Targeting Leukemic Cells with AFM28: A Promising NK Cell Engager for AML and MDS Treatment

The text highlights the development of a new treatment for adult blood cancers, specifically acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The incidence of these diseases is noted to be between 1-6 per 100,000 people per year. The focus is on improving the management of AML and high-risk MDS, particularly for patients with relapsed or refractory conditions and those with minimal residual disease (MRD), who need treatments that can lead to long-term remission.

A new bispecific Innate Cell Engager (ICE), termed AFM28, has been developed using a platform called Redirected Optimized Cell Killing (ROCK). AFM28 is designed to activate natural killer (NK) cells to eliminate leukemic cells and leukemic stem cells (LSCs). The approach is based on the susceptibility of leukemic cells to NK cell-mediated killing and the clinical effectiveness of allogeneic NK cell therapy in treating relapsed diseases.

The drug AFM28 targets the surface antigen CD123, which is commonly found on AML and MDS blasts and LSCs, and it binds to CD16A on NK cells. It does not bind to CD16B found on neutrophils. AFM28 binds with high affinity to CD16A, different from the Fc binding site of IgGs, leading to a stable attachment to NK cells and inducing potent antibody-dependent cell-mediated cytotoxicity (ADCC) against CD123+ AML and MDS cells.

Compared to traditional anti-CD123 antibodies, AFM28 shows superior tumor cell lysis even at low CD123 expression levels. It also maintains its efficacy in the presence of competing IgG, unlike conventional monoclonal antibodies. AFM28 induces a much stronger NK cell activation and inflammatory cytokine release in human whole-blood tests than Fc-enhanced IgG1. It depletes CD123+ plasmacytoid dendritic cells (pDCs) and basophils with a lower risk of cytokine release syndrome.

In animal models, AFM28 exhibits a pharmacokinetic profile similar to monoclonal antibodies and has been shown to be safe and well-tolerated in pre-clinical toxicology studies. The drug is currently being prepared for human clinical trials. Its high affinity binding, potent NK cell activation, and extended retention on cell surfaces suggest that AFM28 could provide NK cells with properties similar to chimeric antigen receptor (CAR) T-cells, potentially offering significant benefits when used in combination with allogeneic NK cell therapy.