Humanized rodents for testing therapeutic agents

Abstract

Provided herein are methods and compositions related to the in vivo testing of therapeutic agents comprising a human Fc in genetically modified rodents (e.g., the testing of the pharmacokinetic and/or pharmacodynamic properties of such a therapeutic agent in genetically modified rodents). In some embodiments the genetically modified rodents express antibodies comprising a human Fc (e.g., a human IgG1 Fc, a human IgG4 Fc). In some embodiments, the rodents express fully human antibodies (i.e., antibodies having human heavy chains and human light (γ or κ) chains). In certain embodiments the genetically modified rodents comprise one or more Fc receptors with a human extracellular domain (e.g., a Neonatal Fc Receptor (FcRn), a β-2-microglobulin polypeptide (β2M), a Fc ε receptor 1 α (FcεR1α), a Fc γ receptor 1 alpha (FcγR1a), a Fc gamma receptor 2a (FcγR2a), a Fc gamma receptor 2b (FcγR2b), a Fc gamma receptor 3a (FcγR3a), a Fc gamma receptor 3b (FcγR3b), a Fc gamma receptor 2c (FcγR2c)). The transmembrane and cytoplasmic domain of such receptors can be human or non-human (e.g., rodent).

What is claimed is: 
     
         1 . A rodent comprising in its genome a neonatal Fc receptor (FcRn) locus comprising a nucleic acid sequence encoding an FcRn polypeptide comprising a human extracellular domain and a rodent cytoplasmic domain. 
     
     
         2 . The rodent of  claim 1 , further comprising in its genome β-2-microglobulin (β2M) locus comprising a nucleic acid sequence encoding a human or humanized β-2-microglobulin (β2M) polypeptide. 
     
     
         3 . A rodent comprising in its genome a Fc epsilon receptor 1 alpha (FcεR1α) locus comprising a nucleic acid sequence encoding FcεR1α polypeptide comprising a human extracellular domain.