Engineering of pH-dependent antigen binding properties for toxin-targeting IgG1 antibodies using light-chain shuffling.

Autor:	Tulika T; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Ruso-Julve F; Department of Pharmacology, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Precision Immunotherapy Alliance (PRIMA), University of Oslo, Oslo, Norway., Ahmadi S; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Ljungars A; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Rivera-de-Torre E; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Wade J; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Fernández-Quintero ML; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Jenkins TP; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Belfakir SB; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark; VenomAid Diagnostics ApS, Lyngby, Denmark., Ross GMS; VenomAid Diagnostics ApS, Lyngby, Denmark., Boyens-Thiele L; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Buell AK; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Sakya SA; Department of Pharmacology, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Precision Immunotherapy Alliance (PRIMA), University of Oslo, Oslo, Norway., Sørensen CV; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Bohn MF; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Ledsgaard L; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Voldborg BG; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Francavilla C; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Schlothauer T; Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany., Lomonte B; Instituto Clodomiro Picado, Facultad de Microbiologia, Universidad de Costa Rica, San Jose, Costa Rica., Andersen JT; Department of Pharmacology, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Precision Immunotherapy Alliance (PRIMA), University of Oslo, Oslo, Norway. Electronic address: j.t.andersen@medisin.uio.no., Laustsen AH; Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark. Electronic address: ahola@bio.dtu.dk.
Jazyk:	angličtina
Zdroj:	Structure (London, England : 1993) [Structure] 2024 Sep 05; Vol. 32 (9), pp. 1404-1418.e7. Date of Electronic Publication: 2024 Aug 14.
DOI:	10.1016/j.str.2024.07.014
Abstrakt:	Immunoglobulin G (IgG) antibodies that bind their cognate antigen in a pH-dependent manner (acid-switched antibodies) can release their bound antigen for degradation in the acidic environment of endosomes, while the IgGs are rescued by the neonatal Fc receptor (FcRn). Thus, such IgGs can neutralize multiple antigens over time and therefore be used at lower doses than their non-pH-responsive counterparts. Here, we show that light-chain shuffling combined with phage display technology can be used to discover IgG1 antibodies with increased pH-dependent antigen binding properties, using the snake venom toxins, myotoxin II and α-cobratoxin, as examples. We reveal differences in how the selected IgG1s engage their antigens and human FcRn and show how these differences translate into distinct cellular handling properties related to their pH-dependent antigen binding phenotypes and Fc-engineering for improved FcRn binding. Our study showcases the complexity of engineering pH-dependent antigen binding IgG1s and demonstrates the effects on cellular antibody-antigen recycling. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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