Antibody Discovery from Immune Competent and Immune Transplanted Mice
Benjamin C. Harman, Jill Giles-Komar and Michael A. Rycyzyn
Affiliation: Biologics Research, Biotechnology Center of Excellence, Janssen Research and Development, PO Box 776, Welsh and McKean Roads, Spring House, PA 19477, USA.
Keywords: Antibody, drug discovery, hybridoma, humanized mice, immune response.
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
Rights & PermissionsPrintExport