Diverse human V_H antibody fragments with bio-therapeutic properties from the Crescendo Mouse

We describe the 'Crescendo Mouse', a human V_H transgenic platform combining an engineered heavy chain locus with diverse human heavy chain V, D and J genes, a modified mouse Cγ1 gene and complete 3' regulatory region, in a triple knock-out (TKO) mouse background devoid of endogenous immunoglobulin expression. The addition of the engineered heavy chain locus to the TKO mouse restored B cell development, giving rise to functional B cells that responded to immunization with a diverse response that comprised entirely 'heavy chain only' antibodies. Heavy chain variable (V_H) domain libraries were rapidly mined using phage display technology, yielding diverse high-affinity human V_H that had undergone somatic hypermutation, lacked aggregation and showed enhanced expression in E. coli. The Crescendo Mouse produces human V_H fragments, or Humabody® V_H, with excellent bio-therapeutic potential, as exemplified here by the generation of antagonistic Humabody® V_H specific for human IL17A and IL17RA.