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

Autor: Carlo V. Bruschi, Lluis Montoliu, Brian Mcguinness, Dmitri Nikitin, Mike Romanos, Philip Hayes, Lorraine Thompson, Anne E. Corcoran, Colette Johnston, Michele Writer, Krešimir Gjuračić, Peter Chovanec, Yun Sanders, Yumin Teng, Joyce Young, Yanjing Zhang, Louise S. Matheson, Bryan Edwards, Valentina Tosato, Beatrice Rossi, Thomas Sandal, Carolyn Edwards, Debora Pinto, Mila Roode, Almudena Fernández
Rok vydání: 2020
Předmět:
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
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ISSN: 1871-6784
DOI: 10.1016/j.nbt.2019.10.003
Popis: © 2019 The Authors.
We describe the ‘Crescendo Mouse’, a human VH 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 (VH) domain libraries were rapidly mined using phage display technology, yielding diverse high-affinity human VH that had undergone somatic hypermutation, lacked aggregation and showed enhanced expression in E. coli. The Crescendo Mouse produces human VH fragments, or Humabody® VH, with excellent bio-therapeutic potential, as exemplified here by the generation of antagonistic Humabody® VH specific for human IL17A and IL17RA.
Databáze: OpenAIRE
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