Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Humanization of pan-HLA-DR mAb 44H10 Hinges on Critical Residues in the Antibody Framework

Version 1 : Received: 21 May 2024 / Approved: 21 May 2024 / Online: 22 May 2024 (14:46:25 CEST)

How to cite: Kassardjian, A.; Ivanochko, D.; Barber, B.; Jetha, A.; Julien, J.-P. Humanization of pan-HLA-DR mAb 44H10 Hinges on Critical Residues in the Antibody Framework. Preprints 2024, 2024051417. https://doi.org/10.20944/preprints202405.1417.v1 Kassardjian, A.; Ivanochko, D.; Barber, B.; Jetha, A.; Julien, J.-P. Humanization of pan-HLA-DR mAb 44H10 Hinges on Critical Residues in the Antibody Framework. Preprints 2024, 2024051417. https://doi.org/10.20944/preprints202405.1417.v1

Abstract

Reducing the immunogenicity of animal-derived monoclonal antibodies (mAbs) for use in humans is critical to maximize therapeutic effectiveness and preclude potential adverse events. While traditional humanization methods have primarily focused on grafting antibody Complementarity-Determining Regions (CDRs) on homologous human antibody scaffolds, framework regions can also play essential roles in antigen binding. Here, we describe the humanization of the pan-HLA-DR mAb 44H10, a murine antibody displaying significant involvement of the framework region in antigen binding. Using a structure-guided approach, we identify and restore framework residues that directly interact with the antigen or indirectly modulate antigen binding by shaping the antibody paratope and engineer a humanized antibody with affinity, biophysical profile, and molecular binding basis comparable to that of the parental 44H10 mAb. As a humanized molecule, this antibody holds promise as a scaffold for the development of MHC class II-targeting therapeutics and vaccines.

Keywords

antibody humanization; framework regions; vernier zone; MHC class II targeting

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

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