Human regulatory T cells are selectively activated by low‐dose application of the CD28 superagonist TGN1412/TAB08

Tabares, Paula; Berr, Susanne; Römer, Paula S.; Chuvpilo, Sergej; Matskevich, Alexey A.; Tyrsin, Dmitry; Fedotov, Yu. V.; Einsele, Hermann; Tony, Hans‐Peter

doi:10.1002/eji.201343967

Cited by 87 publications

(82 citation statements)

References 45 publications

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“…13 Membranes were probed with rabbit anti-human FcgRIIb (Abcam) and goat anti-rabbit IgG horseradish peroxidase (HRP) F(ab9) 2 , and the signal was visualized by using enhanced chemiluminescence (GE Healthcare Life Sciences).…”

Section: Western Blotmentioning

confidence: 99%

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Upregulation of FcγRIIb on monocytes is necessary to promote the superagonist activity of TGN1412

Hussain

Hargreaves

Roghanian

et al. 2015

Blood

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Key Points• TGN1412-induced T-cell activation following highdensity preculture of PBMCs is a consequence of FcgRIIb upregulation on monocytes.• In vivo, cytokine release syndrome may be due to the close association of FcgRIIbbearing cells with T cells in lymphoid tissues.The anti-CD28 superagonist antibody TGN1412 caused life-threatening cytokine release syndrome (CRS) in healthy volunteers, which had not been predicted by preclinical testing. T cells in fresh peripheral blood mononuclear cells (PBMCs) do not respond to soluble TGN1412 but do respond following high-density (HD) preculture. We show for the first time that this response is dependent on crystallizable fragment gamma receptor IIb (FcgRIIb) expression on monocytes. This was unexpected because, unlike B cells, circulating monocytes express little or no FcgRIIb. However, FcgRIIb expression is logarithmically increased on monocytes during HD preculture, and this upregulation is necessary and sufficient to explain TGN1412 potency after HD preculture. B-cell FcgRIIb expression is unchanged by HD preculture, but B cells can support TGN1412-mediated T-cell proliferation when added at a frequency higher than that in PBMCs. Although lowdensity (LD) precultured PBMCs do not respond to TGN1412, T cells from LD preculture are fully responsive when cocultured with FcgRIIb-expressing monocytes from HD preculture, which shows that they are fully able to respond to TGN1412-mediated activation. Our novel findings demonstrate that cross-linking by FcgRIIb is critical for the superagonist activity of TGN1412 after HD preculture, and this may contribute to CRS in humans because of the close association of FcgRIIb-bearing cells with T cells in lymphoid tissues. (Blood. 2015;125(1):102-110)

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Section: Western Blotmentioning

confidence: 99%

“…There has been a keen focus on the development of therapeutic anti-CD28 mAbs for a range of diseases, including autoimmunity and cancer. [1][2][3] However, anti-CD28 mAbs suffered a major setback when the first-in-man trial of TGN1412 caused life-threatening CRS.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of FcγRIIb on monocytes is necessary to promote the superagonist activity of TGN1412

Hussain

Hargreaves

Roghanian

et al. 2015

Blood

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“…30 Interestingly, recent data suggest that CD28SA-activated and -expanded human Treg are very potent suppressors of inflammatory cytokine release in PBMC cultures from patients with rheumatoid arthritis. 34 The same study also showed that slow infusion of much lower doses (≤7 μg/kg) than used in the ill-fated HV trial of 2006 (bolus injection of 100 μg/kg) is well tolerated and leads to systemic release of IL-10 but not of proinflammatory cytokines. Further studies in different indications are needed to determine whether transient polyclonal Treg activation could be a safe and effective approach for stroke and other indications.…”

Section: Strokementioning

confidence: 88%

Amplification of Regulatory T Cells Using a CD28 Superagonist Reduces Brain Damage After Ischemic Stroke in Mice

Mracskó

Liesz

et al. 2015

Stroke

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Background and Purpose-Neuroinflammation plays an important role in ischemic brain injury. Regulatory T cells (Treg) are important endogenous immune modulators. We tested the hypothesis that Treg amplification with a CD28 superagonistic monoclonal antibody (CD28SA) reduces brain damage in murine cerebral ischemia. Methods-Cerebral ischemia was induced by coagulation of the distal middle cerebral artery or by 60 minutes filament occlusion of the proximal middle cerebral artery in C57BL6 mice. 150 μg CD28SA was injected intraperitoneally 3 or 6 hours after ischemia onset. Outcome was determined by infarct volumetry and behavioral testing. Brain-infiltrating leukocyte subpopulations were analyzed by flow cytometry and immunohistochemistry 3 and 7 days after middle cerebral artery occlusion. Results-CD28SA reduced infarct size in both models and attenuated functional deficit 7 days after stroke induction. Mice treated with CD28SA increased numbers of Treg in spleen and brain. Tregs were functionally active and migrated into the brain where they accumulated and proliferated in the peri-infarct area. More than 60% of brain infiltrating Treg produced interleukin-10 in CD28SA compared with 30% in control. Conclusions-In

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“…The WBCA is therefore not considered to be predictive of the clinical severity of adverse effects of mAb therapeutics and not suitable for ranking the risk, but is rather a tool for hazard identification. The severity of CRS could be decreased by an appropriate dosage regimen (Hale et al, 2004;Tabares et al, 2014) or by medication with anti-inflammatory agents (Lee et al, 2014). We considered that the WBCA is able to detect the potential of severe CRS occurring with high frequency in the worst case.…”

Section: Discussionmentioning

confidence: 99%

Is an <i>in vitro</i> whole blood cytokine assay useful to detect the potential risk of severe infusion reaction of monoclonal antibody pharmaceuticals?

et al. 2016

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-After the life-threatening cytokine release syndrome (CRS) occurred in the clinical study of the anti-CD28 monoclonal antibody (mAb) TGN1412, in vitro cytokine release assays using human blood cells have been proposed for non-clinical evaluation of the potential risk of CRS. Two basic assay formats are frequently used: human peripheral blood mononuclear cells (PBMC) with immobilized mAbs, and whole blood with aqueous mAbs. However, the suitability of the whole blood cytokine assay (WBCA) has been questioned, because an unrealistically large sample size would be required to detect the potential risk of CRS induced by TGN1412, which has low sensitivity. We performed a WBCA using peripheral blood obtained from 68 healthy volunteers to compare two high risk mAbs, the TGN1412 analogue anti-CD28 superagonistic mAb (CD28SA) and the FcγR-mediated alemutuzumab, with a low risk mAb, panitumumab. Based on the cytokine measurements in this study, the sample size required to detect a statistically significant increase in cytokines with 90% power and 5% significance was determined to be n = 9 for CD28SA and n = 5 for alemtuzumab. The most sensitive marker was IL-8. The results suggest that WBCA is a practical test design that can warn of the potential risk of FcγR-mediated alemtuzumab and T-cell activating CD28SA but, because there was apparently a lower response to CD28SA, it cannot be used as a risk-ranking tool. WBCA is suggested to be a helpful tool for identifying potential FcγR-mediated hazards, but further mechanistic understanding of the response to CD28SA is necessary before applying it to T cell-stimulating mAbs.

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Human regulatory T cells are selectively activated by low‐dose application of the CD28 superagonist TGN1412/TAB08

Abstract: CD28 superagonists (CD28SAs) are potent T-cell-activating monoclonal antibodies (mAbs).

Cited by 87 publications

References 45 publications

Upregulation of FcγRIIb on monocytes is necessary to promote the superagonist activity of TGN1412

Upregulation of FcγRIIb on monocytes is necessary to promote the superagonist activity of TGN1412

Amplification of Regulatory T Cells Using a CD28 Superagonist Reduces Brain Damage After Ischemic Stroke in Mice

Is an <i>in vitro</i> whole blood cytokine assay useful to detect the potential risk of severe infusion reaction of monoclonal antibody pharmaceuticals?

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