Mice that make heavy chain antibodies

A method of providing a rodent that expresses IgG heavy chain antibodies lacking a CH1 domain and also expresses IgM antibodies comprised of two light chains and two heavy chains, which IgM heavy chains each include a functional CH1 domain, the method comprising:

• (i) genetically modifying a rodent embryonic stem(ES) cell such that it comprises, at an endogenous Ig heavy chain constant region,
• (a) an endogenous IgM constant region gene that encodes an endogenous IgM isotype comprising a CH1 domain, and
• (b) a replacement of an endogenous IgG constant region gene with a genetically modified rodent IgG constant region gene,
• wherein the endogenous IgG constant region gene and the genetically modified rodent IgG constant region gene encode the same isotype, and
• wherein the genetically modified rodent IgG constant region gene comprises:
• a nucleotide sequence comprising from 5′ to 3′:
• an endogenous switch region, a splice acceptor, a CH2 exon, a CH2 intron, and a CH3 exon, and
• deletion in a sequence encoding a CH1 domain, and encodes a rodent IgG isotype devoid of a CH1 domain and
• (ii) generating a genetically modified rodent from the genetically modified rodent ES cell,
• wherein the generated rodent expresses
• (a) an IgM immunoglobulin heavy chain that comprises an Ig heavy chain variable domain operably linked to the endogenous IgM isotype comprising a CH1 domain, and
• (b) an IgG immunoglobulin heavy chain that consists essentially of, from N-terminal to C-terminal, an Ig heavy chain variable domain operably linked to the rodent IgG isotype devoid of a CH1 domain, and
• wherein the rodent is a rat or a mouse.