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

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...

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Bibliographic Details
Published in:Antibodies (Basel) 2024-07, Vol.13 (3), p.57
Main Authors: Kassardjian, Audrey, Ivanochko, Danton, Barber, Brian, Jetha, Arif, Julien, Jean-Philippe
Format: Article
Language:English
Subjects:
Antibodies
antibody humanization
Antigens
Binding
Candidates
Complementarity
Crystal structure
Drug development
framework regions
Histocompatibility antigen HLA
Immunogenicity
Light
Major histocompatibility complex
MHC class II targeting
Molecular structure
Monoclonal antibodies
Mutation
Residues
Scaffolds
Vaccines
Vernier Zone
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Summary: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.
ISSN:2073-4468
2073-4468
DOI:10.3390/antib13030057