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Restoring the potency of neutralizing antibody via guided hypermutation with hyper-antibody editor [Antibody_sequencing]

ABSTRACT: Somatic hypermutation (SHM) drives antibody affinity maturation in B cells, and mimicking this process has advanced therapeutic antibody development. Unlike conventional base editing, antibody diversification requires diverse mutations within the antibody complementary determining region (CDR) loops. Here, we engineered a hyper-antibody editor, HAE1, by integrating cytosine and adenine deaminases with a nicked, PAMless Cas9 variant, SpRY. HAE1 enables broad-spectrum mutagenesis with unrestricted targeting, fully covering mutation types observed in nature. Moreover, we developed a dual-expression system in mammalian cells that allows simultaneous expression of both transmembrane and secreted full-length antibodies, streamlining mutation, selection, and validation within the same cells. Using this platform, we rejuvenated the SARS-CoV-2 antibody CV07-209, restoring potency against Omicron variants. These results demonstrate the effectiveness of HAE1 as a powerful tool for antibody engineering, offering a practical strategy for evolving antibodies to address rapidly mutating pathogens and other therapeutic challenges.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281292 | GEO | 2025/12/06

REPOSITORIES: GEO

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Project description:Background Omicron subvariants have led to millions of coronavirus disease 2019 (COVID-19) cases worldwide. Although Omicron breakthrough infections (BTIs) exhibit lower hospitalization rates than previous variants, post-COVID conditions persist. However, the immune response dynamics, lymphocyte subsets, and immune repertoire features following BA.5 sublineage BTI remain poorly understood. Methods In a longitudinal cohort, we monitored the recovery dynamics in patients with BTI at various time points. We employed single-cell transcriptomics, T cell receptor (TCR)/BCR sequencing, and antibody mass spectrometry to sequentially assess the immune response following BA.5.2 or BF.7 BTI. Findings Serological analysis revealed active cellular and humoral immunity 2 weeks post-BTI, with significant increases in cytokines (CKs) like IFN-γ, TNFβ, IL-2, and neutralizing antibodies. CK levels reverted to pre-infection levels, while broadly neutralizing antibodies remained high 1 month post-infection. Single-cell sequencing demonstrated robust immune activation and antiviral responses in NK, T, and B lymphocytes within 1 month post-BTI. Interestingly, the immune system maintained its strength to combat viral infection at 2 weeks post-BTI, transitioning toward repair and tissue damage elimination at 1 month. TCR/BCR library analysis revealed a higher clonal type in the BTI_2w group, mainly in NKT, memory T or B, and plasma cells, crucial for immune memory and antigen clearance. The BTI_1m group exhibited more IgG and IgA BCR subtypes, with somatic hypermutation indicating mature antibodies. Biological function verification of IgG and IgA-type monoclonal antibodies corresponding to expanded BCRs revealed antigen-specific and broad-spectrum antibodies. Interpretation Our study elucidated the dynamic immune profiling of individuals 2 weeks and 1 month after Omicron BA.5 sublineage BTI. This provided essential insights into pathogenicity, sequential immune status, recovery mechanisms of Omicron subvariant BTI, and novel concepts for broad-spectrum antibody development.

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Restoring the potency of neutralizing antibody via guided hypermutation with hyper-antibody editor [Antibody_sequencing]

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