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Title: Switching Heavy Chain Constant Domains Denatures the Paratope 3D Architecture of Influenza Monoclonal Antibodies
Authors: Malisheni, Moffat MM
Chong, Cheng-Shoong
Murali, Tanusya MM 
Purushotorman, Kiren 
Qian, Xinlei 
Laiman, Alfred
Tan, Yee-Joo 
MacAry, Paul AA 
Keywords: Science & Technology
Life Sciences & Biomedicine
heavy chain constant domain
VR-analogous IgG variants
monoclonal Ab
Issue Date: Jan-2023
Publisher: MDPI
Citation: Malisheni, Moffat MM, Chong, Cheng-Shoong, Murali, Tanusya MM, Purushotorman, Kiren, Qian, Xinlei, Laiman, Alfred, Tan, Yee-Joo, MacAry, Paul AA (2023-01). Switching Heavy Chain Constant Domains Denatures the Paratope 3D Architecture of Influenza Monoclonal Antibodies. PATHOGENS 12 (1). ScholarBank@NUS Repository.
Abstract: Several human monoclonal Abs for treating Influenza have been evaluated in clinical trials with limited success despite demonstrating superiority in preclinical animal models including mice. To conduct efficacy studies in mice, human monoclonal Abs are genetically engineered to contain mouse heavy chain constant domain to facilitate the engagement of Fc-receptors on mouse immune effector cells. Although studies have consistently reported discrepancies in Ab effectiveness following genetic engineering, the structural and mechanistic basis for these inconsistencies remain uncharacterized. Here, we use homology modeling to predict variable region (VR) analogous monoclonal Abs possessing human IgG1, mouse IgG1, and mouse IgG2a heavy chain constant domains. We then examine predicted 3D structures for variations in the spatial location and orientation of corresponding paratope amino acid residues. By structurally aligning crystal structures of Fabs in complex with hemagglutinin (HA), we show that corresponding paratope amino acid residues for VR-analogous human IgG1, mouse IgG1, and mouse IgG2a monoclonal Abs interact differentially with HA suggesting that their epitopes might not be identical. To demonstrate that variations in the paratope 3D fine architecture have implications for Ab specificity and effectiveness, we genetically engineered VR-analogous human IgG1, human IgG4, mouse IgG1, and mouse IgG2a monoclonal Abs and explored their specificity and effectiveness in protecting MDCK cells from infection by pandemic H1N1 and H3N2 Influenza viruses. We found that VR-analogous monoclonal Abs placed on mouse heavy chain constant domains were more efficacious at protecting MDCK cells from Influenza virus infection relative to those on human heavy chain constant domains. Interestingly, mouse but not human heavy chain constant domains increased target breadth in some monoclonal Abs. These data suggest that heavy chain constant domain sequences play a role in shaping Ab repertoires that go beyond class or sub-class differences in immune effector recruitment. This represents a facet of Ab biology that can potentially be exploited to improve the scope and utilization of current therapeutic or prophylactic candidates for influenza.
Source Title: PATHOGENS
ISSN: 2076-0817
DOI: 10.3390/pathogens12010051
Appears in Collections:Staff Publications

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