Simultaneous selection of nanobodies for accessible epitopes on immune cells in the tumor microenvironment

Thillai V. Sekar, Eslam A. Elghonaimy, Katy L. Swancutt, Sebastian Diegeler, Isaac Gonzalez, Cassandra Hamilton, Peter Q. Leung, Jens Meiler, Cristina E. Martina, Michael Whitney and Todd A. Aguilera ()
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Thillai V. Sekar: the University of Texas Southwestern Medical Center
Eslam A. Elghonaimy: the University of Texas Southwestern Medical Center
Katy L. Swancutt: the University of Texas Southwestern Medical Center
Sebastian Diegeler: the University of Texas Southwestern Medical Center
Isaac Gonzalez: the University of Texas Southwestern Medical Center
Cassandra Hamilton: the University of Texas Southwestern Medical Center
Peter Q. Leung: the University of Texas Southwestern Medical Center
Jens Meiler: Vanderbilt University
Cristina E. Martina: Vanderbilt University
Michael Whitney: University of California San Diego
Todd A. Aguilera: the University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract In the rapidly advancing field of synthetic biology, there exists a critical need for technology to discover targeting moieties for therapeutic biologics. Here we present INSPIRE-seq, an approach that utilizes a nanobody library and next-generation sequencing to identify nanobodies selected for complex environments. INSPIRE-seq enables the parallel enrichment of immune cell-binding nanobodies that penetrate the tumor microenvironment. Clone enrichment and specificity vary across immune cell subtypes in the tumor, lymph node, and spleen. INSPIRE-seq identifies a dendritic cell binding clone that binds PHB2. Single-cell RNA sequencing reveals a connection with cDC1s, and immunofluorescence confirms nanobody-PHB2 colocalization along cell membranes. Structural modeling and docking studies assist binding predictions and will guide nanobody selection. In this work, we demonstrate that INSPIRE-seq offers an unbiased approach to examine complex microenvironments and assist in the development of nanobodies, which could serve as active drugs, modified to become drugs, or used as targeting moieties.

Date: 2023
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DOI: 10.1038/s41467-023-43038-z

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