Exploring TCR-like Antibodies in Cancer Immunotherapy

T-cell receptor (TCR)-like antibodies represent a novel and promising class of therapeutic agents that combine the specificity of T-cell receptors with the versatility of antibodies. These antibodies are designed to recognize and bind to peptide-major histocompatibility complex (pMHC) molecules, similar to TCRs, allowing them to target intracellular antigens presented on the cell surface.

TCR-Like Antibodies Mechanism of Action in Cancer Immunotherapy

TCR-like antibodies target pMHC complexes, which consist of small peptide fragments from intracellular proteins presented on the cell surface by MHC molecules. This unique targeting mechanism enables TCR-like antibodies to bind to tumor-specific antigens that are otherwise inaccessible to conventional antibodies, which typically target extracellular or cell surface proteins. By binding to these complexes, TCR-like antibodies can mediate specific immune responses against tumor cells.¹

Generation and Engineering

The development of TCR-like antibodies involves advanced biotechnological techniques, including phage display for initial selection and affinity maturation for performance optimization. Phage display libraries are used to screen for antibody variants that can bind specific pMHC complexes with high affinity and specificity. Subsequent affinity maturation processes further enhance the binding properties of these antibodies. The generated antibodies are then characterized for their specificity, stability, and therapeutic potential. 

The selective binding of TCR-like antibodies to a single tumor-specific peptide antigen presented by human leukocyte antigens (HLA) is crucial for their therapeutic efficacy and patient safety. Traditionally, selectivity assessments have relied on peptide library screening and predictive modeling.

However, an experimental platform by Marrer-Berger et al. was developed to identify interactomes of TCR-like antibodies directly in human tissues using mass spectrometry. The strategy offered an accurate and scalable method for evaluating the non-clinical safety profile of TCR-like antibody therapeutics before their first-in-human clinical application.² Peripheral blood samples are often used during preclinical evaluations to detect binding selectivity and off-target interactions, providing key data on the molecular mechanism of antigen recognition. Understanding these mechanisms helps ensure that tumor antigen-specific T cells are effectively engaged without triggering harmful autoimmune responses.

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Therapeutic Applications

TCR-like antibodies have shown promise in treating various cancers, including melanoma, leukemia, and solid tumors. They target tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs), such as NY-ESO-1, MAGE-A, and WT1, which are overexpressed or mutated in cancer cells. These antibodies can induce potent anti-tumor immune responses, often in conjunction with other immunotherapeutic strategies.

One of the main challenges in developing TCR-like antibodies is the downregulation of MHC molecules by tumor cells, which can limit the availability of pMHC targets. Strategies to overcome this include enhancing the expression of target peptides and selecting epitopes with high affinity for MHC molecules, ensuring stable and robust target presentation.

Current Research and Future Directions

While there are no TCR-like antibodies currently undergoing clinical trials, several studies show promising proof-of-concepts. Liu et al. demonstrated the successful development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 via human scFv phage library. Potential antitumor activity by TCR-like CAR-T cells both in vitro and in vivo were also shown, warranting further preclinical and clinical evaluation of the antibody in patients.³ Future research aims to expand the repertoire of targetable pMHC complexes, improve the engineering techniques for higher specificity and affinity, and explore combination therapies to enhance therapeutic outcomes. The continued advancement in this field holds the potential to revolutionize cancer treatment by providing highly specific and effective immunotherapeutic options.

Conclusion

TCR-like antibodies represent an emerging frontier in cancer immunotherapy, providing unique access to intracellular antigens presented on the cell surface by major histocompatibility complex (MHC) molecules. As antibody engineering technologies advance and clinical experience grows, TCR-like monoclonal antibodies have the potential to become a key component of next-generation therapeutic strategies for solid tumors and other malignancies.

References:

1. He, Q., Liu, Z., Liu, Z. et al. TCR-like antibodies in cancer immunotherapy. J Hematol Oncol 12, 99 (2019). https://jhoonline.biomedcentral.com/articles/10.1186/s13045-019-0788-4

2. Marrer-Berger, E., Nicastri, A., Augustin, A., Kramar, V., Liao, H., Hanisch, L. J., Carpy, A., Weinzierl, T., Durr, E., Schaub, N., Nudischer, R., Stucki, J., Hobi, N., Raggi, G., Cabon, L., Lezan, E., Umaña, P., Woodhouse, I., Bujotzek, A., Klein, C., . . . Ternette, N. (2024). The physiological interactome of TCR-like antibody therapeutics in human tissues. Nature Communications, 15(1), 1-14. https://www.nature.com/articles/s41467-024-47062-5

3. Liu, X., Xu, Y., Xiong, W., Yin, B., Huang, Y., Chu, J., Xing, C., Qian, C., Du, Y., Duan, T., Wang, H. Y., Zhang, N., Yu, J. S., An, Z., & Wang, R. (2022). Original research: Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy. Journal for Immunotherapy of Cancer, 10(3). https://jitc.bmj.com/content/10/3/e004035