Natural Killer Cell Engagers (NKCEs): a new frontier in cancer immunotherapy

Abstract

Natural Killer (NK) cells are a type of innate lymphoid cells that play a crucial role in immunity by killing virally infected or tumor cells and secreting cytokines and chemokines. NK cell-mediated immunotherapy has emerged as a promising approach for cancer treatment due to its safety and effectiveness. NK cell engagers (NKCEs), such as BiKE (bispecific killer cell engager) or TriKE (trispecific killer cell engager), are a novel class of antibody-based therapeutics that exhibit several advantages over other cancer immunotherapies harnessing NK cells. By bridging NK and tumor cells, NKCEs activate NK cells and lead to tumor cell lysis. A growing number of NKCEs are currently undergoing development, with some already in clinical trials. However, there is a need for more comprehensive studies to determine how the molecular design of NKCEs affects their functionality and manufacturability, which are crucial for their development as off-the-shelf drugs for cancer treatment. In this review, we summarize current knowledge on NKCE development and discuss critical factors required for the production of effective NKCEs.

Bispecific immune cell engager enhances the anticancer activity of CD16+ NK cells and macrophages in vitro, and eliminates cancer metastasis in NK humanized NOG mice

“… 34 Another class of immunotherapeutic modalities harnessing NK cells, known as NK cell engagers (NKCEs), has recently emerged and exhibited several advantages over the abovementioned strategies. 35 …”

“…34 Another class of immunotherapeutic modalities harnessing NK cells, known as NK cell engagers (NKCEs), has recently emerged and exhibited several advantages over the abovementioned strategies. 35 In this context, we have previously reported the sequence of a new NKCE (BiKE:E5C1) and have shown under in vitro conditions that it forms an immunologic synapse between laNK92 cells and HER2+ cancer cells, leading to the lysis of cancer cells. 10 As a first step toward achieving our objective, we evaluated the ability of BiKE:E5C1 to activate other immune cells that express CD16a receptor.…”

Chimeric antigen receptor-natural killer cell therapy: current advancements and strategies to overcome challenges

“…There are two types of NK cell engagers: BiKE (bispecific killer cell engager) and TriKE (trispecific killer cell engager) which bridge NK cells with cancer cells more effectively, thus enhancing the efficacy of NK cells to eliminate cancer cells. Various activating and inhibitory receptors on NK cells have been targeted by NK cell engagers to improve NK cells in cancer eradication, including CD16a, CD160, CD96, NKG2A, NKG2D, NKG2C, Nkp30, Nkp46, Nkp80, KIR2DS/KIR3DS, KIR2DL/KIR2DS, DNAM-1, 2B4, PD-1, IL-2/IL-15, TIGIT, and TIM-3 ( 95 ). Nonetheless, each receptor possesses pros and cons when targeted with NK cell engagers.…”

The role and novel use of natural killer cells in graft-versus-leukemia reactions after allogeneic transplantation

“…They account for 5 to 15% of peripheral blood lymphocytes and are the third most abundant lymphocyte lineage in the peripheral blood ( 22 – 26 ). NK cells can identify stressed cells through their expression of ligands associated with cellular stress (NKG2D or DNAM-1) or through absence of expression of HLA class 1 molecules ( 27 , 28 ). NK cell activation is mediated by the balance of activating and inhibitory signals received upon contact with host or foreign cells: either via a lack of interaction between a NK cell inhibitory receptor and its cognate ligand, an interaction between a NK cell activating receptor and its cognate ligand, or a predominance of activating over inhibitory signals ( 27 , 29 , 30 ).…”

“…NK cells can identify stressed cells through their expression of ligands associated with cellular stress (NKG2D or DNAM-1) or through absence of expression of HLA class 1 molecules ( 27 , 28 ). NK cell activation is mediated by the balance of activating and inhibitory signals received upon contact with host or foreign cells: either via a lack of interaction between a NK cell inhibitory receptor and its cognate ligand, an interaction between a NK cell activating receptor and its cognate ligand, or a predominance of activating over inhibitory signals ( 27 , 29 , 30 ). The inhibitory receptors found on NK cells, which include inhibitory killer immunoglobulin-like receptors (iKIRs), CD94/NKG2A, and LILRB1 among many others ( Table 1 ), interact with HLA class I molecules and promote self-tolerance, preventing the initiation of NK cell cytotoxicity ( 30 ).…”