Immunotherapeutic targeting of activating natural killer cell receptors and their ligands in cancer

Abstract

Summary Natural killer (NK) cells exert an important role in cancer immune surveillance. Recognition of malignant cells and controlled activation of effector functions are facilitated by the expression of activating and inhibitory receptors, which is a complex interplay that allows NK cells to discriminate malignant cells from healthy tissues. Due to their unique profile of effector functions, the recruitment of NK cells is attractive in cancer treatment and a key function of NK cells in antibody therapy is widely appreciated. In recent years, besides the low-affinity fragment crystallizable receptor for immunoglobulin G (FcγRIIIA), the activating natural killer receptors p30 (NKp30) and p46 (NKp46), as well as natural killer group 2 member D (NKG2D), have gained increasing attention as potential targets for bispecific antibody-derivatives to redirect NK cell cytotoxicity against tumors. Beyond modulation of the receptor activity on NK cells, therapeutic targeting of the respective ligands represents an attractive approach. Here, novel therapeutic approaches to unleash NK cells by engagement of activating NK-cell receptors and alternative strategies targeting their tumor-expressed ligands in cancer therapy are summarized.

NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

“…Several of FcγRIIIa‐specific NKCEs are currently investigated in clinical trials (Bartlett et al, 2020; Demaria et al, 2021). Another route that is presently pursued relies on targeting the array of activating NK cell receptors for the construction of potent NKCEs (Peipp et al, 2022). This has been accomplished in several different ways.…”

Regulatory considerations in the design, development and quality of monoclonal antibodies and related products for the diagnosis and treatment of cancer

“…Full length constructs are engineered to promote heterodimerization over homodimerization of heavy chains and pair the correct light chains and heavy chains ( 72 ).The majority of BsAbs in clinical development are for oncology indications and most of those products are designed to engage T cells ( Figure 2A ), while targeting a tumor antigen. More recent designs incorporate an arm designed to engage NK cells ( 78 , 79 ) or antigen presenting cells instead of T cells ( 80 ). Since 2017, many products have one or two arms that target a checkpoint inhibitor or immunostimulatory molecule, with the remaining constructs targeting two tumor antigens.…”

Viral escape from NK‐cell‐mediated immunosurveillance: A lesson for cancer immunotherapy?

“…Optimizing binding potency between NK-cell receptors and engagers to enable efficient engagement despite low ligand expression density [62], discussed in [63] Treatment with bispecific NKG2D/CD16 fusion molecules Utilizing potent activation through CD16 for NKG2D-specific engagement of tumor cells to achieve activation despite low expression of NKG2D-ligands [64] Treatment with multifunctional NK-cell engagers Merging two activating receptors into a combined targeting approach for enhanced activation to reduce dependency on one ligand-receptor pair [65] Treatment with sensitizing agents…”

“…Biochemical engineering has been successfully used to considerably increase the affinity between NK-cell receptors and their ligands [62]. The development of ligand-specific engagers with supraphysiological functional avidity has the potential to reach the required activation threshold of NK cells despite low ligand density [63]. Bispecific fusion proteins, which contain extracellular NKG2D domains as antigen-binding component coupled to Fab-fragments of anti-CD16 as cross-linking module, can potentiate NK-cell activation [64].…”