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TriTACs, a Novel Class of T-Cell-Engaging Protein Constructs Designed for the Treatment of Solid Tumors
Richard J Austin1, Bryan D Lemon2, Wade H Aaron2
1Harpoon Therapeutics, South San Francisco, California. raustin@harpoontx.com.
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.
Insights
Researchers developed a novel Trispecific T-cell Activating Construct (TriTAC) to improve T-cell therapy for solid tumors. This new format, exemplified by HPN424 targeting PSMA, shows promise for treating metastatic castration-resistant prostate cancer.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- T cells are crucial for cancer elimination but face immune evasion by cancer cells.
- Current T-cell therapies show success in hematologic cancers but limited efficacy in solid tumors.
- Novel T-cell engager formats are needed to overcome solid tumor treatment challenges.
Purpose of the Study:
- To develop and characterize a novel T-cell engager format, Trispecific T-cell Activating Construct (TriTAC).
- To engineer TriTACs for improved patient safety and enhanced activity against solid tumors.
- To establish the structure/activity relationship of TriTACs and develop a PSMA-targeting agent for prostate cancer.
Main Methods:
- Development and characterization of the TriTAC format with optimized features for stability, size, and specificity.
- Evaluation of TriTACs for potent and specific redirected lysis of cancer cells.
- Structure/activity relationship studies of TriTACs.
- Development of HPN424, a PSMA-targeting TriTAC.
Main Results:
- TriTACs engineered with features for improved safety and solid tumor activity.
- Demonstrated high stability, small size, flexible linkers, and long serum half-life.
- Established structure/activity relationships for TriTACs.
- Developed HPN424, a PSMA-targeting TriTAC for clinical development.
Conclusions:
- TriTACs represent a novel T-cell engager format with potential for improved solid tumor therapy.
- HPN424, a PSMA-targeting TriTAC, is under clinical development for metastatic castration-resistant prostate cancer.
- The engineered features of TriTACs aim to enhance patient safety and therapeutic efficacy.
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