TriTACs, a Novel Class of T-Cell–Engaging Protein Constructs Designed for the Treatment of Solid Tumors

Abstract

T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T-cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This last modality is based on antibody constructs that bind a surface antigen on cancer cells and an invariant component of the T-cell receptor. Although high response rates were observed with T-cell engagers specific for CD19, CD20, or BCMA in patients with hematologic cancers, the treatment of solid tumors has been less successful. Here, we developed and characterized a novel T-cell engager format, called TriTAC (for Trispecific T-cell Activating Construct). TriTACs are engineered with features to improve patient safety and solid tumor activity, including high stability, small size, flexible linkers, long serum half-life, and highly specific and potent redirected lysis. The present study establishes the structure/activity relationship of TriTACs and describes the development of HPN424, a PSMA- (FOLH1-) targeting TriTAC in clinical development for patients with metastatic castration-resistant prostate cancer.

A Novel Her2/VEGFR2/CD3 trispecific antibody with an optimal structural design showed improved T-cell-redirecting antitumor efficacy

“…A similar linker strategy was previously used successfully to fuse EPO, GCSF and Exendin-4 into CDR or non-CDR loops of human or bovine antibodies [28,[53][54][55][56]. Different from TriTACs [57] and TriTE [20], which showed impaired functionalities due to steric hindrance, our Fab-based bsAbs and tsAbs using the special linker design and the site-specific recombination strategy potentially retained the affinity of each antibody domain. This recognized method for bsAb or tsAb design produces a variety of structural options and thus results in the different scenarios in which an artificial IS forms when mimicking physiological membrane spanning or does not efficiently form when distal or close epitope binding is applied.…”

Changing the History of Prostate Cancer with New Targeted Therapies

“…These models, called Tri-TAC ("Trispecific T-cell Activating Constructs"), have three domains that bind specifically to tumor antigens, human serum albumin, and the CD3-epsilon subunit of the T-cell receptor complex. Austin et al recently described a novel PSMA-targeted TriTAC (HPN424) in patients with mCRPC [103]. HPN424 is currently being evaluated as monotherapy in a phase I study in patients with mCRPC (NCT03577028).…”

Activity-based urinary biomarkers of response and resistance to checkpoint blockade immunotherapy

“…This implies that assigning protease specificity to the cleavage signals will be challenging without developing probes with exquisite selectivity for target proteases, which may be possible with non-natural amino acids 53,54 , or mathematical algorithms to deconvolve complex protease signatures 55,56 . Looking forward, phase 1 studies are necessary to establish the safety of αPD1-peptide conjugates, which we anticipate to be well-tolerated in humans given its composition is similar to protease-activatable masked antibodies 29 and T cell engagers 57 that are undergoing clinical efficacy studies. The classifiers we described in this study are relevant for the mouse models and should not be directly mapped to humans without conducting separate training and validation studies.…”