Generation of nanobodies from transgenic ‘LamaMice’ lacking an endogenous immunoglobulin repertoire

Thomas Eden, Alessa Z. Schaffrath, Janusz Wesolowski, Tobias Stähler, Natalie Tode, Nathalie Richter, Waldemar Schäfer, Julia Hambach, Irm Hermans-Borgmeyer, Jannis Woens, Camille M. Gall, Sabrina Wendler, Christian Linke-Winnebeck, Martina Stobbe, Iwona Budnicki, Amelie Wanney, Yannic Heitz, Lena Schimmelpfennig, Laura Schweitzer, Dennis Zimmer, Erik Stahl, Fabienne Seyfried, Anna J. Gebhardt, Lynn Dieckow, Kristoffer Riecken, Boris Fehse, Peter Bannas, Tim Magnus, Martijn Verdoes, Carl G. Figdor, Klaus F. Hartlepp, Hubertus Schleer, Jonas Füner, Nicola M. Tomas, Friedrich Haag, Björn Rissiek, Anna M. Mann, Stephan Menzel and Friedrich Koch-Nolte ()
Additional contact information
Thomas Eden: University Medical Center Hamburg-Eppendorf
Alessa Z. Schaffrath: University Medical Center Hamburg-Eppendorf
Janusz Wesolowski: University Medical Center Hamburg-Eppendorf
Tobias Stähler: University Medical Center Hamburg-Eppendorf
Natalie Tode: University Medical Center Hamburg-Eppendorf
Nathalie Richter: University Medical Center Hamburg-Eppendorf
Waldemar Schäfer: University Medical Center Hamburg-Eppendorf
Julia Hambach: University Medical Center Hamburg-Eppendorf
Irm Hermans-Borgmeyer: University Medical Center Hamburg-Eppendorf
Jannis Woens: University Medical Center Hamburg-Eppendorf
Camille M. Gall: Radboud University Medical Center
Sabrina Wendler: Germany - A part of Proteintech Group
Christian Linke-Winnebeck: Germany - A part of Proteintech Group
Martina Stobbe: Germany - A part of Proteintech Group
Iwona Budnicki: Genovac GmbH
Amelie Wanney: Genovac GmbH
Yannic Heitz: Genovac GmbH
Lena Schimmelpfennig: Genovac GmbH
Laura Schweitzer: Genovac GmbH
Dennis Zimmer: Genovac GmbH
Erik Stahl: Preclinics GmbH
Fabienne Seyfried: University Medical Center Hamburg-Eppendorf
Anna J. Gebhardt: University Medical Center Hamburg-Eppendorf
Lynn Dieckow: University Medical Center Hamburg-Eppendorf
Kristoffer Riecken: University Medical Center Hamburg-Eppendorf
Boris Fehse: University Medical Center Hamburg-Eppendorf
Peter Bannas: University Medical Center Hamburg-Eppendorf
Tim Magnus: University Medical Center Hamburg-Eppendorf
Martijn Verdoes: Radboud University Medical Center
Carl G. Figdor: Radboud University Medical Center
Klaus F. Hartlepp: Germany - A part of Proteintech Group
Hubertus Schleer: Genovac GmbH
Jonas Füner: Preclinics GmbH
Nicola M. Tomas: University Medical Center Hamburg-Eppendorf
Friedrich Haag: University Medical Center Hamburg-Eppendorf
Björn Rissiek: University Medical Center Hamburg-Eppendorf
Anna M. Mann: University Medical Center Hamburg-Eppendorf
Stephan Menzel: University Medical Center Hamburg-Eppendorf
Friedrich Koch-Nolte: University Medical Center Hamburg-Eppendorf

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Due to their exceptional solubility and stability, nanobodies have emerged as powerful building blocks for research tools and therapeutics. However, their generation in llamas is cumbersome and costly. Here, by inserting an engineered llama immunoglobulin heavy chain (IgH) locus into IgH-deficient mice, we generate a transgenic mouse line, which we refer to as ‘LamaMouse’. We demonstrate that LamaMice solely express llama IgH molecules without association to Igκ or λ light chains. Immunization of LamaMice with AAV8, the receptor-binding domain of the SARS-CoV-2 spike protein, IgE, IgG2c, and CLEC9A enabled us to readily select respective target-specific nanobodies using classical hybridoma and phage display technologies, single B cell screening, and direct cloning of the nanobody-repertoire into a mammalian expression vector. Our work shows that the LamaMouse represents a flexible and broadly applicable platform for a facilitated selection of target-specific nanobodies.

Date: 2024
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DOI: 10.1038/s41467-024-48735-x

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