# A superantigen-based MHC class II-targeted cancer immunotherapy for the treatment of acute myeloid leukemia

## TL;DR

A new immunotherapy targeting CD33 on AML cells via MHC class II shows strong anti-leukemia effects in mice.

## Contribution

Development of a novel CD33-targeted immunotherapy that bypasses existing antibody limitations and leverages MHCII for enhanced immune response.

## Key findings

- M2T-CD33 induces a robust anti-CD33 humoral response with full immunoglobulin repertoire.
- The therapy elicits an anti-AML response in mice dependent on CD4+ and CD8+ T cells.
- M2T-CD33 is effective against both full-length and spliced CD33 and is safe at high doses.

## Abstract

The treatment of acute myeloid leukemia (AML) remains a challenge due to disease heterogeneity, which undermines efforts to develop targeted therapeutics, leaving conventional chemotherapy as the standard of care (SOC). Sialic acid binding Ig-like lectin 3 (CD33) is a myeloid cell surface glycoprotein that is highly expressed on AML blasts. However, while ~90% of AML cases express CD33, 50% of these patients harbor a single nucleotide polymorphism (SNP) that eliminates the antibody binding epitope for existing CD33-targeted antibody therapeutics. In this study, we developed an immunotherapy (M2T-CD33) that targets CD33 directly to MHC class II (MHCII) molecules on antigen presenting cells for enhanced presentation to the immune system. We found that M2T-CD33 induces a robust polyclonal anti-CD33 humoral response composed of the full immunoglobulin repertoire. M2T-CD33 induced an anti-AML response in a syngeneic mouse model that was dependent on CD4+ and CD8+ T cells. The immune response was elicited against both the full length and spliced version of CD33 and showed no evidence of toxicity at concentrations 40-fold higher than the efficacious dose. Finally, M2T-CD33 was enhanced by combinations with anti-PD-1 therapy. These experiments demonstrate the preclinical potential of M2T-CD33 in AML and emphasize the importance of MHCII for cancer immunotherapy.