NKp46-based NKCE Platform for NK Cell Engagement

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Interest has recently focused on the use of natural killer (NK) cells for therapeutic interventions, as these cells have anti-tumor properties. NK cells express several activating receptors that can be targeted to induce NK-cell-mediated anti-tumor immunity, such as cluster of differentiation 16 (CD16, also known as FcgRIIIA), natural killer group 2D (NKG2D), signaling lymphocyte activation molecule (SLAM)-family members, and the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. The full activation of NK cells has been shown to require the co-engagement of different cell-surface receptors.

Creative Biolabs has developed a novel trifunctional natural killer (NK) cell engagers (NKCEs) technology, consisting of mAb fragments targeting the activating NK-cell receptor NKp46 and activating receptor CD16 expressed on NK cells. NKCEs are effective against several tumor types in vitro, with no off-target cytotoxicity. In vivo, NKCEs are more potent than intact anti-TA mAbs, such as rituximab and obinutuzumab, in both invasive and solid tumors. The NKCEs platform exhibit the potential to expand treatment options for next-generation cancer immunotherapy, both as monotherapy and in combination with other agents or adoptive NK cell transfer.

NKCE Mode of Action

NK cells express many activation receptors, including CD16 (also known as FcγRIIA), NKG2D, members of the SLAM family and natural cytotoxic receptors NKp30, NKp44 and NKp46. Among them, NKp46 has been identified as a particularly promising target because it is often expressed by tumor-infiltrating NK cells, and it has been reported that the sustained expression of NKp46 is associated with the down-regulation of other activated receptors. Several types of human cancers have been reported. The infiltrating NKp46 tumor. Trifunctional antibodies that engage natural killer cells by binding NKp46 and CD16, in addition to an antigen on cancer cells, show higher potency than current clinically available therapeutic antibodies.

Design and function of NKCEs

Fig.1 Design and function of NKCEs.

Key Features of our NKCE Platform

NKCEs are multifunctional Abs targeting tumor antigens, NKp46 and CD16
NKCEs bring tumor cells and NK cells together and trigger tumor-cell destruction
NKCEs can show killing potency superior to therapeutic Abs in vitro and in vivo

Prospect of our NKCE Platform

Our NKCE technology provides a versatile platform with many different format options and the potential to co-engage up to three activating receptors on NK cells and two different tumor antigens on cancer cells. With the trifunctional NKCEs reported, the binding affinities for NKp46 and CD16 should favor NK cell targeting to the tumor microenvironment, in which NKp46 expression levels remain high in many tumor conditions, by contrast to CD16. The co-targeting of NKp46 and CD16 thus led to full NK cell activation. Together with the stronger antitumor activity of these molecules in preclinical models than of gold standard mAbs, such rituximab, obinituzumab and cetuximab, these results support the clinical development of NKCEs for cancer immunotherapy, as a complement to existing immuno-oncology approaches.

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