Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice

• DOI: 10.1073/pnas.1324022111
• Publication Date: 2014-03-26T01:11:36Z
• Authors: Andrew J. Murphy; Lynn E. Macdonald; Sean Stevens; Margaret Karow; Anthony T. Dore; Kevin Pobursky; Tammy T. Huang; William T. Poueym...; Lakeisha Esau; Melissa Meola; Warren Mikulka; Pamela Krueger; Jeanette Fairhurst; David M. Valenzuela; Nicholas Papadopo...; George D. Yancopo...
• Keywords: 0301 basic medicine; B-Lymphocytes; Multidisciplinary; Genes, Immunoglobulin; Flow Cytometry; 3. Good health; Mice; 03 medical and health sciences; Antibody Formation; Mutation; Animals; Humans; Alleles

Mice genetically engineered to be humanized for their Ig genes allow human antibody responses within a mouse background (HumAb mice), providing valuable platform the generation of fully therapeutic antibodies. Unfortunately, existing HumAb mice do not have functional immune systems, perhaps because manner in which genetic humanization was carried out. Heretofore, been generated by disrupting endogenous and simultaneously introducing transgenes at different random location; KO-plus-transgenic humanization. As we describe companion paper, attempted make that more efficiently use variable region segments humoral precisely replacing 6 Mb heavy kappa light germ-line gene with counterparts while leaving constant regions intact, using unique situ approach. We reasoned introduced would function indistinguishably new location, whereas retained optimal interactions selection resulting antibodies environment. show these mice, termed VelocImmune they were VelociGene technology, produce human:mouse hybrid (that are rapidly convertible antibodies) systems indistinguishable from those WT mice. The efficiency approach is confirmed rapid progression 10 into clinical trials.