Antibody discovery from immune competent and immune transplanted mice

Since Kohler and Milstein developed the process of generating hybridomas by fusing antibody secreting B cells with an immortal myeloma cell line, the techniques used to develop monoclonal antibodies for use as human therapeutics have progressed significantly. Here, we will briefly review hybridoma technology and the evolution of therapeutic antibodies for the treatment of human disease. We will focus on the evolution of humanized mouse models for the generation of therapeutic human antibodies, comparing the early models, such as severe combined immunodeficient (SCID) mice which do not engraft human leukocytes well due to residual innate immunity, to the more recently developed models such as non-obese diabetic (NOD)/SCID IL-2Rγ-deficient mice in which numerous human hematopoietic lineages can be cultivated. Building on the identification of suitable host strains for the reconstitution of human immune cells, focus has now shifted onto humanizing the murine microenvironment in order to support human immune cell function. Although several recent studies have shown that the provision of human soluble factors can support maturation and function of human immune cells, particularly within the myeloid compartment, this does not appear to impact antibody production significantly. Moreover, models in which grafting of human tissues is performed to provide human microenvironments which support human leukocyte maturation do show improved humoral immune function, but require several surgical manipulations for generation of the model. Ultimately the most desirable scenario is to generate transgenic models that can be bred efficiently and express a sufficient number of human molecules to support functional human immune cells and several groups have made progress in making this idea a reality. These studies in the context of the generation of human antibodies will be discussed.