Enhancement of antibody-dependent cell-mediated cytotoxicity by endowing IgG with FcαRI (CD89) binding

Borrok, M. Jack; Luheshi, Nadia; Beyaz, Nurten; Davies, G C; Legg, James; Wu, Herren; Dall’Acqua, William F.; Tsui, Ping

doi:10.1080/19420862.2015.1047570

Cited by 57 publications

(56 citation statements)

References 41 publications

(45 reference statements)

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“…Finally, an IgGA antibody has been developed that has the capacity to bind to both FcγRs and FcαRI . This so‐called tandem IgG1/IgA2 antibody with a trastuzumab variable domain had a comparable half‐life in vivo in mice as regular IgG antibodies and showed enhanced ADCC by human neutrophils in vitro .…”

Section: The Role Of Neutrophils In Antibody Therapy Against Cancermentioning

confidence: 99%

Neutrophils in cancer

Treffers

Hiemstra

Kuijpers

et al. 2016

Immunological Reviews

167

145

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Summary Neutrophils play an important role in cancer. This does not only relate to the well‐established prognostic value of the presence of neutrophils, either in the blood or in tumor tissue, in the context of cancer progression or for the monitoring of therapy, but also to their active role in the progression of cancer. In the current review, we describe what is known in general about the role of neutrophils in cancer. What is emerging is a complex, rather heterogeneous picture with both pro‐ and anti‐tumorigenic roles, which apparently differs with cancer type and disease stage. Furthermore, we will discuss the well‐known role of neutrophils as myeloid‐derived suppressor cells (MDSC), and also on the role of neutrophils as important effector cells during antibody therapy in cancer. It is clear that neutrophils contribute substantially to cancer progression in multiple ways, and this includes both direct effects on the cancer cells and indirect effect on the tumor microenvironment. While in many cases neutrophils have been shown to promote tumor progression, for instance by acting as MDSC, there are also protective effects, particularly when antibody immunotherapy is performed. A better understanding of the role of neutrophils is likely to provide opportunities for immunomodulation and for improving the treatment of cancer patients.

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Section: The Role Of Neutrophils In Antibody Therapy Against Cancermentioning

confidence: 99%

Neutrophils in cancer

Treffers

Hiemstra

Kuijpers

et al. 2016

Immunological Reviews

167

145

View full text Add to dashboard Cite

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“…Similarly, an IgG1/IgA1 tandem antibody format was recently described that was based on the IgG anti‐HER2 mAb trastuzumab. The IgG1/IgA2 tandem antibody augmented myeloid cell‐mediated effector functions via FcαRI, but also retained the optimal pharmacokinetics of the parental IgG . Thus, engineering IgA in order to improve half‐life may unleash the potent capacity of targeting FcαRI on effector cells like macrophages and neutrophils.…”

Section: Fcαri In Anti‐tumor Immunotherapymentioning

confidence: 99%

The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target in disease

Aleyd

Heineke

Egmond

2015

Immunological Reviews

101

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Immunoglobulin A (IgA) is the most prevalent antibody at mucosal sites, and has an important role in defense by preventing invasion of pathogens. Traditionally, IgA has been thought of as a non-inflammatory antibody that helps to maintain homeostasis in the mucosa. However, in the last decade it has become clear that IgA is a very potent stimulus to initiate pro-inflammatory cellular processes, especially after triggering the IgA Fc receptor (FcαRI) on neutrophils. It was furthermore described that FcαRI acts as a regulator between anti- and pro-inflammatory responses of IgA. Although neutrophil activation is beneficial in (mucosal) infections, abnormal or excessive IgA immune complexes can induce disproportionate neutrophil migration and in this way initiate a perpetuating neutrophil recruitment and activation loop, which will result in severe tissue damage. Increasing evidence on this process plays a detrimental role in several diseases, including autoimmune IgA blistering diseases, a subtype of rheumatoid arthritis and ulcerative colitis. Inhibiting FcαRI-mediated activation may dampen inflammation in these patients. This process also opens up the possibility of targeting FcαRI in antibody immunotherapy of cancer. Thus, interfering with IgA-mediated FcαRI activation may represent an attractive novel therapeutic strategy for multiple maladies.

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“…As reported recently, hybrid IgG1/IgA antibodies might be a promising way to create antitumor molecules efficiently employing a broad repertoire of effector cells with adequate plasma exposure. 50 …”

mentioning

confidence: 99%

A comparison of anti-HER2 IgA and IgG1 in vivo efficacy is facilitated by high N-glycan sialylation of the IgA

Rouwendal

Lee

Meyer

et al. 2015

mAbs

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Monomeric IgA has been proposed as an alternative antibody format for cancer therapy. Here, we present our studies on the production, purification and functional evaluation of anti-HER2 IgA antibodies as anti-cancer agents in comparison to the anti-HER2 IgG1 trastuzumab. MALDI-TOF MS analysis showed profound differences in glycosylation traits across the IgA isotypes and cell lines used for production, including sialylation and linkage thereof, fucosylation (both core and antennary) and the abundance of high-mannose type species. Increases in sialylation proved to positively correlate with in vivo plasma half-lives. The polymerization propensity of anti-HER2 IgA2m2 could be suppressed by an 18-aa deletion of the heavy chain tailpiece -coinciding with the loss of high-mannose type N-glycan species -as well as by 2 cysteine to serine mutations at positions 320 and 480. The HER2 F(ab')2-mediated antiproliferative effect of the IgA2m1 and IgA2m2 subtypes was similar to IgG1, whereas the IgA1 isotype displayed considerably lower potency and efficacy. The Fc-mediated induction of antibody-dependent cell-mediated cytotoxicity (ADCC) using human whole blood ADCC assays did not demonstrate such clear differences between the IgA isotypes. However, the potency of the anti-HER2 IgA antibodies in these ADCC assays was found to be significantly lower than that of trastuzumab. In vivo anti-tumor activity of the anti-HER2 IgA antibodies was compared to that of trastuzumab in a BT-474 breast cancer xenograft model. Multiple dosing and sialylation of the IgA antibodies compensated for the short in vivo half-life of native IgA antibodies in mice compared to a single dose of IgG1. In the case of the IgA2m2 antibody, the resulting high plasma exposure levels were sufficient to cause clear tumor stasis comparable to that observed for trastuzumab at much lower plasma exposure levels.

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Enhancement of antibody-dependent cell-mediated cytotoxicity by endowing IgG with FcαRI (CD89) binding

Cited by 57 publications

References 41 publications

Neutrophils in cancer

Neutrophils in cancer

The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target in disease

A comparison of anti-HER2 IgA and IgG1 in vivo efficacy is facilitated by high N-glycan sialylation of the IgA

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