Exploring the role of framework mutations in enabling breadth of a cross-reactive antibody (CR3022) against the SARS-CoV-2 RBD and its variants of concern

Saini, Samvedna; Agarwal, Manusmriti; Pradhan, Amartya; Pareek, Savitha; Singh, Ashish Kumar; Dhawan, Gagan; Dhawan, Uma; Kumar, Yatender

doi:10.1080/07391102.2022.2030800

Cited by 5 publications

(4 citation statements)

References 51 publications

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“…28 This insight is valuable for understanding autoimmune diseases triggered by microbial infections, aiding in early diagnosis. In addition, the cross-reactivity of antibodies to newly emerging pathogenic microbial variants can also be improved by enhancing the conformational flexibility of the antibody skeleton region, which is crucial for the development of effective universal vaccines, 33 which provides a new idea for our future research.…”

Section: Notementioning

confidence: 99%

Cross‐reaction mediated by distinct key amino acid combinations in the complementary‐determining region (CDR) of a monoclonal antibody

Guo,

Feng,

Xie

et al. 2024

Journal of Medical Virology

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In immunology, cross‐reaction between antigens and antibodies are commonly observed. Prior research has shown that various monoclonal antibodies (mAbs) can recognize a broad spectrum of epitopes related to influenza viruses. However, existing theories on cross‐reactions fall short in explaining the phenomena observed. This study explored the interaction characteristics of H1‐74 mAb with three peptides: two natural peptides, LVLWGIHHP and LPFQNI, derived from the hemagglutinin (HA) antigen of the H1N1 influenza virus, and one synthetic peptide, WPFQNY. Our findings indicate that the complementarity‐determining region (CDR) of H1‐74 mAb comprised five antigen‐binding sites, containing eight key amino acid residues from the light chain variable region and 16 from the heavy chain variable region. These critical residues formed distinct hydrophobic or hydrophilic clusters and functional groups within the binding sites, facilitating interaction with antigen epitopes through hydrogen bonding, salt bridge formation, and π–π stacking. The study revealed that the formation of the antibody molecule led to the creation of binding groups and small units in the CDR, allowing the antibody to attach to a variety of antigen epitopes through diverse combinations of these small units and functional groups. This unique ability of the antibody to bind with antigen epitopes provides a new molecular basis for explaining the phenomenon of antibody cross‐reaction.

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Section: Notementioning

confidence: 99%

Cross‐reaction mediated by distinct key amino acid combinations in the complementary‐determining region (CDR) of a monoclonal antibody

Guo,

Feng,

Xie

et al. 2024

Journal of Medical Virology

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“…Peterle et al hypothesized that the observed long-range effects of the somatic mutation Asn32Thr may be relevant to the recognition function of the LC in the antibody (228). Somatic mutations that modulate the antibody conformational flexibility has been suggested to contribute to biologically relevant properties, such as cross-reactivity and broad neutralizing capacity against surface proteins of diverse strains of rapidly evolving viral pathogens, such as SARS-CoV 2 (218, 236,237). Thus, the study conducted by Peterle et al highlights the potentially deleterious consequences of somatic mutations which, playing a beneficial role in enhancing antibody recognition properties, can cause highly disabling diseases by promoting LC aggregation (217).…”

Section: Role Of Somatic Mutations In Light Chain Amyloid Aggregation...mentioning

confidence: 99%

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

et al. 2023

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The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.

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“…The structures of CR3022 bound to SARS-CoV and SARS-CoV-2 were rapidly solved (112), and experimental work determined that residue P384 drove the majority of the difference in CR3022 binding affinity between SARS-CoV and SARS-CoV-2, with the P384A mutation on SARS-CoV-2 restoring CR3022 binding affinity to that of its activity against SARS-CoV (113). These insights have since enabled engineering efforts to improve the therapeutic potential of CR3022 via molecular dynamics-based affinity maturation (114)(115)(116), directed evolution (116), framework engineering (117), and Fc engineering (118), demonstrating the widespread accessibility of tools for rapid repurposing and engineering of antibodies targeting homologous protein epitopes. Indeed, the directed evolution approach obtained a CR3022 derivative, eCR3022, with 1000-fold increased binding affinity for SARS-CoV-2 which resulted in restoration of neutralization (116).…”

Section: Cross-reactivity Of Abs Targeting Monomeric Protein Epitopesmentioning

confidence: 99%

Complexity of Viral Epitope Surfaces as Evasive Targets for Vaccines and Therapeutic Antibodies

et al. 2022

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The dynamic interplay between virus and host plays out across many interacting surfaces as virus and host evolve continually in response to one another. In particular, epitope-paratope interactions (EPIs) between viral antigen and host antibodies drive much of this evolutionary race. In this review, we describe a series of recent studies examining aspects of epitope complexity that go beyond two interacting protein surfaces as EPIs are typically understood. To structure our discussion, we present a framework for understanding epitope complexity as a spectrum along a series of axes, focusing primarily on 1) epitope biochemical complexity (e.g., epitopes involving N-glycans) and 2) antigen conformational/dynamic complexity (e.g., epitopes with differential properties depending on antigen state or fold-axis). We highlight additional epitope complexity factors including epitope tertiary/quaternary structure, which contribute to epistatic relationships between epitope residues within- or adjacent-to a given epitope, as well as epitope overlap resulting from polyclonal antibody responses, which is relevant when assessing antigenic pressure against a given epitope. Finally, we discuss how these different forms of epitope complexity can limit EPI analyses and therapeutic antibody development, as well as recent efforts to overcome these limitations.

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Exploring the role of framework mutations in enabling breadth of a cross-reactive antibody (CR3022) against the SARS-CoV-2 RBD and its variants of concern

Cited by 5 publications

References 51 publications

Cross‐reaction mediated by distinct key amino acid combinations in the complementary‐determining region (CDR) of a monoclonal antibody

Cross‐reaction mediated by distinct key amino acid combinations in the complementary‐determining region (CDR) of a monoclonal antibody

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

Complexity of Viral Epitope Surfaces as Evasive Targets for Vaccines and Therapeutic Antibodies

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