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Impact of Human Fc?R Gene Polymorphisms on IgG-Triggered Cytokine Release: Critical Importance of Cell Assay Format.

ABSTRACT: Monoclonal antibody (mAb) immunotherapy has transformed the treatment of allergy, autoimmunity, and cancer. The interaction of mAb with Fc gamma receptors (Fc?R) is often critical for efficacy. The genes encoding the low-affinity Fc?R have single nucleotide polymorphisms (SNPs) and copy number variation that can impact IgG Fc:Fc?R interactions. Leukocyte-based in vitro assays remain one of the industry standards for determining mAb efficacy and predicting adverse responses in patients. Here we addressed the impact of Fc?R genetics on immune cell responses in these assays and investigated the importance of assay format. Fc?R genotyping of 271 healthy donors was performed using a Multiplex Ligation-Dependent Probe Amplification assay. Freeze-thawed/pre-cultured peripheral blood mononuclear cells (PBMCs) and whole blood samples from donors were stimulated with reagents spanning different mAb functional classes to evaluate the association of Fc?R genotypes with T-cell proliferation and cytokine release. Using freeze-thawed/pre-cultured PBMCs, agonistic T-cell-targeting mAb induced T-cell proliferation and the highest levels of cytokine release, with lower but measurable responses from mAb which directly require Fc?R-mediated cellular effects for function. Effects were consistent for individual donors over time, however, no significant associations with Fc?R genotypes were observed using this assay format. In contrast, significantly elevated IFN-? release was associated with the FCGR2A-131H/H genotype compared to FCGR2A-131R/R in whole blood stimulated with Campath (p ? 0.01) and IgG1 Fc hexamer (p ? 0.05). Donors homozygous for both the high affinity FCGR2A-131H and FCGR3A-158V alleles mounted stronger IFN-? responses to Campath (p ? 0.05) and IgG1 Fc Hexamer (p ? 0.05) compared to donors homozygous for the low affinity alleles. Analysis revealed significant reductions in the proportion of CD14hi monocytes, CD56dim NK cells (p ? 0.05) and Fc?RIIIa expression (p ? 0.05), in donor-matched freeze-thawed PBMC compared to whole blood samples, likely explaining the difference in association between Fc?R genotype and mAb-mediated cytokine release in the different assay formats. These findings highlight the significant impact of FCGR2A and FCGR3A SNPs on mAb function and the importance of using fresh whole blood assays when evaluating their association with mAb-mediated cytokine release in vitro. This knowledge can better inform on the utility of in vitro assays for the prediction of mAb therapy outcome in patients.

SUBMITTER: Hussain K

PROVIDER: S-EPMC6417454 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Impact of Human FcγR Gene Polymorphisms on IgG-Triggered Cytokine Release: Critical Importance of Cell Assay Format.

Hussain Khiyam K Hargreaves Chantal E CE Rowley Tania F TF Sopp Joshua M JM Latham Kate V KV Bhatta Pallavi P Sherington John J Cutler Rona M RM Humphreys David P DP Glennie Martin J MJ Strefford Jonathan C JC Cragg Mark S MS

Frontiers in immunology 20190307

Monoclonal antibody (mAb) immunotherapy has transformed the treatment of allergy, autoimmunity, and cancer. The interaction of mAb with Fc gamma receptors (FcγR) is often critical for efficacy. The genes encoding the low-affinity FcγR have single nucleotide polymorphisms (SNPs) and copy number variation that can impact IgG Fc:FcγR interactions. Leukocyte-based <i>in vitro</i> assays remain one of the industry standards for determining mAb efficacy and predicting adverse responses in patients. He ...[more]

PMID: 30899264

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Project description:BackgroundCytokine release syndrome (CRS) plays a pivotal role in the pathophysiology and progression of Coronavirus disease-2019 (COVID-19). Therapeutic plasma exchange (TPE) by removing the pathogenic cytokines is hypothesized to dampen CRS.ObjectiveTo evaluate the outcomes of the patients with COVID-19 having CRS being treated with TPE compared to controls on the standard of care.MethodologyRetrospective propensity score-matched analysis in a single centre from 1st April to 31st July 2020. We retrospectively analyzed data of 280 hospitalized patients developing CRS initially. PSM was used to minimize bias from non-randomized treatment assignment. Using PSM 1:1, 90 patients were selected and assigned to 2 equal groups. Forced matching was done for disease severity, routine standard care and advanced supportive care. Many other Co-variates were matched. Primary outcome was 28 days overall survival. Secondary outcomes were duration of hospitalization, CRS resolution time and timing of viral clearance on Polymerase chain reaction testing.ResultsAfter PS-matching, the selected cohort had a median age of 60 years (range 32-73 in TPE, 37-75 in controls), p = 0.325 and all were males. Median symptoms duration was 7 days (range 3-22 days' TPE and 3-20 days controls), p = 0.266. Disease severity in both groups was 6 (6.6%) moderate, 40 (44.4%) severe and 44 (49%) critical. Overall, 28-day survival was significantly superior in the TPE group (91.1%), 95% CI 78.33-97.76; as compared to PS-matched controls (61.5%), 95% CI 51.29-78.76 (log rank 0.002), p<0.001. Median duration of hospitalization was significantly reduced in the TPE treated group (10 days vs 15 days) (p< 0.01). CRS resolution time was also significantly reduced in the TPE group (6 days vs. 12 days) (p< 0.001). In 71 patients who underwent TPE, the mortality was 0 (n = 43) if TPE was done within the first 12 days of illness while it was 17.9% (deaths 5, n = 28 who received it after 12th day (p = 0.0045).ConclusionAn earlier use of TPE was associated with improved overall survival, early CRS resolution and time to discharge compared to SOC for COVID-19 triggered CRS in this selected cohort of PS-matched male patients from one major hospital in Pakistan.

Dataset Information

Impact of Human Fc?R Gene Polymorphisms on IgG-Triggered Cytokine Release: Critical Importance of Cell Assay Format.

Publications

Impact of Human FcγR Gene Polymorphisms on IgG-Triggered Cytokine Release: Critical Importance of Cell Assay Format.

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