Antibody Afucosylation Augments CD16-Mediated Serial Killing and IFNγ Secretion by Human Natural Killer Cells

Karampatzakis, Alexandros; Brož, Petr; Rey, Camille; Önfelt, Björn; Matos, Gabriela Dos Santos Cruz De; Rycroft, Daniel; Ambrose, Ashley R.; Davis, Daniel M.

doi:10.3389/fimmu.2021.641521

Cited by 14 publications

(12 citation statements)

References 60 publications

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“…CD16 expression on NK cells expanded using non-coated rituximab was lower than NK cells expanded with coated rituximab. Loss of CD16 has recently been shown to be important for NK cell detachment and sequential engagement of multiple target cells ( 38 ). Rapid detachment between NK cells and target cells increased engagement of NK cells and multiple targets and enabled a greater proportion of NK cells to perform serial killing.…”

Section: Discussionmentioning

confidence: 99%

Non-Coated Rituximab Induces Highly Cytotoxic Natural Killer Cells From Peripheral Blood Mononuclear Cells via Autologous B Cells

Niu

Chen

et al. 2021

Front. Immunol.

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Natural killer (NK) cells are becoming valuable tools for cancer therapy because of their cytotoxicity against tumor cells without prior sensitization and their involvement in graft-versus-host disease; however, it is difficult to obtain highly cytotoxic NK cells without adding extra feeder cells. In this study, we developed a new method for obtaining highly cytotoxic NK cells from peripheral blood mononuclear cells (PBMCs) independently of extra feeder cell addition using rituximab not coated on a flask (non-coated rituximab). We found that rituximab could promote both the activation and expansion of NK cells from PBMCs, irrespective of being coated on a flask or not. However, NK cells activated by non-coated rituximab had much greater antitumor activity against cancer cells, and these effects were dependent on autologous living B cells. The antibody-dependent cellular cytotoxicity effect of NK cells activated by non-coated rituximab was also more substantial. Furthermore, these cells expressed higher levels of CD107a, perforin, granzyme B, and IFN-γ. However, there was no difference in the percentage, apoptosis, and cell-cycle progression of NK cells induced by coated and non-coated rituximab. Non-coated rituximab activated NK cells by increasing AKT phosphorylation, further enhancing the abundance of XBP1s. In conclusion, we developed a new method for amplifying NK cells with higher antitumor functions with non-coated rituximab via autologous B cells from PBMCs, and this method more efficiently stimulated NK cell activation than by using coated rituximab.

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Section: Discussionmentioning

confidence: 99%

Non-Coated Rituximab Induces Highly Cytotoxic Natural Killer Cells From Peripheral Blood Mononuclear Cells via Autologous B Cells

Niu

Chen

et al. 2021

Front. Immunol.

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“…Several studies indicate that afucosylated IgG1 antibodies induce a more rapid and intense cytokine release by NK cells, monocytes/macrophages, PMN and/or ɣd T cells compared to their fully fucosylated counterparts. Induced cytokines include IFN-ɣ, MCP1, IL-6, TNF, MIP1ab, Rantes, IL-8 (55,100,107,(113)(114)(115). The level of cytokines induced in vitro is however generally quite low and the significance of such release in vivo is not fully clear.…”

Section: Cytokine Release By Immune Cellsmentioning

confidence: 99%

Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies

2022

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The presence of fucose on IgG1 Asn-297 N-linked glycan is the modification of the human IgG1 Fc structure with the most significant impact on FcɣRIII affinity. It also significantly enhances the efficacy of antibody dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells in vitro, induced by IgG1 therapeutic monoclonal antibodies (mAbs). The effect of afucosylation on ADCC or antibody dependent phagocytosis (ADCP) mediated by macrophages or polymorphonuclear neutrophils (PMN) is less clear. Evidence for enhanced efficacy of afucosylated therapeutic mAbs in vivo has also been reported. This has led to the development of several therapeutic antibodies with low Fc core fucose to treat cancer and inflammatory diseases, seven of which have already been approved for clinical use. More recently, the regulation of IgG Fc core fucosylation has been shown to take place naturally during the B-cell immune response: A decrease in α-1,6 fucose has been observed in polyclonal, antigen-specific IgG1 antibodies which are generated during alloimmunization of pregnant women by fetal erythrocyte or platelet antigens and following infection by some enveloped viruses and parasites. Low IgG1 Fc core fucose on antigen-specific polyclonal IgG1 has been linked to disease severity in several cases, such as SARS-CoV 2 and Dengue virus infection and during alloimmunization, highlighting the in vivo significance of this phenomenon. This review aims to summarize the current knowledge about human IgG1 Fc core fucosylation and its regulation and function in vivo, in the context of both therapeutic antibodies and the natural immune response. The parallels in these two areas are informative about the mechanisms and in vivo effects of Fc core fucosylation, and may allow to further exploit the desired properties of this modification in different clinical contexts.

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“…Pairing NK cellular therapy with existing monoclonals thus provides a wide range of applications for a single cellular product. Alterations in the design of human monoclonals, including glycosylation [ 20 ], particularly afucosylation [ 21 ], can further improve the killing dynamics of NK cells. Design alterations to CD16 are also being tested in preclinical models.…”

Section: Ignorance Of Tumormentioning

confidence: 99%

Challenges to the broad application of allogeneic natural killer cell immunotherapy of cancer

2022

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Natural killer (NK) cells are innate immune cells that recognize malignant cells through a wide array of germline-encoded receptors. Triggering of activating receptors results in cytotoxicity and broad immune system activation. The former is achieved through release of cytotoxic granules and presentation of death receptor ligands, while the latter is mediated by inflammatory cytokines, such as interferon-γ and tumor necrosis factor α. Early success with ex vivo activation of NK cells and adoptive transfer suggest they are a safe therapeutic with promising responses in advanced hematologic malignancies. In particular, adoptive NK cell therapies can serve as a ‘bridge’ to potentially curative allogeneic stem cell transplantation. In addition, strategies are being developed that expand large numbers of cells from limited starting material and mature NK cells from precursors. Together, these make ‘off-the-shelf’ NK cells possible to treat a wide range of cancers. Research efforts have focused on creating a range of tools that increase targeting of therapeutic NK cells toward cancer—from therapeutic antibodies that drive antibody-dependent cellular cytotoxicity, to chimeric antigen receptors. As these novel therapies start to show promise in clinical trials, the field is rapidly moving toward addressing other challenges that limit NK cell therapeutics and the goal to treat solid tumors. This review describes the state of therapeutic NK cell targeting of tumors; discusses the challenges that need to be addressed before NK cells can be applied as a wide-ranging treatment for cancer; and points to some of the innovations that are being developed to surmount these challenges. Suppressive cells in the tumor microenvironment pose a direct threat to therapeutic NK cells, through presentation of inhibitory ligands and secretion of suppressive cytokines and metabolites. The nutrient- and oxygen-starved conditions under which NK cells must function necessitate an understanding of therapeutic NK cell metabolism that is still emerging. Prior to these challenges, NK cells must find their way into and persist in the tumor itself. Finally, the desirability of a ‘single-shot’ NK cell treatment and the problems and benefits of a short-lived rejection-prone NK cellular product are discussed.

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Antibody Afucosylation Augments CD16-Mediated Serial Killing and IFNγ Secretion by Human Natural Killer Cells

Cited by 14 publications

References 60 publications

Non-Coated Rituximab Induces Highly Cytotoxic Natural Killer Cells From Peripheral Blood Mononuclear Cells via Autologous B Cells

Non-Coated Rituximab Induces Highly Cytotoxic Natural Killer Cells From Peripheral Blood Mononuclear Cells via Autologous B Cells

Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies

Challenges to the broad application of allogeneic natural killer cell immunotherapy of cancer

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