In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1824-1824
Abstract:
Background: TCEs are effective in leukemias but have been challenging in solid tumors due to on-target, off-tumor toxicity. Attempts to circumvent cytokine release syndrome (CRS) including step-up dosing and/or complex molecular designs have been unsuccessful due to toxicity and/or enhanced immunogenicity. HER2-XPAT, or XTENylated Protease-Activated bispecific T-Cell Engager, is a prodrug TCE 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. Attached to the core, two unstructured polypeptide masks (XTEN) 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 potent TCE with short T1/2, further improving the TI. Methods: Preclinical studies were conducted to characterize the activity of HER2-XPAT, HER2-PAT (cleaved XPAT), and HER2-NonClv (a non-cleavable XPAT) for cytotoxicity in vitro, anti-tumor efficacy and cleavage in xenograft models, stability in human plasma, and safety in NHPs. Results: The unmasked HER2-PAT demonstrated potent in vitro T-cell cytotoxicity (EC50 1-2pM) and target-dependent T-cell activation and cytokine production by hPBMCs. HER2-XPAT provided up to 14,000-fold protection against killing of HER2 tumor cells and exhibited only minimal cytotoxicity against cardiomyocytes at 1μM. In vivo, HER2-XPAT induced complete tumor regressions (CRs) in BT-474 tumors with equimolar dosing as HER2-PAT, whereas HER2-NonClv lacked efficacy, supporting a requirement of protease cleavage. HER2-XPAT was also highly efficacious in the HER2 low-expressing HT-55 colorectal model. Preferential proteolytic cleavage of fluorescent-labeled HER2-XPAT in tumors vs healthy organs was demonstrated in vivo. In NHP, HER2-XPAT has been dose-escalated safely up to 42mg/kg (MTD). HER2-XPAT demonstrated early T-cell margination at 2mg/kg but largely spared CRS, cytokines, and major tissue toxicity up to 42mg/kg. In vivo, the PK of HER2-XPAT was comparable to its non-cleavable counterpart, consistent with its ex vivo stability for cleavage in cancer pts plasma for 7 days at 37°C. Continuous infusion of HER2-PAT induced lethal CRS and cytokine spikes at 0.3mg/kg/d but was tolerated at 0.25mg/kg/d, providing HER2-XPAT with 500-fold protection in tolerated Cmax vs HER2-PAT. Conclusions: HER2-XPAT is a potent, prodrug TCE exhibiting protease-dependent tumor efficacy in mouse xenografts and a wide TI with no CRS in NHPs. XTEN's low immunogenicity has already been demonstrated in humans (growth hormone and FVIII). HER2-XPAT represents a promising solution for HER2-high tumors with potential expansion to HER2 low expressing tumors. IND studies are ongoing. Citation Format: Fiore Cattaruzza, Ayesha Nazeer, Zachary Lange, Caitlin Koski, Mikhail Hammond, Milton To, Pete Yeung, Sharon Lam, Mika K. Derynck, Bryan Irving, Volker Schellenberger. HER2-XPAT, a novel protease-activatable T-cell engager (TCE) with potent T-cell activation and efficacy in solid tumors and large safety margins in non-human primate (NHP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1824.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2021-1824
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
Permalink
