Abstract 382: TRX-214-1002, An antibody drug conjugate (ADC) targeting CD33 with a novel GSPT1 molecular glue for treatment of acute myeloid leukemia

Several promising therapies for acute myeloid leukemia (AML) targeting specific genetic and epigenetic mutations have been reported. However, there remains a critical need for novel therapies with higher efficacy and favorable safety profiles particularly for patients with poor-risk cytogenetic features, such as TP53 mutation, or those with relapsed and refractory AML. G1 to S phase transition 1 (GSPT1) is a small GTPase that interacts with eRF1, the translation termination factor, to facilitate the process of translation termination. GSPT1 has been well known to play a critical role in the proliferation of AML and MYC-driven lung cancer. Recently, molecular glue degraders (MGDs) targeting GSPT1 have emerged as a new class of cancer therapies and have shown early promise in clinical trials for AML. However, clinical development of GSPT1 MGDs, such as CC-885 and CC-90009, has been hampered by off-target toxicities. To improve both target specificity and the therapeutic window, we discovered TRX-214-1002, a CD33-targeting ADC that used the same monoclonal antibody (mAb) as Mylotarg, conjugated with a novel proprietary GSPT1 MGD as the payload. The in vitro and in vivo pharmacology of TRX-214-1002 were compared with ORM-6151 (another GSPT1 MG degrader-based CD33 ADC) and Mylotarg. TRX-214-1002 demonstrated superior and sustained degradability against GSPT1 compared to ORM-6151, and it exhibited potent anti-leukemic activity with picomolar GI50 values in TP53 or FLT3 mutated AML cell lines. Importantly, it highly spared CD33-negative leukemia cell and human PBMC, with an in vitro therapeutic index greater than 100-fold. We also observed that TRX-214-1002 significantly upregulated integrated stress response markers (ATF4, CHOP, ATF3) and impaired neo-protein synthesis, consistent with apoptosis induction. Interestingly, TRX-214-1002 maintained potent anti-leukemic activity even in venetoclax-resistant HL-60 cells and in drug-resistant milieu derived from bone marrow stromal HS-5 cells. Furthermore, a single 1 mg/kg dose of TRX-214-1002 completely regressed tumors in MV4-11 and HL-60 xenograft models without tumor regrowth until day 42, whereas the ORM-6151-treated group led to transient tumor regression. Pharmacodynamic studies in the HL-60 tumor model showed dose-dependent degradation of GSPT1. In addition, we estimated that the minimum therapeutically effective dose was less than single 1 mg/kg in a disseminated tumor model. Collectively, TRX-214-1002 highlighted the noticeable GSPT1 degradability and enhanced antileukemic activity, particularly in TP53 mutated and venetoclax-resistant AML cell lines, along with significant antitumor activity superior to competitor ADCs. Our preclinical data suggest that TRX-214-1002 has the high potential to provide a novel treatment strategy for CD33 positive relapse/refractory AML patients. Citation Format: Hee Kyu Lee, Seongrak Kim, Dohoon Kim, Seulgi Choi, Jookyung Lee, Sungwon Lee, Eunhyun Choi, Sang Won Park, Kwangwoo Chun, Koo Lee. TRX-214-1002, An antibody drug conjugate (ADC) targeting CD33 with a novel GSPT1 molecular glue for treatment of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 382.