BCR repertoire analysis and cloning of antibody candidates targeting native and Asp7-isomerized beta-amyloid
Nikolaev, N. A.; Kolobova, E. A.; Myshkin, M. Y.; Shagina, I. A.; Barsova, E. V.; Kechko, O. I.; Grogoreva, T. V.; Mitkevich, V. A.; Merzlyak, E. M.; Kozin, S.; Makarov, A. A.; Chudakov, D. M.; Lukyanov, S. A.; Grigorova, I. L.; Britanova, O. V.
Show abstract
Computational approaches are increasingly used to predict monoclonal antibody (mAb) candidates from BCR-seq datasets. However, the reliable identification of B cells encoding antibodies against rare antigenic epitopes remains challenging. We employed a repertoire-guided workflow combining antigen-tetramer sorting of B cells from immunized mice, followed by low-input bulk BCR-seq yielding informative clonal repertoires. Clustering and supporting somatic hypermutation (SHM) lineage analysis allowed us to identify IGH and IGK clonotypes potentially targeting {beta}-amyloid and its isoAsp7 variant (isoD7-A{beta}1-16), implicated in Alzheimers disease. We observed recurrent IGHV8-12 and IGKV1-117 usage, consistent with canonical mouse anti-A{beta} responses. Focusing on isoD7-A{beta} binders, we selected ten candidate IGH-IGK pairs for recombinant expression. One recombinant mAb demonstrated preferential binding to isoD7-A{beta} by microscale thermophoresis, supporting the feasibility of the approach but underscoring the challenge of accurate chain pairing. This highlights the potential of bioinformatic workflows to identify mAbs even under low-input conditions.
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