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Immunotherapy targeting inhibitory Fc? receptor IIB (CD32b) in the mouse is limited by monoclonal antibody consumption and receptor internalization

Immunotherapy targeting inhibitory Fc? receptor IIB (CD32b) in the mouse is limited by monoclonal antibody consumption and receptor internalization
Immunotherapy targeting inhibitory Fc? receptor IIB (CD32b) in the mouse is limited by monoclonal antibody consumption and receptor internalization
Genetic deficiency of the inhibitory Fc receptor, Fc?RIIB (CD32b), has been shown to augment the activity of activatory Fc?R and promote mAb immunotherapy. To investigate whether mAbs capable of blocking Fc?RIIB have similar capacity, we recently generated a panel of specific anti-mouse Fc?RIIB mAbs that do not cross-react with other FcRs, allowing us to study the potential of Fc?RIIB as a therapeutic target. Previous work revealed a number of these mAbs capable of eliciting programmed cell death of targets, and in the present study we demonstrated their ability to promote target cell phagocytosis. However, in a variety of murine tumor models, anti-Fc?RIIB mAbs demonstrated limited therapeutic activity despite optimized treatment regimens. Unexpectedly, we observed that the anti-Fc?RIIB mAbs are rapidly and extensively consumed in vivo, both by the tumor and host cells, including B cells, leading to a precipitous loss from the circulation. Closer analysis revealed that the anti-Fc?RIIB mAbs become extensively internalized from the cell surface within 24 h in vivo, likely explaining their suboptimal efficacy. Subsequent studies revealed that anti-Fc?RIIB mAb immunotherapy was effective when used against Fc?RIIB+ tumors in Fc?RIIB?/? recipients, indicating that consumption of the mAb by nontumor cells is the primary limitation of these reagents. Importantly, similar rates of internalization were not seen on human target cells, at least in vitro. These studies further highlight the need to determine the propensity of mAb therapeutics to internalize target receptors and also identify potential key differences between human and mouse cells in this respect.
0022-1767
4130-4140
Williams, E.L.
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Tutt, A.L.
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Beers, S.A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
French, R.R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Chan, C.H.T.
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Cox, K.L.
7305c27e-9cdc-4e37-b994-ac55d7d1dfd2
Roghanian, A.
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Penfold, C.A.
400d743e-a639-45ea-a027-5b778800f6d3
Butts, C.L.
0b92b326-fc9d-441a-bbb5-fdc352e3e602
Boross, P.
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Verbeek, J.S.
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Cragg, M.S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, M.J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Williams, E.L.
08adaeea-f0e2-4ae5-a46d-fc9e515e7e8e
Tutt, A.L.
46ce577b-aea1-412d-84ea-fc4dab794469
Beers, S.A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
French, R.R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Chan, C.H.T.
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Cox, K.L.
7305c27e-9cdc-4e37-b994-ac55d7d1dfd2
Roghanian, A.
e2b032c2-60a0-4522-a3d8-56a768792f36
Penfold, C.A.
400d743e-a639-45ea-a027-5b778800f6d3
Butts, C.L.
0b92b326-fc9d-441a-bbb5-fdc352e3e602
Boross, P.
373c8487-9398-4091-9d4c-4cfb790df594
Verbeek, J.S.
84596980-e9a7-4ef5-909c-43ea5349b065
Cragg, M.S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, M.J.
9f6f0eff-4560-48c2-80cd-0ec116110ded

Williams, E.L., Tutt, A.L., Beers, S.A., French, R.R., Chan, C.H.T., Cox, K.L., Roghanian, A., Penfold, C.A., Butts, C.L., Boross, P., Verbeek, J.S., Cragg, M.S. and Glennie, M.J. (2013) Immunotherapy targeting inhibitory Fc? receptor IIB (CD32b) in the mouse is limited by monoclonal antibody consumption and receptor internalization. Journal of Immunology, 191 (8), 4130-4140. (doi:10.4049/jimmunol.1301430). (PMID:24026082)

Record type: Article

Abstract

Genetic deficiency of the inhibitory Fc receptor, Fc?RIIB (CD32b), has been shown to augment the activity of activatory Fc?R and promote mAb immunotherapy. To investigate whether mAbs capable of blocking Fc?RIIB have similar capacity, we recently generated a panel of specific anti-mouse Fc?RIIB mAbs that do not cross-react with other FcRs, allowing us to study the potential of Fc?RIIB as a therapeutic target. Previous work revealed a number of these mAbs capable of eliciting programmed cell death of targets, and in the present study we demonstrated their ability to promote target cell phagocytosis. However, in a variety of murine tumor models, anti-Fc?RIIB mAbs demonstrated limited therapeutic activity despite optimized treatment regimens. Unexpectedly, we observed that the anti-Fc?RIIB mAbs are rapidly and extensively consumed in vivo, both by the tumor and host cells, including B cells, leading to a precipitous loss from the circulation. Closer analysis revealed that the anti-Fc?RIIB mAbs become extensively internalized from the cell surface within 24 h in vivo, likely explaining their suboptimal efficacy. Subsequent studies revealed that anti-Fc?RIIB mAb immunotherapy was effective when used against Fc?RIIB+ tumors in Fc?RIIB?/? recipients, indicating that consumption of the mAb by nontumor cells is the primary limitation of these reagents. Importantly, similar rates of internalization were not seen on human target cells, at least in vitro. These studies further highlight the need to determine the propensity of mAb therapeutics to internalize target receptors and also identify potential key differences between human and mouse cells in this respect.

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e-pub ahead of print date: 11 September 2013
Published date: 15 October 2013
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 359294
URI: http://eprints.soton.ac.uk/id/eprint/359294
ISSN: 0022-1767
PURE UUID: 8ef51c26-d76c-4b61-9d20-9959c5de9daf
ORCID for S.A. Beers: ORCID iD orcid.org/0000-0002-3765-3342
ORCID for C.H.T. Chan: ORCID iD orcid.org/0000-0003-0530-9480
ORCID for A. Roghanian: ORCID iD orcid.org/0000-0003-1316-4218
ORCID for M.S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 25 Oct 2013 12:47
Last modified: 15 Mar 2024 03:34

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Contributors

Author: E.L. Williams
Author: A.L. Tutt
Author: S.A. Beers ORCID iD
Author: R.R. French
Author: C.H.T. Chan ORCID iD
Author: K.L. Cox
Author: A. Roghanian ORCID iD
Author: C.A. Penfold
Author: C.L. Butts
Author: P. Boross
Author: J.S. Verbeek
Author: M.S. Cragg ORCID iD
Author: M.J. Glennie

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