Data from Engineered SH3-Derived Sherpabodies Function as a Modular Platform for Targeted T-cell Immunotherapy

• DOI: 10.1158/0008-5472.c.7819764
• Publication Date: 2025-05-15T12:48:08Z
• Authors: Rogelio A. Hernán...; Tapio Kesti; Anna R. Mäkelä; Zhe Zhao; Wei Yu; Yurie Tonai; Hector J. Monzo; Kerttu Kalander; Sirpa Leppä; Päivi M. Ojala; Wendell A. Lim; Kalle Saksela

<div>Abstract<p>Engineered T-cell therapies have emerged as a promising approach for cancer treatment, yet their application to solid tumors remains challenging because of the limited specificity and persistence current antigen recognition strategies. In this study, we introduce sherpabodies, engineered from human SH3 domain scaffold, class antibody-mimetic proteins capable precise tumor-associated (TAA) recognition. A phage display library identified sherpabodies against panel popular TAAs, which were subsequently incorporated into second-generation chimeric receptor (CAR) constructs that termed sherpabody-guided CARs (SbCAR). These SbCARs demonstrated potent <i>in vitro</i> cytotoxicity without cross-reactivity closely related proteins. The modularity, versatility, small size enabled generation multispecific SbCARs, in particular trispecific with OR logic could robustly activate cells expressing any or combinations three cognate TAA targets, well circuits IF–THEN combination synthetic Notch. <i>In vivo</i>, SbCAR T elicited dose-dependent antitumor response xenograft mouse models, highlighting potential therapeutic application. Furthermore, an inducible system displayed enhanced activity when compared constitutive CARs. findings suggest represent versatile platform next CAR therapies, particularly tumors.</p><p><b>Significance:</b> Sherpabodies biological targeting technology help extend success therapy treating leukemias lymphomas treatment cancers.</p></div>