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

Upregulation of FcyRIIb on monocytes is necessary to promote the superagonist activity of TGN1412
Upregulation of FcyRIIb on monocytes is necessary to promote the superagonist activity of TGN1412
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 (Fc?RIIb) expression on monocytes. This was unexpected because, unlike B cells, circulating monocytes express little or no Fc?RIIb. However, Fc?RIIb 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 Fc?RIIb 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 low-density (LD) precultured PBMCs do not respond to TGN1412, T cells from LD preculture are fully responsive when cocultured with Fc?RIIb-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 Fc?RIIb 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 Fc?RIIb-bearing cells with T cells in lymphoid tissues.
0006-4971
102-110
Hussain, K.
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Hargreaves, C.E.
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Roghanian, A.
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Oldham, R.J.
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Chan, H.T.C.
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Mockridge, C.I.
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Frendeus, B.
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Harper, K.S.
f6d2022b-2a6c-46ac-8702-575927dd74b3
Strefford, J.C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Cragg, M.S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, M.J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Williams, A.P.
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French, R.R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Chowdhury, Ferdousi D
928d9123-aed8-4ea5-87a6-297c5fe04742
Hussain, K.
9468f252-81d0-4251-b800-702433b610f8
Hargreaves, C.E.
19adb5c3-4559-4ebc-8c28-4c28767d225e
Roghanian, A.
e2b032c2-60a0-4522-a3d8-56a768792f36
Oldham, R.J.
f43d1416-0b93-4dfd-a504-2850cb43e87e
Chan, H.T.C.
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Mockridge, C.I.
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Frendeus, B.
ea6161a4-2041-4317-9802-95f623219fa6
Harper, K.S.
f6d2022b-2a6c-46ac-8702-575927dd74b3
Strefford, J.C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Cragg, M.S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, M.J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Williams, A.P.
973ff46f-46f1-4d7c-b27d-0f53221e4c44
French, R.R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Chowdhury, Ferdousi D
928d9123-aed8-4ea5-87a6-297c5fe04742

Hussain, K., Hargreaves, C.E., Roghanian, A., Oldham, R.J., Chan, H.T.C., Mockridge, C.I., Frendeus, B., Harper, K.S., Strefford, J.C., Cragg, M.S., Glennie, M.J., Williams, A.P., French, R.R. and Chowdhury, Ferdousi D (2015) Upregulation of FcyRIIb on monocytes is necessary to promote the superagonist activity of TGN1412. Blood, 125 (1), 102-110. (doi:10.1182/blood-2014-08-593061). (PMID:25395427)

Record type: Article

Abstract

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 (Fc?RIIb) expression on monocytes. This was unexpected because, unlike B cells, circulating monocytes express little or no Fc?RIIb. However, Fc?RIIb 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 Fc?RIIb 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 low-density (LD) precultured PBMCs do not respond to TGN1412, T cells from LD preculture are fully responsive when cocultured with Fc?RIIb-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 Fc?RIIb 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 Fc?RIIb-bearing cells with T cells in lymphoid tissues.

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More information

Accepted/In Press date: 24 October 2014
e-pub ahead of print date: 13 November 2014
Published date: 1 January 2015
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 390378
URI: http://eprints.soton.ac.uk/id/eprint/390378
ISSN: 0006-4971
PURE UUID: 4635f6b1-609b-443d-80fe-e7a4a70ac9d3
ORCID for A. Roghanian: ORCID iD orcid.org/0000-0003-1316-4218
ORCID for H.T.C. Chan: ORCID iD orcid.org/0000-0003-0530-9480
ORCID for J.C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for M.S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 01 Apr 2016 08:18
Last modified: 15 Mar 2024 03:34

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Contributors

Author: K. Hussain
Author: C.E. Hargreaves
Author: A. Roghanian ORCID iD
Author: R.J. Oldham
Author: H.T.C. Chan ORCID iD
Author: C.I. Mockridge
Author: B. Frendeus
Author: K.S. Harper
Author: J.C. Strefford ORCID iD
Author: M.S. Cragg ORCID iD
Author: M.J. Glennie
Author: A.P. Williams
Author: R.R. French
Author: Ferdousi D Chowdhury

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