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Walter, J.D.* ; Beffinger, M.* ; Egloff, P.* ; Zimmermann, I.* ; Hürlimann, L.M.* ; Ackle, F.* ; Seifert, M.* ; Kobold, S. ; vom Berg, J.* ; Seeger, M.A.*

Flycodes enable simultaneous preclinical analysis for dozens of antibodies in single cassette-dosed mice.

Proc. Natl. Acad. Sci. U.S.A. 122:e2426481122 (2025)

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Protein therapeutics such as antibodies require in-depth in vivo characterization during development and consequently account for a large proportion of laboratory animal consumption in the pharmaceutical industry. Currently, antibody candidates are exhaustively tested one-by-one in animal models to determine pharmacokinetic and pharmacodynamic (PK/PD) profiles. The simultaneous analysis of antibody mixtures in single animals, called cassette-dosing, could in principle overcome this bottleneck, but is currently limited to small cassette sizes. Here, we demonstrate how the use of genetically encoded peptide tags (flycodes), designed for maximal detectability in liquid chromatography-mass spectrometry, can allow for the simultaneous characterization of large pools of drug candidates, from single cassette-dosed mice. We demonstrate the simultaneous assessment of PK parameters for a group of >20 marketed/development-stage antibodies. Biodistribution experiments in mice bearing EGFR-expressing tumors correctly identified the two pool members recognizing EGFR, while organ analysis registered liver accumulation of an antibody targeting glucagon receptor, a protein profoundly expressed in that organ. In analogy to an early-phase drug development campaign, we performed biophysical and PK analysis for a cassette of 80 unique bispecific DARPin-sybody molecules. The data shown in this study originate from only 18 cassette-dosed mice, thereby demonstrating how flycode technology efficiently advances preclinical discovery pipelines allowing a direct comparison of drug candidates under identical experimental conditions.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Antibodies ; Cassette Dosing ; Flycodes ; Mass Spectrometry ; Sybodies; Glucagon Receptor Antibody; Half-life Extension; Monoclonal-antibody; Albumin-binding; Pharmacokinetics; Protein; Biotherapeutics; Expression; Generation

ISSN (print) / ISBN 0027-8424

e-ISSN 1091-6490

Journal Proceedings of the National Academy of Sciences of the United States of America

Quellenangaben Volume: 122, Issue: 12, Article Number: e2426481122

Publisher National Academy of Sciences

Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa

Reviewing status Peer reviewed

Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)

Grants Swiss National Science Foundation (SNF)
Elite Network of Bavaria
Institutional Strategy LMU excellent of Ludwig Maximilian University of Munich
European Research Council (ERC)
Ernst Jung Stiftung
Swiss Cancer Research
Lindonlight Collective LLC
Swiss NSF
Swiss Life Jubilaeumsstiftung
Novartis Foundation for Medical-Biological Research
SNSF Professorship of the Swiss NSF
BioEntrepreneur-Fellowship of the University of Zurich
Go-Bio-Initiative,the m4-Award of the Bavarian Ministry for Economical Affairs, Bundesministerium fur Bildung und Forschung
Melanoma Research Alliance
ERC

Hector Foundation
DeutscheJose Carreras Leukaemie Stiftung
Wilhelm Sander-Stiftung
German Cancer Aid
Fritz-Bender Foundation
Else Kroener-Fresenius-Stiftung
Deutsche Forschungsgemeinschaft (DFG)
European Union
SNSF BRIDGE proof of concept grant