HER3 is a unique member of the EGFR family of
tyrosine kinases, which is broadly expressed in several
cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and
bladder cancers and is often associated with poor patient outcomes and therapeutic resistance. U3-1402/
Patritumab-GGFG-DXd is the first successful HER3-targeting
antibody-drug conjugate (ADC) with clinical efficacy in
non-small cell lung cancer. However, over 60% of patients are nonresponsive to
U3-1402 due to low target expression levels and responses tend to be in patients with higher target expression levels.
U3-1402 is also ineffective in more challenging
tumor types such as
colorectal cancer. AMT-562 was generated by a novel anti-HER3 antibody Ab562 and a modified self-immolative
PABC spacer (T800) to conjugate
exatecan.
Exatecan showed higher cytotoxic potency than its derivative DXd. Ab562 was selected because of its moderate affinity for minimizing potential toxicity and improving
tumor penetration purposes. Both alone or in combination
therapies, AMT-562 showed potent and durable antitumor response in low HER3 expression xenograft and heterogeneous patient-derived xenograft/organoid models, including digestive system and lung
tumors representing of unmet needs. Combination
therapies pairing AMT-562 with therapeutic
antibodies, inhibitors of CHEK1, KRAS, and
tyrosine kinase inhibitor showed higher synergistic efficacy than
Patritumab-GGFG-DXd. Pharmacokinetic and safety profiles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg in cynomolgus monkeys. AMT-562 has potential to be a superior HER3-targeting ADC with a higher therapeutic window that can overcome resistance to generate higher percentage and more durable responses in U3-1402-insensitive
tumors.