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

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Engineered T-cell therapies show promise for cancer treatment but face challenges with solid tumors due to limited antigen recognition specificity and persistence.
• Current chimeric antigen receptor (CAR) T-cell strategies struggle with precise targeting of solid tumor-associated antigens (TAAs).

Purpose of the Study:

• To introduce sherpabodies, novel antibody-mimetic proteins, as a new platform for precise TAA recognition in engineered T-cell therapies.
• To develop and evaluate sherpabody-guided CARs (SbCARs) for enhanced specificity, efficacy, and versatility in targeting solid tumors.

Main Methods:

• Engineered sherpabodies from a human SH3 domain scaffold were developed using phage display for TAA recognition.
• Sherpabodies were incorporated into second-generation CAR constructs (SbCARs) and tested for in vitro specificity and cytotoxicity.
• Multispecific and inducible SbCAR systems were designed and evaluated in xenograft mouse models.

Main Results:

• Sherpabodies demonstrated precise TAA recognition without cross-reactivity to related proteins.
• SbCARs exhibited potent in vitro specificity and cytotoxicity against solid cancer TAAs.
• In vivo studies showed dose-dependent antitumor responses with SbCAR T cells, and an inducible system enhanced persistence and activity.

Conclusions:

• Sherpabodies represent a versatile and small-sized protein platform for next-generation CAR T-cell therapies, particularly for solid tumors.
• SbCARs show significant potential to overcome current limitations in CAR T-cell therapy for solid cancers.
• This technology could extend the success of CAR T-cell therapy from hematological malignancies to solid tumors.