Cancer therapy has witnessed revolutionary advancements with modalities like antibody-drug conjugates (ADCs), T cell engagers (TCEs), and chimeric antigen receptor (CAR)-T cell therapies. Despite extensive research into T cell receptors (TCRs) and transgenic T cells as cancer immunotherapy, their outcomes have been inconsistent and must be approached with considerable caution—largely because natural TCRs tend to be cross-reactive, leading to significant off-target effects. T cell receptor-mimic (TCRm) antibodies are a promising alternative. TCRm have been engineered to bind peptide-loaded major histocompatibility complexes (MHC), allowing the use of well-established antibody engineering techniques to overcome the inherent limitations of traditional TCRs. By marrying the specificity of TCRs with the pharmacological advantages of conventional antibodies, TCRm antibodies are well-positioned to address previously undruggable targets and expand cancer treatment. In this post, we explore the use of TCRm approaches in cancer therapy.
What are TCRs?
TCRs have long been considered to be the “Swiss army knife” of our immune system, thanks to their remarkable ability to recognize a diverse array of antigens [1]. Researchers discovered TCRs by isolating antigen-specific T cells from patient samples using techniques like tetramer staining, flow cytometry, and high-throughput sequencing. These methods allow researchers to identify and characterize TCRs that naturally recognize specific peptide-MHC. Natural TCRs have evolved to strike a delicate balance between sensitivity and specificity, ensuring precise immune response; however, their intrinsic affinity typically falls within the micromolar range, which can limit their potency compared to antibody-based therapeutics [2].
The Challenge of Using TCRs as Drugs
Although TCRs play a critical role in immune surveillance, using them directly as drugs presents significant challenges due to their inherent instability. When removed from their native cellular environment, TCRs tend to lose their proper conformation and are prone to aggregation and rapid degradation [3]. This instability not only limits their shelf-life but also hinders their manufacturability in a soluble form that is suitable for systemic administration. In a soluble format, TCRs lack the stabilizing support provided by the T cell membrane and co-receptors, such as CD3 domains, which are crucial for maintaining TCRα and TCRβ stability. However, when attempting to engineer TCR-based therapeutics in a soluble format, integrating CD3 domains becomes a significant challenge. Their multi-subunit, transmembrane nature makes them difficult to express and properly assemble outside of the cellular context. Consequently, the complexities involved in reconstituting these domains often necessitate alternative strategies, such as using TCRm antibodies or engineered constructs that bypass the need for full CD3 integration, to achieve a stable and functional therapeutic product
Moreover, it’s important to note that TCRs are naturally low-affinity receptors. Evolution has optimized them to bind peptide-MHC in the micromolar range, a design that minimizes the risk of autoimmune overactivation while ensuring precise immune responses. To be regarded as viable therapeutics, soluble biologics typically require much higher affinities (less than nanomolar), thereby further limiting the potential of TCR-based therapeutics.
Exploring the Intracellular World
Traditional antibody therapeutics are typically limited to targeting extracellular proteins, leaving a vast array of intracellular antigens inaccessible. TCRm antibodies overcome this limitation by recognizing peptides derived from intracellular proteins presented on MHC molecules. This breakthrough expands the target space to include many disease-associated proteins that were once considered “undruggable” by standard antibody therapies. As such, these antibodies open new therapeutic avenues, particularly in oncology, where intracellular oncoproteins play a critical role in tumor development and progression.
In contrast to TCRs, TCRm antibodies regularly display high affinities (sub-nanomolar range) supported by an established history of stability and scalability of antibody-based therapeutics [4]. Like conventional antibodies, TCRm are engineered to tightly and specifically bind their antigen (peptide-MHC) thereby ensuring robust recognition even at low antigen density. This heightened affinity not only improves therapeutic efficacy but also enhances tumor specificity, reducing potential off-target effects. TCRm retain the favorable pharmacological properties of conventional antibodies and possess a favorable pharmacokinetics with exceptional stability. Additionally, their ease of manufacturing and simplicity of dosing positions them as a scalable and cost-effective solution for large-scale clinical applications.
Beyond simple antigen recognition, TCRm can be adapted into diverse modalities, including TCEs, CAR-T, and ADCs. While ADCs are traditionally antibody-based, engineered TCRs can also be designed for ADC applications, though this approach differs mechanistically from antibody-based ADCs. Moreover, TCRm can leverage cytotoxicity mechanisms unique to antibodies, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Soluble TCRs fused with an hIgG Fc domain can also engage these pathways, further expanding therapeutic possibilities. Collectively, these advantages of TCRm provide researchers and biopharma companies with opportunities to extend existing pharmaceutical strategies to a broader range of targets.
Preclinical Promise and Beyond
Recent preclinical studies have demonstrated that TCRm, whether used as standalone agents or as part of TCE constructs, can induce potent, dose-dependent cytotoxicity against tumor cells and HIV reservoirs [5]. Even more recently, when targeting p53 peptides presented by MHC class I molecules, TCRm demonstrated 10 to 100 times higher sensitivity than CARs [6]. These promising results pave the way for further exploration in clinical trials, potentially positioning TCRm as off-the-shelf immunotherapies that can be rapidly deployed in diverse clinical settings.
Innovation to Enablement
The emergence of TCRm antibodies represents an evolution in cancer therapy, challenging long-held assumptions about the limits of antibody targeting. By combining the broad target range of TCRs with the durable, well-characterized properties of conventional antibodies, this innovative approach is set to overcome key hurdles in cancer treatment and beyond. The transition of TCRm antibodies from the research lab to preclinical and clinical development marks a significant milestone in biotherapeutics. Nona Biosciences is at the forefront of this innovation. Having already taken multiple antibody therapeutics from our Harbour Mice® platform into the clinic in multiple modalities, we have now extended the platform to generate fully human TCRm in either traditional IgG or heavy chain-only (HCAb) formats, generating compelling preclinical data in the process. The ability to target intracellular antigens not only broadens the spectrum of treatable cancers but also offers new opportunities in autoimmune and other complex diseases. As the biopharmaceutical field continues to evolve, TCRm antibodies are expected to complement and, in some cases, surpass existing therapeutic modalities. Nona can enable you to build your pipeline with TCRm antibodies through our Idea to IND program, including engineering next-generation modalities such as TCEs and ADCs. To learn more, please explore our website or contact us to see how we can help.
- Attaf, M., et al., The T cell antigen receptor: the Swiss army knife of the immune system. Clin Exp Immunol, 2015. 181(1): p. 1-18.
- Duan, Z. and M. Ho, T-Cell Receptor Mimic Antibodies for Cancer Immunotherapy. Mol Cancer Ther, 2021. 20(9): p. 1533-1541.
- Robinson, R.A., et al., Engineering soluble T-cell receptors for therapy. Febs j, 2021. 288(21): p. 6159-6173.
- Gerber, H.P. and L.G. Presta, TCR mimic compounds for pHLA targeting with high potency modalities in oncology. Front Oncol, 2022. 12: p. 1027548.
- Sengupta, S., et al., TCR-mimic bispecific antibodies to target the HIV-1 reservoir. Proceedings of the National Academy of Sciences, 2022. 119(15): p. e2123406119.
- Huang, D., et al., TCR-mimicking STAR conveys superior sensitivity over CAR in targeting tumors with low-density neoantigens. Cell Reports, 2024. 43(11): p. 114949.
Summary of the key differences between natural TCRs and TCRm antibodies:
This comparison highlights that while TCRm antibodies provide improved affinity and manufacturing advantages, natural TCRs continue to be valued for their evolved specificity and nuanced immune modulation.
