Monoclonal antibodies in the prehybridoma era: a brief historical perspective and personal reminiscence.

Emil von Behring, an immunologist, received the first Nobel Prize in Physiology or Medicine in 1901 for his studies on serum therapy of diphtheria. Seventeen Nobel Prizes have been awarded to scientists for their work in immunology and related disciplines. E. Metchnikoff and P. Ehrlich were pioneers who became associated with cellular and humoral theories of immunity, respectively. Almroth Wright described opsonins and was a vigorous advocate of vaccine therapy for bacterial diseases. He was an influential scientist and mentor who served as the model for Bernard Shaw's play, The Doctor's Dilemma. Immunochemistry developed through the work of K. Landsteiner, M. Heidelberger, E. Kabat, and many others. At mid-20th century, cell-selection theories of antibody formation championed by N. Jerne and F.M. Burnet shifted the field from a chemical to a biological orientation. Myeloma immunoglobulins, Bence Jones proteins, and monoclonal macroglobulins from patients and mice played a central role in elucidation of normal immunoglobulin structure, genetics, synthesis, and metabolism. By the late 1960s, antibody activity in some human myeloma and Waldenström macroglobulin paraproteins had been documented. Subsequently, other human paraproteins were shown to have antigen-binding properties, principally to auto- or bacterial antigens. The development of hybridoma technology by G. Köhler and C. Milstein revolutionized immunology after 1975. These investigators demonstrated that antibody-producing cells of virtually any desired specificity could be fused with a myeloma cell line, the result being unlimited amounts of homogeneous (monoclonal) antibodies carrying that specificity. Monoclonal antibodies have been shown to have efficacy in cancer therapy, particularly in patients with lymphoma and breast cancer. It is likely that this approach, alone and in combination with other modalities, will prove useful for patients with additional types of malignancies.