In fact, seven human antibodies approved for clinical use by the US Food and Drug Administration were discovered using transgenic mice first developed over 20 years ago 5. This approach allows highly evolved in vivo mechanisms, such as hypermutation in germinal centers, to be exploited to generate high-affinity antibodies with optimal biophysical properties 2, 3, 4. One attractive approach for generating fully human antibodies is to use transgenic animals engineered to express a human antibody repertoire. They can also be immunogenic in patients, leading to attenuation of their efficacy over time. These antibodies often have suboptimal biophysical attributes, leading to difficulties in manufacture and in poor pharmacokinetics. However, antibodies discovered using phage libraries show limited diversity and non-native pairing of immunoglobulin heavy and light chains moreover, improving their affinity requires iterative, time-consuming, in vitro methods, which take place outside the natural controls on a mammalian B cell. More recently, fully human antibodies have been generated using phage libraries and transgenic animals. The first approved therapeutic monoclonal antibodies (mAbs) were derived by humanization of rodent antibodies. In drug development, antibodies are often preferred over small molecules since they are natural products with exquisite specificity and potency, have a known volume of distribution in the body and generally have superior safety profiles. These mice provide a robust system for the discovery of therapeutic human monoclonal antibodies as a surrogate readout of the human antibody response, they may also aid vaccine design efforts.Īntibodies constitute the fastest-growing and most advanced class of pharmaceuticals today 1. Antigen immunization results in production of high-affinity antibodies with long human-like complementarity-determining region 3 (CDR3H), broad epitope coverage and strong signatures of somatic hypermutation. These transgenic mice are viable and fertile, with an immune system resembling that of wild-type mice. Here, using repetitive cycles of genome engineering in embryonic stem cells, we have inserted the entire human immunoglobulin variable-gene repertoire (2.7 Mb) into the mouse genome, leaving the mouse constant regions intact. However, technical limitations inherent to conventional transgenic technology and sequence divergence between the human and mouse immunoglobulin constant regions limit the utility of these mice. If immunized with an antigen of interest, transgenic mice with large portions of unrearranged human immunoglobulin loci can produce fully human antigen-specific antibodies several such antibodies are in clinical use.
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