Enhanced AML Targeting by Second-Generation Camelid Trike in Pre-Clinical NK Cell Models

A study has demonstrated that a modified immunotherapy approach using IL-2 can lead to remissions in a significant proportion of patients with a difficult-to-treat form of blood cancer known as acute myeloid leukemia (AML). However, the effectiveness of this treatment is limited due to the activation of regulatory T cells and the lack of specific antigen targeting. To overcome these challenges, researchers have developed a new molecule called a trispecific killer engager (TriKE), which is designed to activate natural killer (NK) cells and target myeloid cells.

The first-generation TriKE, named 161533, was found to have functional scFv domains but was less potent than expected, likely due to structural hindrances during refolding. To enhance its performance, a second-generation molecule, cam161533, was created by replacing the original anti-CD16 scFv with a humanized camelid single-domain antibody. This change resulted in improved stability, solubility, and antigen recognition, as well as preventing mispairing issues.

In vitro tests revealed that cam161533 significantly increased NK cell activity, as evidenced by enhanced degranulation, interferon-gamma production, and proliferation rates when compared to the first-generation molecule. Additionally, cam161533 demonstrated superior binding stability in pre-incubated peripheral blood mononuclear cells.

Preclinical testing in a mouse model with human NK cells and AML tumor targets showed that both TriKE molecules reduced tumor burden, but cam161533 was significantly more effective, resulting in a substantial decrease in tumor luminescence.

The second-generation TriKE, cam161533, has shown promising results and is expected to undergo clinical trials at the University of Minnesota. The findings indicate that this new molecule has substantial functional benefits and could lead to more effective treatments for AML. The development of camelid-based TriKEs is a promising direction for future cancer immunotherapy.