Rapid affinity optimization of an anti-TREM2 clinical lead antibody by cross-lineage immune repertoire mining

Yi-Chun Hsiao, Heidi Ackerly Wallweber, Robert G. Alberstein, Zhonghua Lin, Changchun Du, Ainhoa Etxeberria, Theint Aung, Yonglei Shang, Dhaya Seshasayee, Franziska Seeger, Andrew M. Watkins, David V. Hansen, Christopher J. Bohlen, Peter L. Hsu and Isidro Hötzel ()
Additional contact information
Yi-Chun Hsiao: Genentech
Heidi Ackerly Wallweber: Genentech
Robert G. Alberstein: a Genentech Accelerator
Zhonghua Lin: Genentech
Changchun Du: Genentech
Ainhoa Etxeberria: Genentech
Theint Aung: Genentech
Yonglei Shang: Genentech
Dhaya Seshasayee: Genentech
Franziska Seeger: a Genentech Accelerator
Andrew M. Watkins: a Genentech Accelerator
David V. Hansen: Genentech
Christopher J. Bohlen: Genentech
Peter L. Hsu: Genentech
Isidro Hötzel: Genentech

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract We describe a process for rapid antibody affinity optimization by repertoire mining to identify clones across B cell clonal lineages based on convergent immune responses where antigen-specific clones with the same heavy (VH) and light chain germline segment pairs, or parallel lineages, bind a single epitope on the antigen. We use this convergence framework to mine unique and distinct VH lineages from rat anti-triggering receptor on myeloid cells 2 (TREM2) antibody repertoire datasets with high diversity in the third complementarity-determining loop region (CDR H3) to further affinity-optimize a high-affinity agonistic anti-TREM2 antibody while retaining critical functional properties. Structural analyses confirm a nearly identical binding mode of anti-TREM2 variants with subtle but significant structural differences in the binding interface. Parallel lineage repertoire mining is uniquely tailored to rationally explore the large CDR H3 sequence space in antibody repertoires and can be easily and generally applied to antibodies discovered in vivo.

Date: 2024
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DOI: 10.1038/s41467-024-52442-y

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