AB Science's AB8939 Shows Promise Against Refractory Acute Myeloid Leukemia with Novel Dual-Target Mechanism
核心洞察
AB Science (搜索) published preclinical data on bioRxiv demonstrating AB8939's novel dual mechanism targeting both proliferating tumor cells through microtubule disruption and resistant stem cells via ALDH inhibition.
The compound showed nanomolar potency against hematopoietic cancers and overcame major drug resistance mechanisms including P-glycoprotein efflux and β3-tubulin expression in preclinical studies.
In patient-derived xenograft models of high-risk AML with MECOM rearrangements, AB8939 monotherapy was effective and combination with azacitidine achieved near-complete disease clearance.
AB Science (搜索) has published new preclinical data on bioRxiv demonstrating the therapeutic potential of AB8939, a novel synthetic compound designed to treat refractory acute myeloid leukemia (AML). The research, led by Professor Olivier Hermine from Necker Hospital and member of the French Academy of Sciences, reveals a unique dual-targeting mechanism that addresses both proliferating tumor cells and resistant stem cells.
Novel Dual-Target Mechanism Shows Promise
AB8939 operates through two distinct pathways that differentiate it from conventional AML therapies. The compound acts as a microtubule-targeting agent by binding to the colchicine-binding site on β-tubulin, disrupting the microtubule network and leading to cell cycle arrest in the G2/M phase followed by apoptosis. Simultaneously, through reverse proteomics analysis, researchers identified aldehyde dehydrogenases (ALDH1 (搜索) and ALDH2 (搜索)) as secondary targets, with AB8939 serving as a potent inhibitor of these enzymes that are overexpressed in tumors and associated with cancer stem cells.
"Our preclinical research has identified AB8939 as a powerful compound with a novel dual mechanism of action, which holds potential for treating high-risk acute myeloid leukemia," commented Professor Hermine. "The data indicate that AB8939 disrupts microtubule formation, a classic anti-cancer strategy, and inhibits ALDH enzymes, which are implicated in therapy resistance and the survival of leukemic stem cells."
Overcoming Drug Resistance Mechanisms
The preclinical studies demonstrated AB8939's ability to circumvent several major drug resistance pathways that limit the effectiveness of current AML treatments. Unlike conventional chemotherapeutics such as doxorubicin and vincristine, AB8939 is not a substrate for the P-glycoprotein efflux pump, allowing it to remain effective in cancer cells that overexpress P-gp. The compound also retained efficacy in cell lines with high expression of β3-tubulin, another factor linked to resistance against microtubule-targeting agents.
AB8939 showed broad-spectrum antiproliferative activity against various human cancer cell lines, with particularly high potency against hematopoietic cancers, achieving IC₅₀ values in the nanomolar range. The compound demonstrated high cytotoxicity against AML patient blasts, including those resistant to standard-of-care agents such as cytarabine and vincristine.
Promising In Vivo Results
In vivo studies provided compelling evidence for AB8939's therapeutic potential. In an Ara-C-resistant AML mouse model (MOLM-14), AB8939 treatment significantly inhibited tumor growth and increased survival rates. More notably, in a patient-derived xenograft model of high-risk AML (TG-LAM-75 with MECOM rearrangement), AB8939 monotherapy proved effective, and its combination with azacitidine led to near-complete disease clearance with a manageable safety profile.
The research also demonstrated AB8939's ability to effectively eradicate leukemic stem cells in an AML PDX model (TG-AML-36), suggesting potential for reducing disease relapse risk. Professor Hermine emphasized this finding: "Most importantly, our work in advanced preclinical models shows that it can eradicate the leukemic stem cells that fuel this disease, a critical step toward preventing relapse."
Clinical Development Progress
AB8939 is currently being evaluated in a Phase I/II clinical trial (AB18001, NCT05211570) for patients with refractory and relapsed AML. AB Science (搜索) recently received regulatory approval to initiate the third stage of this study, which combines AB8939 with venetoclax. The first two stages of Phase 1 were completed with 28 and 13 patients enrolled respectively, establishing the maximum tolerated dose of AB8939 at 21.3 mg/m² for both 3-day and 14-day treatment cycles.
The clinical trial follows a staged approach: Stage 1 determined the MTD after three consecutive days of AB8939 alone, Stage 2 established the MTD after 14 consecutive days of monotherapy, and Stage 3 will evaluate the MTD for 14-day treatment combining AB8939 with venetoclax. A planned Stage 4 will assess the triple combination with venetoclax and azacitidine.
Intellectual Property and Regulatory Status
AB Science (搜索) maintains full ownership of AB8939's intellectual property rights, with patent protection extending until 2026 across major markets including Europe, the United States, Canada, China, and other key territories. A second patent application for medical use could extend protection until 2044 for specific AML subpopulations with chromosomal abnormalities.
The compound has received orphan drug designation for AML from both the European Medicines Agency and the US Food and Drug Administration, conferring 10 and 7 years of marketing exclusivity respectively from product registration. Additionally, AB8939 is eligible for regulatory data protection in numerous countries, preventing generic competition for up to 8 years from registration.