Recombinant antibodies targeting MHC/neopeptide complexes include TCR-like antibodies, bi-specific T-cell engagers (BITEs) in the format of CD3 x TCR-like antibodies, or CD3 x soluble TCR. Several T cell receptor-mimetic antibodies (TCRms) demonstrated therapeutic effects in xenograft mouse models. The advantage of IgG TCRm antibodies is their stability compared to soluble TCRs. But in contrast to TCRs, TCRm antibodies demonstrate more cross-reactivity through binding to hotspots on the HLA/peptide complex surface, whereas the binding of the T cell receptor is dispersed over multiple residues. Over 100 BITEs are under clinical investigation and 7 of them are FDA-approved. In addition, intrabodies neutralizing neoantigens inside tumor cells have recently been developed. They seem to be a very promising additional tool to inhibit cancer growth because of their easy selection and high specificity compared to TCR-like antibodies and soluble TCRs. In the near future, a transfer of intrabodies embedded in lipid-nanoparticles should bring them into clinical practice. Most promising T cell-based therapies targeting cell surface proteins or neoantigens use T cells expressing a chimeric antigen receptor (CAR) or a recombinant complete TCR (TCR-T cell). Seven CAR T-cell therapies and one TCR-T cell therapy have been FDA-approved. The effectivity of therapies with BITEs and CARs are similar, such as with BITE Mosunetuzumab (CD3 x CD20), which produces similar high response rates in patients compared to CAR T-cell therapy, as demonstrated in relapsed/refractory follicular lymphoma therapy. The most important adverse events were cytokine release syndrome (CRS), fatigue, neutropenia, immune-effector-cell-associated neurotoxicity syndrome (ICANS) and infections with a lower risk of CRS or ICANS than in patients who had received CAR-T cell therapy.

Overall, T-cell therapy is particularly limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility, which will not be of concern in intrabody therapy.