Augmented antibody-based anticancer therapeutics boost neutrophil cytotoxicity

Heemskerk, Niels; Gruijs, Mandy; Temming, A. Robin; Heineke, Marieke H.; Gout, Dennis Y.; Hellingman, Tessa; Tuk, Cornelis W.; Winter, Paula J.; Lissenberg-Thunnissen, Suzanne N.; Bentlage, Arthur E. H.; Donatis, Marco De; Bögels, Marijn; Rösner, Thies; Valerius, Thomas; Bakema, Jantine E.; Vidarsson, Gestur; Egmond, Marjolein van

doi:10.1172/jci134680

Cited by 39 publications

(23 citation statements)

References 77 publications

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“…Long-term exposure to IgA-antigen complexes is required to initiate cell activation and ultimately to induce chronic inflammation. Unfortunately, hIgA has a short half-life in mice ( 35 ). As such, we first determined the stability of our IgA antibodies in vivo by defining the presence of antibody within the ear dermis over time after a single dose injection of anti-mCOL17 hIgA antibodies.…”

Section: Resultsmentioning

confidence: 99%

Anti-FcαRI Monoclonal Antibodies Resolve IgA Autoantibody-Mediated Disease

et al. 2022

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Immunoglobulin A (IgA) is generally considered as a non-inflammatory regulator of mucosal immunity, and its importance in diversifying the gut microbiota is increasingly appreciated. IgA autoantibodies have been found in several autoimmune or chronic inflammatory diseases, but their role in pathophysiology is ill-understood. IgA can interact with the Fc receptor FcαRI on immune cells. We now established a novel IgA autoimmune blistering model, which closely resembles the human disease linear IgA bullous disease (LABD) by using genetically modified mice that produce human IgA and express human FcαRI. Intravital microscopy demonstrated that presence of IgA anti-collagen XVII, - the auto-antigen in LABD-, resulted in neutrophil activation and extravasation from blood vessels into skin tissue. Continued exposure to anti-collagen XVII IgA led to massive neutrophil accumulation, severe tissue damage and blister formation. Importantly, treatment with anti-FcαRI monoclonal antibodies not only prevented disease, but was also able to resolve existing inflammation and tissue damage. Collectively, our data reveal a novel role of neutrophil FcαRI in IgA autoantibody-mediated disease and identify FcαRI as promising new therapeutic target to resolve chronic inflammation and tissue damage.

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Section: Resultsmentioning

confidence: 99%

Anti-FcαRI Monoclonal Antibodies Resolve IgA Autoantibody-Mediated Disease

et al. 2022

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“…However, mice do not express a natural homolog for FcαRI; therefore, in vivo studies generally exclude the influence of FcαRI-mediated activation in the experimental readouts. By contrast, crosslinking of FcαRI on human neutrophils triggers potent pro-inflammatory functions including degranulation, phagocytosis, chemotaxis, antibody-dependent cellular cytotoxicity [ 27 , 28 , 29 ], and production of proinflammatory cytokines including IL6, TNFα, and IL1β [ 25 ]. This would not occur with murine neutrophils, as they do not express FcαRI.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, SIgA poorly initiates myeloid cell activation, whereas serum IgA and dIgA complexes can crosslink FcαRI and potently induce proinflammatory functions [ 23 , 26 ]. Although monomeric IgA induces inhibitory signals, crosslinking FcαRI by IgA complexes has been described to induce degranulation, phagocytosis, chemotaxis, and antibody-dependent cellular cytotoxicity [ 27 , 28 , 29 ]. Moreover, serum IgA-mediated myeloid cell activation triggers production of proinflammatory cytokines including interleukin-6 (IL6), tumor necrosis factor-α (TNFα), and interleukin-1β [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Fcα Receptor-1-Activated Monocytes Promote B Lymphocyte Migration and IgA Isotype Switching

Bos

Gool

Breedveld

et al. 2022

IJMS

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Patients with inflammatory bowel disease (IBD) produce enhanced immunoglobulin A (IgA) against the microbiota compared to healthy individuals, which has been correlated with disease severity. Since IgA complexes can potently activate myeloid cells via the IgA receptor FcαRI (CD89), excessive IgA production may contribute to IBD pathology. However, the cellular mechanisms that contribute to dysregulated IgA production in IBD are poorly understood. Here, we demonstrate that intestinal FcαRI-expressing myeloid cells (i.e., monocytes and neutrophils) are in close contact with B lymphocytes in the lamina propria of IBD patients. Furthermore, stimulation of FcαRI-on monocytes triggered production of cytokines and chemokines that regulate B-cell differentiation and migration, including interleukin-6 (IL6), interleukin-10 (IL10), tumour necrosis factor-α (TNFα), a proliferation-inducing ligand (APRIL), and chemokine ligand-20 (CCL20). In vitro, these cytokines promoted IgA isotype switching in human B cells. Moreover, when naïve B lymphocytes were cultured in vitro in the presence of FcαRI-stimulated monocytes, enhanced IgA isotype switching was observed compared to B cells that were cultured with non-stimulated monocytes. Taken together, FcαRI-activated monocytes produced a cocktail of cytokines, as well as chemokines, that stimulated IgA switching in B cells, and close contact between B cells and myeloid cells was observed in the colons of IBD patients. As such, we hypothesize that, in IBD, IgA complexes activate myeloid cells, which in turn can result in excessive IgA production, likely contributing to disease pathology. Interrupting this loop may, therefore, represent a novel therapeutic strategy.

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“…Despite the promise of IgA as a new anticancer modality, the development of IgA as a cancer therapeutic agent is confounded by IgA's short half-life and weak activation capability of NK cells 9 . The combination of IgG and IgA antibodies exhibited greater efficacy in inducing tumor killing than either IgA or IgG alone.…”

Section: Introductionmentioning

confidence: 99%

“…However, IgGA did not bind to CD16a or FcRn. Heemskerk et al generated a bispecific antibody referred to as TrisomAb 9 , in which one arm targets CD89 and the other targets a tumor-associated antigen. TrisomAb effectively recruited NK cells, macrophages, and neutrophils as effector cells for the eradication of tumor cells in vitro and in vivo .…”

Section: Introductionmentioning

confidence: 99%

Self-assembly of X-shaped antibody to combine the activity of IgG and IgA for enhanced tumor killing

Liang¹,

Li²,

Peng³

et al. 2022

Theranostics

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Rationale: IgA can induce activation of neutrophils which are the most abundant cell type in blood, but the development of IgA as therapeutic has been confounded by its short half-life and a weak ability to recruit NK cells as effector cells. Therefore, we generated an X-shaped antibody (X-body) based on the principle of molecular self-assembly that combines the activities of both IgG and IgA, which can effectively recruit and activate NK cells, macrophages, and neutrophils to kill tumor cells. Methods: X-body was generated by using a self-assembly strategy. The affinity of the X-body with the antigen and Fc receptors was tested by surface plasmon resonance. The shape of X-body was examined using negative staining transmission electron microscopy. The tumor cell killing activity of X-body was assessed in vitro and in multiple syngeneic mouse models. To explore the mechanism of X-body, tumor-infiltrating immune cells were analyzed by single-cell RNA-seq and flow cytometry. The dependence of neutrophil, macrophage, and NK cells for the X-body efficacy was confirmed by in vivo depletion of immune cell subsets. Results: The X-body versions of rituximab and trastuzumab combined the full spectrum activity of IgG and IgA and recruited NK cells, macrophages, and neutrophils as effector cells for eradication of tumor cells. Treatment with anti-hCD20 and anti-hHER2 X-bodies leads to a greater reduction in tumor burden in tumor-bearing mice compared with the IgA or IgG counterpart, and no obvious adverse effect is observed upon X-body treatment. Moreover, the X-body has a serum half-life and drug stability comparable to IgG. Conclusions: The X-body, as a myeloid-cell-centered therapeutic strategy, holds promise for the development of more effective cancer-targeting therapies than the current state of the art.

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Augmented antibody-based anticancer therapeutics boost neutrophil cytotoxicity

Cited by 39 publications

References 77 publications

Anti-FcαRI Monoclonal Antibodies Resolve IgA Autoantibody-Mediated Disease

Anti-FcαRI Monoclonal Antibodies Resolve IgA Autoantibody-Mediated Disease

Fcα Receptor-1-Activated Monocytes Promote B Lymphocyte Migration and IgA Isotype Switching

Self-assembly of X-shaped antibody to combine the activity of IgG and IgA for enhanced tumor killing

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