TCR mimic compounds for pHLA targeting with high potency modalities in oncology

Abstract

pHLA complexes represent the largest class of cell surface markers on cancer cells, making them attractive for targeted cancer therapies. Adoptive cell therapies expressing TCRs that recognize tumor specific pHLAs take advantage of the unique selectivity and avidity of TCR: pHLA interactions. More recently, additional protein binding domains binding to pHLAs, known as TCR mimics (TCRm), were developed for tumor targeting of high potency therapeutic modalities, including bispecifics, ADCs, CAR T and -NK cells. TCRm compounds take advantage of the exquisite tumor specificity of certain pHLA targets, including cell lineage commitment markers and cancer testis antigens (CTAs). To achieve meaningful anti-tumor responses, it is critical that TCRm compounds integrate both, high target binding affinities and a high degree of target specificity. In this review, we describe the most advanced approaches to achieve both criteria, including affinity- and specificity engineering of TCRs, antibodies and alternative protein scaffolds. We also discuss the status of current TCRm based therapeutics developed in the clinic, key challenges, and emerging trends to improve treatment options for cancer patients treated with TCRm based therapeutics in Oncology.

Keywords: Antibody Drug Conjugates; Bispecifics; CAR T; TCR mimic compounds; cancer testis antigen; high potency modalities; protein binder scaffolds; targeted cancer therapy.

Figure 1

Left panel: Many first-generation high potency compounds developed in oncology displayed significant platform toxicities that were not target related. Such platform toxicities were either caused by linker instability (ADC), tonic signaling (CAR T), target cross-reactivities (TCRs) or immunogenicity (bispecifics). For many first generation, high potency modalities, the maximum tolerated dose levels (MTD) in the clinic were defined by the platform toxicity. The therapeutic index (TI) is a product of the differences between the minimum effective dose (MED) required to achieve anti-tumor activity and either the on target-, or platform MTD. Platform toxicities frequently limited the drug exposure of first-generation high potency compounds to levels that were close to the levels required for anti-tumor responses (i.e. narrow TIs). Middle panel: Protein engineering approaches were successfully applied to reduce platform related toxicities, enabling higher clinical dose levels and consequently, drug exposure levels with the purpose to increase the therapeutic index. However, despite the reduction in platform toxicities, the cell surface antigens expression on normal tissues posed a significant obstacle to increase overall drug exposure levels and anti-tumor activities of second-generation high potency compounds. Thus, despite the successful reduction of the initial platform toxicity, normal tissue expression of conventional cell surface antigens interfered with the full potential of high potency modalities, resulting in only moderate TI improvements. Right panel: Combining second generation, high potency modalities with reduced platform toxicity (middle panel) with targets that have higher tumor to normal tissue expression ratios, such as pHLA targets, provides a framework to fully leverage the progress made in platform engineering and to improve the TIs of high potency modalities. Some tumor specific, intracellular pHLA targets are not present on normal tissues (Tumor specific antigens (TSAs)), or are displayed at significantly lower levels (Tumor associated antigens, TAAs) (5). Targeting pHLA targets belonging to the TAA or TSA class with high affinity and specificity TCRm compounds may enable higher dose levels and improved anti-tumor effects in solid tumors.

Figure 2

TCRm formats used for high potency modalities in Oncology. (A) (upper panel): Graphic display of the therapeutic formats used for TCRm-CD3 bispecific compounds. TBD, to be determined. (B) (lower panel): Graphic display of the therapeutic formats used for TCRm-ADCs and TCRm-CAR T and -CAR NK cells. N/A, not applicable.