Harpoon Therapeutics Presents Encouraging Preclinical Data for HPN601 EpCAM ProTriTAC™ Program at 35th SITC Annual Meeting
The oral presentation today highlighted the following data:
- The successful use of a humanized rodent tumor xenograft model to assess therapeutic index by simultaneously measuring efficacy and toxicity in the same tumor-bearing animal
- A surrogate EpCAM ProTriTAC has a 10x improved therapeutic index compared to its corresponding constitutively active T cell engager control when measuring efficacy and toxicity in the same animal
- Improved tolerability of HPN601 in non-human primates and more potent anti-tumor activity in a rodent tumor model over the corresponding constitutively active T cell engager control
- Potent anti-tumor activity across multiple EpCAM-expressing tumor models, demonstrating the ability of HPN601 to be activated in multiple tumor types
“ProTriTAC represents a new and improved approach to engineer conditionally active T cell engager prodrugs that are designed to provide enhanced tumor specificity and enable an improved safety profile,” said
Preclinical Results Presented for HPN601
The oral presentation at SITC, titled “HPN601 is a protease-activated EpCAM-targeting T cell engager with an improved safety profile for the treatment of solid tumors,” included the results of several preclinical investigations that support further development of this agent for the potential treatment of EpCAM-expressing solid tumors.
EpCAM is a tumor antigen that is broadly and uniformly expressed in many solid tumors; however, expression on some normal tissues has hindered its potential as a therapeutic target due to on-target, off-tumor toxicity as observed in clinical studies from past EpCAM targeted T cell engagers. Local administration of an EpCAM T cell engager was able to minimize normal tissue liability, but is not practical for the treatment of metastatic disease. The goal of developing HPN601, a conditionally active drug candidate, is to target all metastatic tumors by systemic administration and have an acceptable safety profile in line with local administration.
To assess therapeutic index, a humanized rodent tumor xenograft model was used to simultaneously measure efficacy and toxicity. A surrogate molecule of HPN601 was safely administered at a dose 10x higher than the minimal efficacious dose required for durable tumor regression. Higher doses produced clinically relevant toxicity including elevated liver transaminases and bilirubin, body weight loss, and evidence of tissue damage by histopathology. In contrast, a constitutively active EpCAM-targeting T cell engager could only be dosed safely up to its minimum efficacious dose, suggesting that the EpCAM ProTriTAC has a 10x improved therapeutic index.
The improved safely profile of HPN601 was also supported by a toxicokinetic study in non-human primates. HPN601 was better tolerated in non-human primates, with significantly attenuated cytokine production, than its constitutively active T cell engager control. Despite its better safety profile, HPN601 was also more efficacious than its constitutively active T cell engager control in a rodent tumor xenograft model. Taken together, the data indicates that HPN601, as a conditionally active T cell engager, has an expanded therapeutic index compared to a constitutively active T cell engager.
Given the breadth of EpCAM-expressing tumors, HPN601 was also assessed for its ability to be processed in different tumor types. HPN601 was tested in four different tumor xenograft models. Tumor regression was found in all four tumor models, with very good potency in three of the four models tested. This observation shows that HPN601, as a prodrug requiring proteolytic activation in the tumor, can be processed and activated in multiple tumor types.
Based on these encouraging preclinical data, as well as other preclinical and manufacturability assessments, HPN601 has been nominated as a clinical candidate and IND-enabling studies are now underway.
A copy of the presentation will be available on the company’s website at https://ir.harpoontx.com/events-and-presentations shortly after the event.
Harpoon designed the ProTriTAC™ platform to expand the universe of addressable targets and indications for T cell engagers. IND enabling studies are underway for the first ProTriTAC™ clinical candidate, HPN601. ProTriTAC™ applies a prodrug concept to create a therapeutic T cell engager that remains inactive until it reaches the tumor. Upon entering a tumor, tumor-associated proteases cleave off the blocking domain of the ProTriTAC™, thereby enabling the engagement of T cells to subsequently kill tumor cells. This activation process also diminishes the half-life of the resulting T cell engager. If active molecules leave the tumor tissue, they are rapidly eliminated from the body, further limiting the potential side effects in normal tissues.
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