Transgenic mammals and methods of use thereof

A method of producing antibodies comprising fully canine heavy and/or light chain variable domains and mouse constant domains, the method comprising:

• (i) providing a transgenic mouse with a genome in which an entire endogenous immunoglobulin variable gene locus has been deleted and replaced with an engineered partly canine immunoglobulin locus comprising canine immunoglobulin variable gene VH, D and JH and/or canine VL and JL coding sequences and mouse immunoglobulin variable gene locus non-coding regulatory sequences, wherein the engineered partly canine immunoglobulin locus of the transgenic mouse is functional and expresses immunoglobulin chains comprised of canine variable domains and mouse constant domains;
• and
• (ii) isolating the antibodies comprising canine variable regions and mouse constant regions expressed by the transgenic mouse.