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A Novel Siglec-4 Derived Spacer Improves the Functionality of CAR T Cells Against Membrane-Proximal Epitopes

Schäfer, Daniel; Henze, Janina; Pfeifer, Rita; Schleicher, Anna 1; Brauner, Janina; Mockel-Tenbrinck, Nadine; Barth, Carola; Gudert, Daniela; Al Rawashdeh, Wa'el; Johnston, Ian C. D.; Hardt, Olaf
1 Fakultät für Chemie und Biowissenschaften (CHEM-BIO), Karlsruher Institut für Technologie (KIT)


A domain that is often neglected in the assessment of chimeric antigen receptor (CAR) functionality is the extracellular spacer module. However, several studies have elucidated that membrane proximal epitopes are best targeted through CARs comprising long spacers, while short spacer CARs exhibit highest activity on distal epitopes. This finding can be explained by the requirement to have an optimal distance between the effector T cell and target cell. Commonly used long spacer domains are the CH2-CH3 domains of IgG molecules. However, CARs containing these spacers generally show inferior in vivo efficacy in mouse models compared to their observed in vitro activity, which is linked to unspecific Fcγ-Receptor binding and can be abolished by mutating the respective regions. Here, we first assessed a CAR therapy targeting membrane proximal CD20 using such a modified long IgG1 spacer. However, despite these mutations, this construct failed to unfold its observed in vitro cytotoxic potential in an in vivo model, while a shorter but less structured CD8α spacer CAR showed complete tumor clearance. Given the shortage of well-described long spacer domains with a favorable functionality profile, we designed a novel class of CAR spacers with similar attributes to IgG spacers but without unspecific off-target binding, derived from the Sialic acid-binding immunoglobulin-type lectins (Siglecs). ... mehr

Verlagsausgabe §
DOI: 10.5445/IR/1000130088
Veröffentlicht am 26.02.2021
DOI: 10.3389/fimmu.2020.01704
Zitationen: 20
Zitationen: 23
Cover der Publikation
Zugehörige Institution(en) am KIT Fakultät für Chemie und Biowissenschaften (CHEM-BIO)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2020
Sprache Englisch
Identifikator ISSN: 1664-3224
KITopen-ID: 1000130088
Erschienen in Frontiers in immunology
Verlag Frontiers Media SA
Band 11
Vorab online veröffentlicht am 07.08.2020
Nachgewiesen in Dimensions
Web of Science
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