M2T-CD33 is designed to selectively eliminate CD33-positive leukemic blasts and leukemic stem cells that are known to drive disease progression in AML. CD33 is highly expressed in the majority of AML cases, occurring in approximately 90% of patients.2 Unlike prior CD33-targeted strategies that have demonstrated benefit but carry risks of off-target cytotoxicity, M2T-CD33 incorporates a myeloid-specific targeting platform intended to enhance selectivity and minimize collateral damage to healthy hematopoietic cells.
“We are honored that the FDA has recognized the therapeutic promise of M2T-CD33 by granting orphan drug designation,” Sandeep Gupta, PhD, chief executive officer of Leukogene Therapeutics, stated in a news release.1 “AML remains one of the most challenging hematologic cancers, and outcomes for [patients with] relapsed or refractory [disease] remain poor. The LTI-214 program embodies our commitment to advancing new immunotherapy approaches that are both potent and safer for patients. This designation represents an important step toward our goal of transforming the treatment paradigm for AML.”
Preclinical data have demonstrated robust antileukemic activity across multiple AML models, including marked reductions in leukemic burden and prolonged survival. These effects were observed in both blast-dominant and stem cell–driven disease models, supporting M2T-CD33’s potential to address treatment resistance and measurable residual disease. Notably, investigators reported a favorable safety profile, with minimal off-target toxicity and no evidence of cytokine-release syndrome in preclinical evaluations.
“This is an important step forward for Leukogene and the company’s MHCII engager technology,” Nathan Dolloff, PhD, founder and chief science officer of Leukogene Therapeutics, added in the news release. “The M2T platform is a completely new approach to cancer immunotherapy, and the endorsement from [the] FDA is a testament to its high impact potential.”
M2T-CD33 is not currently being evaluated in any human clinical trials, although Leukogene Therapeutics expects to initiate a first-in-human evaluation in the near term.
What preclinical findings were demonstrated from M2T-CD33?
Preclinical experiments demonstrated that M2T-CD33 induced a targeted anti-AML immune response by leveraging a modified superantigen (SAg) platform.2 Investigators conjugated the CD33 extracellular domain (ECD) to a structurally engineered SMEZ-2 SAg variant, referred to as SAg490, to support selective activation of anti-leukemic immunity. Importantly, the molecule was specifically modified to eliminate T-cell receptor (TCR) binding without affecting MHCII-restricted binding, thereby mitigating the toxic systemic immune activation historically associated with an unmodified SAg. According to investigators, this design enables M2T-CD33 to deliver CD33-associated antigens to MHCII-positive antigen-presenting cells to facilitate controlled immune priming against leukemic cells.
In syngeneic AML mouse models, M2T-CD33 demonstrated significant anti-leukemic efficacy in both prophylactic and therapeutic settings. The antitumor mechanism was shown to involve a polyclonal humoral response, as well as activation of both CD4-positive and CD8-positive T-cell compartments, supporting engagement of both antibody-mediated and cytotoxic immune pathways. Although the investigators noted the limitations of currently available immunocompetent AML mouse models, the ability of M2T-CD33 to demonstrate activity within a narrow therapeutic window suggests a potential for enhanced clinical performance in humans—a hypothesis further supported by evidence of stronger binding affinity to human MHCII alleles vs alleles in mouse counterparts.
References
- U.S. FDA grants orphan drug designation to Leukogene Therapeutics’ M2T-CD33 (LTI-214) for the treatment of acute myeloid leukemia. News Release. Leukogene Therapeutics. November 5, 2025. Accessed November 5, 2025. https://www.biospace.com/press-releases/u-s-fda-grants-orphan-drug-designation-to-leukogene-therapeutics-m2t-cd33-lti-214-for-the-treatment-of-acute-myeloid-leukemia
- Dolloff N, Golick L, Robinson R, Reyes L, Thomas NS, Klinzing K. A superantigen-based MHC class II targeted cancer immunotherapy for the treatment of acute myeloid leukemia. Published online April 18, 2025. doi:10.21203/rs.3.rs-6307085/v1
