the beginning of a unique experiment. By comparing clinical parameters and laboratory measurements, small-scale pilot studies can provide detailed information about mAb biology that both predicts and suggests solutions to the complications of therapy. In this essay I illustrate this concept with reference to three specific areas: lymphocyte depletion, mAb immunogenicity and cytokine-release syndromes. In each case, systematic clinical and laboratory science has improved our understanding of the problem and suggested solutions; most of these solutions have been or are being adopted. Thus, small, open studies are an essential step in the development of novel mAbs, provide an ideal platform for the study of mAb biology, and serve as an early warning system for potential adverse effects.
Isaacs
J D
JD
Rheumatology and Rehabilitation Research Unit/Molecular Medicine Unit, Clinical Sciences Building, St James's University Hospital, Leeds LS9 7TF, UK.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy; D002986:Clinical Trials as Topic; D016207:Cytokines; D015195:Drug Design; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D066298:In Vitro Techniques; D008212:Lymphocyte Depletion; D010865:Pilot Projects; D015202:Protein Engineering; D011961:Receptors, Fc / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D011961:Receptors, Fc; C035311:immunoglobulin M receptor