Recombinant Binding Proteins and Genetically Engineered T-cells Targeting Intracellular Neoantigens

Dear Colleagues,

Two different strategies are currently at the forefront of clinical interest for targeting intracellular neoantigens in benign and malignant diseases: T-cell-receptor (TCR)-engineered T-cells and recombinant antibodies. Recombinant T-cell-based therapies targeting neoantigens use T-cells expressing a recombinant complete TCR (TCR-T-cell), a chimeric antigen receptor with the variable domains of a neoepitope-reactive TCR are fused to the chimeric antigen receptor as a binding domain (TCR-CAR T-cell) or a TCR-like antibody as a binding domain (TCR-like-CAR T-cell). In contrast to the use of recombinant T-cells, recombinant binding proteins, including antibodies, can be directly applied to cancer patients. The recombinant binding proteins targeting MHC/neopeptide complexes include DARPins, TCR-like antibodies, bispecific antibodies in the format CD3 x TCR-like antibody or CD3 x soluble TCR, as well as intrabodies. Both strategies have their pros and cons and will be discussed in this Special Issue.

These developments are becoming intensified through the identification of new neopeptide/MHC complexes with cognate TCRs by screening the T-cell repertoires of healthy donors and cancer patients with dendritic cells presenting the predicted neopeptide/MHC complex or by screening a personalized CD8⁺ T-cell library with soluble neoantigen-MHC capture reagents.

Interestingly, lipid nanoparticles carrying therapeutic mRNA have become a practical tool for the targeted in vivo delivery of TCRs, TCR CARs, TCR-like CARs, bispecific antibodies, and intrabodies. However, different limitations should be considered, such as the loss of neoantigens, the modification of antigen peptide presentation, tumor heterogeneity, and the immunosuppressive activity of the tumor microenvironment. Nevertheless, the simultaneous application of immune-checkpoint-blocking antibodies and CRISPR/Cas9 based-genome-editing tools to engineer different recombinant T-cells with enhanced therapeutic functions could make T-cell therapy more efficient and pave the way for its routine clinical application.

Prof. Dr. Thomas Böldicke
Dr. Ana Maria Waaga-Gasser
Guest Editors

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• neoantigens
• TCR-like antibodies
• intrabodies
• bispecific antibody (CD3 × TCR, CD3 × TCR-like antibody)
• artificial TCR
• TCR CARs
• TCR-like CARs
• therapeutic mRNA
• checkpoint-blocking antibodies
• CRISPR/Cas9-based-genome-editing