Current Developments in NK Cell Engagers for Cancer Immunotherapy: Focus on CD16A and NKp46

Abstract

NK cells are specialized immune effector cells crucial for triggering immune responses against aberrant cells. Although recent advancements have concentrated on creating or releasing T-cell responses specific to tumor Ags, the clinical advantages of this approach have been limited to certain groups of patients and tumor types. This emphasizes the need for alternative strategies. One pioneering approach involves broadening and enhancing anti-tumor immune responses by targeting innate immunity. Consequently, the advent of bi-, tri-, and multi-specific Abs has facilitated the advancement of targeted cancer immunotherapies by redirecting immune effector cells to eradicate tumor cells. These Abs enable the simultaneous binding of surface Ags on tumor cells and the activation of receptors on innate immune cells, such as NK cells, with the ability to facilitate Ab-dependent cellular cytotoxicity to enhance their immunotherapeutic effectiveness in patients with solid tumors. Here, we review the recent advances in NK cell engagers (NKCEs) focusing on NK cell-activating receptors CD16A and NKp46. In addition, we provide an overview of the ongoing clinical trials investigating the safety, efficacy, and potential of NKCEs.

Keywords: Antibody-dependent cell cytotoxicity; Immunotherapy; NK cell receptors; NK cells.

Figure 1. Receptors and ligands of NK cells.

This figure illustrates the array of inhibitory and activating receptors expressed on the surface of NK cells, alongside their corresponding ligands presented on target cells. The diagram provides a comprehensive overview of the interactions between NK cell receptors, such as NKp46, NKp44, NKG2D, and their respective ligands (Created with BioRender.com).

Figure 2. Diverse formats of NKCEs and their interactions with NK cells and tumor cells.

This figure provides a detailed illustration of various formats of NKCEs, including (A) CD16A BiKE (IgG-like), (B) NKp46 BiKE, (C) CD16A TAA1 TAA2 TriKE, and (D) CD16A NKp46 TAA TriKE. Each format is depicted interacting with key activating receptors on NK cells, and their respective ligands on tumor cells. These interactions are crucial for the effective engagement and activation of NK cells, promoting mechanisms such as ADCC, direct cytotoxicity, and cytokine production (Created with BioRender.com).

Figure 3. Mechanism of CD16A and NKp46 in NK cell functions.

This figure elucidates the mechanisms by which CD16A and NKp46 receptors enhance NK cell functions. The binding of the Fc fragment of IgG to CD16A, and the interaction of tumor-associated ligands with NKp46, trigger signal transduction pathways. These pathways involve ITAMs, CD3ζ, and FcRγ, leading to the activation of downstream signaling molecules such as Syk, ZAP-70, PI3K, and PLCγ. This cascade of signaling events results in increased cytotoxic activity and cytokine production, thereby augmenting the immune response against tumor cells (Created with BioRender.com).