Bovine ultralong CDR-H3 derived knob paratopes elicit potent TNF-α neutralization and enable the generation of novel adalimumab-based antibody architectures with augmented features
Author:
Arras Paul123, Zimmermann Jasmin1, Lipinski Britta12, Valldorf Bernhard3, Evers Andreas1ORCID, Elter Desislava1, Krah Simon1, Doerner Achim1, Guarnera Enrico1, Siegmund Vanessa4, Kolmar Harald5ORCID, Pekar Lukas1ORCID, Zielonka Stefan12ORCID
Affiliation:
1. Antibody Discovery & Protein Engineering , Merck Healthcare KGaA , Frankfurter Straße 250, D-64293 Darmstadt , Germany 2. Biomolecular Immunotherapy , Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt , Peter-Grünberg-Strasse 4, D-64287 Darmstadt , Germany 3. Targeted mRNA Delivery , Merck KGaA , Frankfurter Straße 250, D-64293 Darmstadt , Germany 4. Early Protein Supply & Characterization, Merck Healthcare KGaA , Frankfurter Straße 250, D-64293 Darmstadt , Germany 5. Applied Biochemistry , Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt , Peter-Grünberg-Strasse 4, D-64287 Darmstadt , Germany
Abstract
Abstract
In this work we have generated cattle-derived chimeric ultralong CDR-H3 antibodies targeting tumor necrosis factor α (TNF-α) via immunization and yeast surface display. We identified one particular ultralong CDR-H3 paratope that potently neutralized TNF-α. Interestingly, grafting of the knob architecture onto a peripheral loop of the CH3 domain of the Fc part of an IgG1 resulted in the generation of a TNF-α neutralizing Fc (Fcknob) that did not show any potency loss compared with the parental chimeric IgG format. Eventually, grafting this knob onto the CH3 region of adalimumab enabled the engineering of a novel TNF-α targeting antibody architecture displaying augmented TNF-α inhibition.
Publisher
Walter de Gruyter GmbH
Reference45 articles.
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