Harpoon Therapeutics Presents Encouraging Preclinical Data for HPN601 EpCAM ProTriTAC™ Program at 35th SITC Annual Meeting
- Category: Antibodies
- Published on Friday, 13 November 2020 13:13
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SOUTH SAN FRANCISCO, CA, USA I November 12, 2020 I Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing novel T cell engagers, today presented preclinical data on HPN601 for the treatment of solid tumors at the 35th Society for Immunotherapy of Cancer (SITC) virtual annual meeting. HPN601 is the first conditionally active T cell engager program from Harpoon. It targets the tumor antigen epithelial cell adhesion molecule (EpCAM) and is based on Harpoon’s proprietary ProTriTAC™ T cell engager prodrug platform designed to remain inert systemically until its activation in the tumor by tumor-associated proteases and to enable the safe targeting of broadly expressed tumor antigens.
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 Holger Wesche, Ph.D., chief scientific officer of Harpoon Therapeutics. “This enables T cell engagers to target tumor antigens that may otherwise be intractable due to expression on normal tissues. The data presented today for HPN601 support this therapeutic approach.”
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.
About Harpoon Therapeutics
Harpoon Therapeutics is a clinical-stage immunotherapy company developing a novel class of T cell engagers that harness the power of the body’s immune system to treat patients suffering from cancer and other diseases. T cell engagers are engineered proteins that direct a patient’s own T cells to kill target cells that express specific proteins, or antigens, carried by the target cells. Using its proprietary Tri-specific T cell Activating Construct (TriTAC®) platform, Harpoon is developing a pipeline of novel TriTACs initially focused on the treatment of solid tumors and hematologic malignancies. HPN424 targets PSMA and is in a Phase 1/2a trial for metastatic castration-resistant prostate cancer. HPN536 targets mesothelin and is in a Phase 1/2a trial for cancers expressing mesothelin, initially focused on ovarian and pancreatic cancers. HPN217 targets BCMA and is in a Phase 1/2 trial for relapsed, refractory multiple myeloma. HPN328 targets DLL3 and Harpoon plans to initiate a Phase 1/2 trial in the fourth quarter of 2020. Harpoon has also developed a proprietary ProTriTAC™ platform, which applies a prodrug concept to its TriTAC platform to create a therapeutic T cell engager that remains inactive until it reaches the tumor. For additional information about Harpoon Therapeutics, please visit www.harpoontx.com.
SOURCE: Harpoon Therapeutics