On September 17, 2020 Amunix Pharmaceuticals, Inc. ("Amunix"), a biopharmaceutical company developing prodrugs of potent immune-activating biotherapeutics for the treatment of patients with solid tumor cancers, reported that it will present preclinical data on two T cell engager programs: AMX-818, the company’s lead clinical candidate which targets HER2, and a second targeting EGFR (EGFR-XPAT), which is in lead optimization, at the European Society for Medical Oncology Virtual Congress taking place September 19 – 21, 2020 (Press release, Amunix, SEP 17, 2020, View Source [SID1234565286]).
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"We are very excited to present progress on our most advanced T cell engager programs," said Angie You, Ph.D., CEO of Amunix. "Both programs demonstrate the potential of our XPAT platform to significantly widen the therapeutic index of T cell engagers and overcome the challenge of on-target, off-tumor toxicity that is limiting the use of potent immune activators to treat solid tumors. For our HER2-XPAT clinical candidate, AMX-818, we have initiated IND-enabling studies. We are also excited to share progress with EGFR-XPAT, which offers a potential orthogonal approach to small molecule kinase inhibitors to target KRAS mutant tumors. As we progress these two most advanced programs, we are also leveraging our plug and play platform to rapidly develop XPATs against additional tumor targets such as PSMA and TROP2."
Amunix will present two posters at ESMO (Free ESMO Whitepaper), titled, "HER2-XPAT, A Novel Protease-Activatable Pro-Drug T Cell Engager (TCE), Engineered to Address On-Target, Off-Tumor Toxicity and Provide Large Predicted Safety Margins in Non-Human Primate (NHP)" and "EGFR-XPAT, A Novel Pro-Drug T Cell Engager (TCEs) Engineered to Address On-Target, Off-Tumor Toxicity and an Orthogonal Approach for Cancer Immunotherapy in EGFR, KRAS/BRAF Cancers". Both posters show that Amunix’s XPAT technology can improve the toxicity profile of T cell engagers while maintaining their potency against solid tumors. In vitro, protease-activated XPATs showed potent cytotoxic activity against tumor cell lines with EC50s in the single-digit pM range. For both molecules, masking reduced target-directed T cell cytotoxicity and T cell activation by ~5,000 to >10,000-fold. In established xenograft models, both HER2-XPAT and EGFR-XPATs induced complete tumor regressions with efficacious doses within an order of magnitude of the unmasked (active) T cell engager. Importantly, EGFR-XPAT showed strong in vitro cytotoxicity in a KRAS mutant and BRAF mutant setting, as well as potent in vivo anti-tumor xenograft activity in a BRAF mutant background.
Safety data from cynomolgus monkeys demonstrate that masked XPATs have a markedly lower risk of CRS and enable a significant increase in maximum tolerated exposures relative to unmasked, active forms. In contrast to traditional unmasked T cell engagers, which have MTDs in the µg/kg range, HER2-XPAT can be safely dosed up to 42 mg/kg in cynos and EGFR-XPAT up to 1 mg/kg, representing ~500-fold and ~200-fold, respectively, increases in tolerated exposures from masking. Combined with the potency of XPATs in xenograft models, these data suggest a favorable therapeutic index even for targets as broadly expressed as EGFR.
Poster Presentation Details
Title: HER2-XPAT, A Novel Protease-Activatable Pro-Drug T Cell Engager (TCE), Engineered to Address On-Target, Off-Tumor Toxicity and Provide Large Predicted Safety Margins in Non-Human Primate (NHP)
Poster number: 1060P
Abstract Number: 2472
Session: Virtual On-Demand Poster Display
Date: Sep 17, 2020
Title: EGFR-XPAT, A Novel Pro-Drug T Cell Engager (TCEs) Engineered to Address On-Target, Off-Tumor Toxicity and an Orthogonal Approach for Cancer Immunotherapy in EGFR, KRAS/BRAF Cancers
Poster number: 1062P
Abstract Number: 3054
Session: Virtual On Demand Poster Display
Date: Sep 17, 2020