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We are now rather close to understanding the mechanisms whereby antibody combining site diversity is generated. As this story has unfolded over the past several years, a number of unique genetic mechanisms have been uncovered and many of the issues that fueled controversy among laboratories have been resolved.

Herman Moritz Kalckar was born of Ludvig Kalckar and Bertha Melchior in Copenhagen, Denmark, on March 26, 1908. He received his M.D. degree from the University of Copenhagen and later served as Associate Professor in the University’s Institute of Medical Physiology. In January 1939 he left for the United States where he travelled under the auspices of the Rockefeller Foundation. He then worked successively at the Public Health Research Institute of New York and at the National Institutes of Health in Bethesda. In 1958 he was appointed Professor of Biology at Johns Hopkins University, and in 1961 as Professor of Biological Chemistry at Harvard Medical School and Wellcome Biochemist and Chief of Biochemical Research at the Massachusetts General Hospital. At present he is Emeritus Professor at Harvard University and Distinguished Research Professor of Biochemisty at Boston University.

Clinicians and research scientists alike have for years utilized the immune response to generate antibodies to probe physiologic and biochemical systems. Polyclonal antibody found in the course of the humoral response to an antigen may detect, quantify, and localize small amounts of material in complex mixtures. Were it not for the heterogeneity and unpredictability of the immune reponse, immunologic assays might have had an even greater application. With the introduction of somatic cell fusion most of the problems associated with polyclonal antisera and their application to basic and clinical questions are likely to be overcome.

Antibodies are characterized by regions of conserved as well as variable amino acid sequence. Small portions of each molecule, highly variable in structure (the complementarity-determining regions), are arranged to form the surface that binds antigen. The amino acid sequences of the polypeptide chain segments that fold to form this region (approximately 60 amino acid residues) determine the nature of the antigen recognized. Three segments of the heavy and three of the light chain participate in forming the site.

The immune system is characterized by a remarkable diversity of antibody specificities. The massive body of experimental data accumulated by Landsteiner (34) attests to the fact that nearly any complex organic molecule may act as an antigenic determinant and that antibodies may readily differentiate among structures which differ only slightly. Thp capacity to recognize a unique molecule within a complex mixture has been exploited extensively in recent years in the development of specific and, sensitive radioimmunoassays (59).

The explosive growth in the number of laboratories involved in the production of murine monoclonal antibodies in vitro using hybridoma technology (Kohler and Milstein, 1975) is a testimony to the utility of monoclonal antibodies as research tools. It is also clear that monoclonal antibodies produced in vitro are unique reagents which might provide the clinician with an exciting new means of diagnosing and treating human disorders. Xenogeneic-elicited antibodies have already been used in the reversal of drug toxicity in man (Smith et al., 1976), the scintigraphic imaging of myocardial infarcts (Khaw et al., 1978a, b), and the imaging of tumors in man (Chose et al., 1975; Goldenberg et al., 1978). Especially in the case where utilization in vivo of antibody in humans is contemplated, human monoclonal antibodies would be ideal reagents. Administration of human, instead of xenogeneic, antibodies to patients would eliminate the risk of serum sickness, anaphylactic reaction, or other allergic sequelae often associated with the administration of nonhuman protein to patients.

Of all classes of compounds, antibodies provide the greatest range of specificities and affinities. The number of interatomic interactions between an antibody combining site and a large ligand such as a receptor far exceeds those between the common small ligand or drug and its corresponding binding site.1 As a result, there is increased selectivity and affinity. The very large number of potential antibody specificities provides an opportunity to create a finer degree of selectivity than is possible with simpler compounds. Modern studies in the molecular genetics of antibody synthesis indicate that potentially there are at least ten billion different antibody specificities.2,3 This should permit the selective recognition of any structure within the human body.

It has long been believed that the conversion of the inactive decapeptide hormone angiotensin I (AI) to angiotensin II (AII) was mediated by a plasma dicarboxypeptidase (1). More recently the provocative experiments of Ng and Vane (2) suggested that the major site of conversion was the pulmonary circulation and that conversion in plasma could not account for the rapid pressor response to an intravenous injection of AI.