In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PS17-11-PS17-11
Abstract:
Background TCEs are effective at inducing remissions in hematologic cancers but have been challenging in solid tumors due to on-target, off-tumor toxicity. Attempts to circumvent CRS include fractionated or step-up dosing and/or complex molecular designs, but these have been unsuccessful due to toxicity and/or enhanced immunogenicity. Amunix has developed a conditionally active TCE, XPAT or XTENylated Protease-Activated bispecific T-Cell Engager, that exploits the protease activity present in tumors vs. healthy tissue to expand the therapeutic index (TI). The core of the HER2-XPAT (PAT) consists of 2 tandem scFVs targeting CD3 and HER2. Two unstructured polypeptide masks (XTEN) are attached to the core that sterically reduce target engagement and extend T1/2. Protease cleavage sites at the base of the XTEN masks enable proteolytic activation of XPATs in the tumor microenvironment, unleashing a highly potent TCE with a short T1/2 and further improving the TI. Although checkpoint inhibitors have been ineffective in HER2+ or HR+ breast cancer, TCEs can co-opt T-cells regardless of their antigenic specificity, providing the potential to introduce effective T-cell immunity against tumors expressing HER2. HER2-XPAT, as a tumor protease-activatable prodrug with a wide safety margin, offers the potential to induce effective T-cell cytotoxicity against HER2hi tumors and HR+/HER2 1-2+ tumors. Methods Preclinical studies were conducted to characterize the activity of HER2-XPAT, HER2-PAT (cleaved XPAT), and HER2-NonClv (a non-cleavable XPAT) for cytolytic activity in vitro, for anti-tumor efficacy in xenograft models, and for stability and safety in NHPs. Results HER2-PAT (cleaved XPAT) demonstrated potent in vitro tumor-directed T-cell cytotoxicity (EC50 1-2pM) and target-dependent T-cell activation and production of cytokines by PBMCs. HER2-PAT also exhibited cytotoxicity in HR+, HER2 1+ MCF7s at higher doses (EC50 0.13nM). HER2-XPAT provided up to 14,000-fold protection against killing of HER2 tumor cells and exhibited no cytotoxicity against cardiomyocytes at concentrations up to 1uM. In vivo, HER2-XPAT induced complete tumor regressions in BT-474 tumor models with equimolar dosing to HER2-PAT, whereas non-cleavable HER2-NonClv had no efficacy, supporting tumor protease cleavage requirement for T-cell activity. In NHP, HER2-XPAT has been dose-escalated safely up to 42mg/kg (MTD) but was not tolerated at 50mg/kg. HER2-XPAT demonstrated early T-cell margination at 2mg/kg but largely spared CRS, cytokine production, and tissue toxicity at doses up to 42mg/kg. PK profiles of HER2-XPAT and HER2-NonClv were comparable in NHP, indicating minimal systemic cleavage of XPAT, consistent with its ex vivo stability when incubated in the plasma of cancer pts for 7 days at 37°C. Given by continuous infusion, HER2-PAT induced lethal CRS and cytokine spikes at 0.3mg/kg/d, but was tolerated at 0.2mg/kg/d, providing HER2-XPAT with & gt;3000-fold protection in tolerated Cmax versus HER2-PAT, & gt;4 logs over cytotoxicity EC50s for HER2 and HR+ cell lines, and a 20-fold margin of safety over the dose required for pharmacodynamic activity. Conclusions HER2-XPAT is a potent prodrug T-cell engager with promising evidence of activity at low doses while exhibiting minimal CRS and a potentially wide TI based on NHP tolerability at doses up to 42mg/kg. With XTEN’s prior clinical data demonstrating low immunogenicity, the XPAT TCEs provide a promising solution. IND studies are currently ongoing. Additional PK, PD, cytokines, safety, and efficacy data will be presented. Citation Format: Fiore Cattaruzza, Ayesha Nazeer, Zachary Lange, Caitlin Koski, Mikhail Hammond, Angela Henkensiefken, Trang Dao-Pick, Mika K Derynck, Bryan Irving, Volker Schellenberger. Her2-xpat, a novel protease-activatable prodrug t-cell engager (tce), exhibits potent t-cell activation and efficacy in her2 tumors, yielding large predicted safety margins based on non-human primate (nhp) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-11.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.SABCS20-PS17-11
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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