Complex chromosome engineering for production of human antibodies in transgenic animals

A human artificial chromosome (HAC) vector comprising one or more human immunoglobulin heavy and light chain loci that are capable of undergoing rearrangement and expression in B-cells to produce a human immunoglobulin in response to exposure to one or more antigens, wherein said immunoglobulin loci comprise:

• (a) a gene encoding one or more human antibody heavy chains comprising at least a human IgG heavy chain, a human IgA heavy chain or both human IgG and IgA heavy chains, wherein each gene encoding an antibody heavy chain is operatively linked to its own class switch regulatory element upstream of the human antibody heavy chain;
• (b) a gene encoding one or more human antibody light chains;
• and
• (c) a gene encoding a human-ungulate chimeric IgM heavy chain constant region encoding constant heavy (CH) domains CH1, CH2, CH3 and CH4, and transmembrane domains (TM) TM1 and TM2, wherein the encoded CH1, CH2, and CH3 domains are human, and the encoded CH4, TM1 and TM2 domains are ungulate;
• wherein at least one class switch regulatory element of the genes encoding the one or more human antibody heavy chains is replaced with an ungulate class switch regulatory element selected from the group consisting of Imu-Smu (Iμ-Sμ), Igamma-Sgamma (Iγ-Sγ), Ialpha-Salpha (Iα-Sα), and Iepsilon-Sepsilon (Iε-Sε) ungulate class switch regulatory elements.