Human monoclonal antibodies to glycolipids and other carbohydrate antigens: dissection of the humoral immune response in cancer patients.

Of the many fields of study that have benefited by monoclonal antibody technology, the analysis of molecules that comprise the mammalian cell surface has been particularly revolution ized. Although conventional serology with immune sera had built an admirable edifice of knowledge about blood group antigens, histocompatibility antigens, and differentiation anti gens in mice and humans, the advent of monoclonal antibodies has revealed how much more there was to learn about the rich diversity of molecules displayed on the cell surface. Every aspect of the study of surface antigens has been greatly facilitated by monoclonal antibodies, from biochemical characterization, tis sue distribution, and chromosomal mapping to cloning the genetic sequences coding the antigens. In the study of surface antigens in human cancer, most attention has been focused on monoclonal antibodies of mouse origin, and a rather compre hensive picture of surface glycoprotein and glycolipid antigens has begun to emerge (1-4). Comparable information about the repertoire of human cancer antigens recognized by human monoclonal antibodies has lagged behind, primarily because of technical difficulties involved in generating and stabilizing hu man monoclonal antibodies secreting clones. Although these problems have not been completely solved, techniques for pro ducing human monoclonal antibodies have advanced to the stage that the human humoral response to human cancer can be assessed at a clonal level. This survey is just beginning, but it is already clear that the frequency of antibodies to glycolipids, particularly gangliosides, is particularly high. Reactivity against some of these gangliosides was unpredicted on the basis of serum serology and expression in normal tissues; thus surprises can be expected with regard to the immunogenicity of normal autoantigens as well as tumor antigens. To provide a perspective on the emerging new information about glycolipid immunoge nicity that will be forthcoming through the analysis of human monoclonal antibodies, we will summarize current knowledge about (a) the structure of neutral and acidic glycolipids found in normal and neoplastic human tissues, (b) the specificity of standard mouse monoclonal antibodies recognizing major gly colipid structures, and (c) the immunogenicity of glycolipids surmised through the analysis of antibodies present in sera of normal individuals and individuals with cancer and autoim mune diseases. We will then discuss what is known of the reactivity and fine specificity of the antiglycolipid human mono clonal antibodies that have been isolated to date and conclude by reviewing ongoing applications of human monoclonal anti body methodology and technical limits restricting its usefulness.