Abstract Acute myeloid leukemia (AML) remains a challenging disease due to poor survival and high relapse rates as current therapies lack selectivity: cannot eradicate leukemic blasts without causing immune and hematopoietic toxicity, resulting in severe toxicities and low efficacy. Furthermore, current therapies such as hypomethylating agents (HMA) and venetoclax (Ven) fail in patients with TP53 mutations. There is a critical need for therapies that can selectively eliminate leukemic cells while sparing normal hematopoiesis.TRIO-863 is a first-in-class CD33 and TRAIL-R2 targeting bispecific antibody designed to trigger apoptosis selectively in AML blasts through dual engagement of CD33 and TRAIL-R2. By binding CD33 with high affinity and restricting TRAIL-R2 activation to CD33+ cells, TRIO-863 confines apoptotic signaling to leukemic cells minimizing off-target effects. Potency, selectivity, and mechanism of action were evaluated in AML cell lines, including high-risk TP53-mutant and HMA/Ven-refractory patient samples. Safety was assessed ex vivo using human liver microtissue and immune cells.TRIO-863 showed potent CD33-dependent killing of AML cells including high risk TP53-mutant and drug-resistant models, with over 3700-fold greater potency than Mylotarg. It synergized with HMA/Ven and eliminated blasts ex vivo from AML patients who are relapsed/refractory, heavily pre-treated, with unfavorable genetic mutations – including high risk biallelic TP53 mutations. TRIO-863 also exhibited statistically significant and dose-dependent inhibition of TP53-mutant leukemic cell growth in a xenograft model. Anti- leukemic activity of TRIO-863 in vivo requires dual engagement of CD33 and TRAIL-R2 suggesting TRIO-863 remains intact in vivo as a stable drug. CFU assays with non-leukemic CD34+ progenitors from healthy donors demonstrated TRIO-863 spared normal hematopoietic stem and progenitor cells. In contrast, Mylotarg, a CD33-targeting ADC currently approved for use in fit AML patients, killed non-leukemic hematopoietic progenitor cells. Ex vivo safety studies using primary human liver microtissues showed no liver toxicity by TRIO-863 in contrast to monospecific anti-TRAIL-R2 antibodies that showed high toxicity in the assay. Mechanistic studies confirmed apoptosis depends on dual engagement, overcoming resistance from TP53 inactivation and MCL1 upregulation. CD33 and TRAIL-R2 expression will serve as biomarkers for patient selection; analysis of blasts of AML patients exposed to Ven/HMA and 7+3 confirmed expression of the receptors.TRIO-863 represents a mechanistic breakthrough in AML therapy, selectively inducing apoptosis in malignant myeloid cells while preserving normal hematopoiesis. This approach addresses major limitations of current treatments. Clinical trials are planned for relapsed/refractory AML, including TP53-mutant and drug-resistant cases. Citation Format: Shiva Bhowmik, William Brady, Kaitlyn Ko, Sheng Cai, William Grossman, Naval Daver, Jonathan Gerber, Herbert Kim Lyerly. A novel CD33 and TRAIL-R2 targeting bispecific antibody to treat relapsed/refractory acute myeloid leukemia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5852.
Bhowmik et al. (Fri,) studied this question.