Bispecific Antibodies Unleash More Potential of NK Cells

Posted by Candy Swift on February 7th, 2022

Natural killer cells (NK cells) are a component of the innate immune system and provide the first line of defense for the body\'s immune system. They patrol the body and are recruited to destroy tumor cells at the tumor site. In addition to their direct anti-tumor activity, NK cells produce cytokines and chemokines that may activate a variety of immune cells such as dendritic cells and T cells.

Currently, in clinical practice, NK cells exert their anti-tumor effects mainly through IgG1-type antibodies. More than 30 IgG1 monoclonal antibodies have been approved and marketed for tumor treatment. These antibodies play a significant role in the treatment of tumors, but in some cases the expression of tumor-associated antigens is in low levels, thus limiting the therapeutic effect of the antibodies.

Several approaches have been used to enhance the antibody-dependent cellular cytotoxicity (ADCC) effect of some therapeutic antibodies, and bispecific antibodies are a new direction of current research. This article will take stock of the current status of the development of NK cell-expressed activating receptors and related bispecific antibodies.

CD16A-expressing NK cells (NKCEs)

CD16A is a member of the immunoglobulin superfamily with two extracellular Ig-like structures. It is expressed on NK cells, mast cells, macrophages, and monocytes, and acts as a receptor for the Fc fragment of IgG antibodies.

Several bispecific antibodies targeting CD16A are already under study, such as the bispecific antibodies constructed by GTBiopharma through the BiKE and TriKE platforms. The antibodies are mainly composed of scFv, which are linked by linker to enhance the killing ability of NK cells against tumor cells to some extent.

NKp30-NKCEs

NKp30 (NCR3, CD337) is a type I transmembrane activated receptor belonging to the immunoglobulin superfamily. Activation of NKp30 leads to the production of cytotoxicity and cytokine secretion by NK cells. The surface molecule B7-H6 and the nuclear factor HLA-B-associated transcript 3 (BAT3), are released from tumor cells and can bind and activate NKp30.

CTX-8573 is a bispecific antibody targeting NKp30 and BCMA, with the C-terminus of the antibody attached to the anti-NKp Fab and the same light chain to resolve the mismatch. The Fc-terminus has been treated with de-fucose to further enhance the effect of NK cells. CTX-8573 has been shown to have anti-tumor efficacy in vitro and in vivo.

NKp46-NKCEs

NKp46 (NCR1, CD335) belongs to the immunoglobulin superfamily, which contains two extracellular Ig-like structural domains. NKp46 is a human NK cell marker that is highly conserved in mammals. It is involved in the lysis of autologous, allogeneic and xenogeneic cells by NK cells. Studies have shown that NKp46 antibody-mediated cross-linking can stimulate cytotoxic activity and cytokine release from NK cells.

The development of NKp46 bispecific antibodies is currently in preclinical studies, such as CYT-303, CYT308 and IPH6101, IPH21.

NK cells, as immune effector cells, are naturally able to recognize normal and tumor cells, and this property makes them ideal for anti-tumor treatment. Moreover, relevant clinical studies have shown that targeted activation of NK cells can suppress tumors to a certain extent.

In contrast to bispecific antibodies activating T cells and CAR-NK therapies, the development of bispecific antibodies that target activated NK cells is just at the beginning. Based on the well-established platforms, Creative biolabs offers customized target based bispecific antibody design services to help advance related projects from worldwide researchers. 

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Candy Swift

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Candy Swift
Joined: June 6th, 2020
Articles Posted: 49

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