Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity

Binder, Christian; Sellberg, Felix; Cvetkovski, Filip; Berg, Stefan; Berglund, Erik; Berglund, David

doi:10.3389/fimmu.2021.599526

Cited by 7 publications

(5 citation statements)

References 36 publications

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“…This is important because NK cell activation without the presence of target cells may result in NK cell fratricide, resulting in NK cell depletion. 42 , 43 …”

Section: Discussionmentioning

confidence: 99%

Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers

Liao,

Tumanut,

et al. 2024

mAbs

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Natural killer (NK) cells are key players in human innate immunity. Cell engager antibody formats that recruit and activate NK cells more effectively have emerged as a promising immunotherapy approach to target cancer cells through more effective antibody-dependent cell-mediated cytotoxicity (ADCC). Monoclonal antibody drugs with ADCC activity have shown clinical benefit and improved outcomes for patients with certain types of cancer. CD16a, a Fc gamma III receptor, is the major component that is responsible for the ADCC activity of NK cells. Screening AvantGen’s yeast displayed human antibody libraries led to the isolation of 2 antibody clones, #1A2 and #2-2A2, that selectively recognize both isoforms (F and V) of CD16a on primary NK cells with high affinity, yet minimally (#1A2) or do not (#2-2A2) cross-react with both allelotypes of CD16b (NA1 and NA2) expressed by neutrophils. Epitope mapping studies revealed that they bind to an epitope dependent on residue Y158 of CD16a, since mutation of Y158 to the corresponding CD16b residue H158 completely abolishes binding to CD16a. When formatted as bispecific antibodies targeting CD16a and a tumor-associated antigen (TAA, e.g. CD19), they exhibit specific binding to NK cells and induce potent NK cell activation upon encountering tumor cells, resulting in effective tumor cell killing. Notably, these bispecific antibody engagers stimulate NK cell cytokine release during co-culture with target cells, resulting in target cell cytotoxicity. These anti-CD16a antibody clones are promising candidates for combination with any TAA of interest, offering the potential for novel NK cell engager-based cancer therapeutics that are minimally affected by the high concentrations of human IgG in the circulation.

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“…This is important because NK cell activation without the presence of target cells may result in NK cell fratricide, resulting in NK cell depletion. 42 , 43 …”

Section: Discussionmentioning

confidence: 99%

Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers

Liao,

Tumanut,

et al. 2024

mAbs

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“…The cognate interaction of CD2 with CD58 contributes to the generation of an immunological synapse and provides essential costimulatory signals for optimal activation, differentiation/maturation and proliferation of T cells and NK cells ( 44, 56, 75 ). Blockade of CD2-LFA3 engagement is immunoregulatory and shown to be important for suppressing immune responses particularly in the transplantation setting ( 43, 80 ). Siplizumab is an anti-CD2 mAb that has received FDA approval to prevent transplant rejection ( 80 ).…”

Section: Discussionmentioning

confidence: 99%

“…Blockade of CD2-LFA3 engagement is immunoregulatory and shown to be important for suppressing immune responses particularly in the transplantation setting ( 43, 80 ). Siplizumab is an anti-CD2 mAb that has received FDA approval to prevent transplant rejection ( 80 ). Since we found elevated CD2 on NK cell populations and CD4 + T cells in HS, we tested if its blockade has therapeutic potential for the disease.…”

Section: Discussionmentioning

confidence: 99%

NK and NKT cells in the pathogenesis of Hidradenitis suppurativa: Novel therapeutic strategy through targeting of CD2

Kashyap,

Mishra,

Sinha

et al. 2023

Preprint

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Hidradenitis suppurativa (HS) is a chronic debilitating inflammatory skin disease with poorly understood pathogenesis. Single-cell RNAseq analysis of HS lesional and healthy individual skins revealed that NKT and NK cell populations were greatly expanded in HS, and they expressed elevated CD2, an activation receptor. Immunohistochemistry analyses confirmed significantly expanded numbers of CD2+ cells distributed throughout HS lesional tissue, and many co-expressed the NK marker, CD56. While CD4+ T cells were expanded in HS, CD8 T cells were rare. CD20+ B cells in HS were localized within tertiary follicle like structures. Immunofluorescence microscopy showed that NK cells (CD2+CD56dim) expressing perforin, granzymes A and B were enriched within the hyperplastic follicular epidermis and tunnels of HS and juxtaposed with apoptotic cells. In contrast, NKT cells (CD2+CD3+CD56bright) primarily expressed granzyme A and were associated with α-SMA expressing fibroblasts within the fibrotic regions of the hypodermis. Keratinocytes and fibroblasts expressed high levels of CD58 (CD2 ligand) and they interacted with CD2 expressing NKT and NK cells. The NKT/NK maturation and activating cytokines, IL-12, IL-15 and IL-18, were significantly elevated in HS. Inhibition of cognate CD2-CD58 interaction with blocking anti-CD2 mAb in HS skin organotypic cultures resulted in a profound reduction of the inflammatory gene signature and secretion of inflammatory cytokines and chemokines in the culture supernate. In summary, we show that a cellular network of heterogenous NKT and NK cell populations drives inflammation, tunnel formation and fibrosis in the pathogenesis of HS. Furthermore, CD2 blockade is a viable immunotherapeutic approach for the management of HS.

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“…Collectively, this suggests that NK cells do have intrinsically higher resistance to free perforin compared to their common target cells. Despite this, however, NK cells [ 45 ] and CTLs [ 12 , 46 ] are still susceptible to perforin attack from other effector cells, or fratricide. In a not exactly parallel experiment, we found that NK92 can kill YTS cells in coincubation experiments, and the activity is increased by pretreatment of the YTS cells with 7KC.…”

Section: Discussionmentioning

confidence: 99%

Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis

2021

PLoS Biol

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Natural killer (NK) cells kill a target cell by secreting perforin into the lytic immunological synapse, a specialized interface formed between the NK cell and its target. Perforin creates pores in target cell membranes allowing delivery of proapoptotic enzymes. Despite the fact that secreted perforin is in close range to both the NK and target cell membranes, the NK cell typically survives while the target cell does not. How NK cells preferentially avoid death during the secretion of perforin via the degranulation of their perforin-containing organelles (lytic granules) is perplexing. Here, we demonstrate that NK cells are protected from perforin-mediated autolysis by densely packed and highly ordered presynaptic lipid membranes, which increase packing upon synapse formation. When treated with 7-ketocholesterol, lipid packing is reduced in NK cells making them susceptible to perforin-mediated lysis after degranulation. Using high-resolution imaging and lipidomics, we identified lytic granules themselves as having endogenously densely packed lipid membranes. During degranulation, lytic granule–cell membrane fusion thereby further augments presynaptic membrane packing, enhancing membrane protection at the specific sites where NK cells would face maximum concentrations of secreted perforin. Additionally, we found that an aggressive breast cancer cell line is perforin resistant and evades NK cell–mediated killing owing to a densely packed postsynaptic membrane. By disrupting membrane packing, these cells were switched to an NK-susceptible state, which could suggest strategies for improving cytotoxic cell-based cancer therapies. Thus, lipid membranes serve an unexpected role in NK cell functionality protecting them from autolysis, while degranulation allows for the inherent lytic granule membrane properties to create local ordered lipid “shields” against self-destruction.

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Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity

Cited by 7 publications

References 36 publications

Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers

Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers

NK and NKT cells in the pathogenesis of Hidradenitis suppurativa: Novel therapeutic strategy through targeting of CD2

Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis

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