Antibody-peptide-MHC fusion conjugates target non-cognate T cells to kill tumour cells
Antibody-peptide-MHC fusion conjugates target non-cognate T cells to kill tumour cells
Attempts to generate robust anti-tumour cytotoxic T lymphocyte (CTL) responses using immunotherapy are frequently thwarted by exhaustion and anergy of CTL recruited to tumour. One strategy to overcome this is to retarget a population of virus-specific CTL to kill tumour cells. Here, we describe a proof-of-principle study using a bispecific conjugate designed to retarget ovalbumin (OVA)-specific CTL to kill tumour cells via CD20. A single-chain trimer (SCT) consisting of MHCI H-2K(b)/SIINFEKL peptide/beta 2 microglobulin/BirA was expressed in bacteria, refolded and chemically conjugated to one (1:1; F2) or two (2:1; F3) anti-hCD20 Fab' fragments. In vitro, the [SCT × Fab'] (F2 and F3) redirected SIINFEKL-specific OT-I CTL to kill CD20(+) target cells, and in the presence of CD20(+) target cells to provide crosslinking, they were also able to induce proliferation of OT-I cells. In vivo, activated OT-I CTL could be retargeted to kill [SCT × Fab']-coated B cells from hCD20 transgenic (hCD20 Tg) mice and also EL4 and B16 mouse tumour cells expressing human CD20 (hCD20). Importantly, in a hCD20 Tg mouse model, [SCT × Fab'] administered systemically were able to retarget activated OT-I cells to deplete normal B cells, and their performance matched that of a bispecific antibody (BsAb) comprising anti-CD3 and anti-CD20. [SCT × Fab'] were also active therapeutically in an EL4 tumour model. Furthermore, measurement of serum cytokine levels suggests that [SCT × Fab'] are associated with a lower level of inflammatory cytokine release than the BsAb and so may be advantageous clinically in terms of reduced toxicity.
1093-1105
King, Ben C.
aee5fe5f-fc9c-4cc1-8a11-08f099d20a1d
Hamblin, Angela D.
1c6da054-f1e8-4e58-a180-1c99b4f0a33a
Savage, Philip M.
eea178be-7195-4a66-abd5-24b9f4b06bb0
Douglas, Leon R.
049b5f33-6870-4773-ae34-663489b472ba
Hansen, Ted H.
dab738fa-2068-49fa-bf6b-c095e6d6a512
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Johnson, Peter W.M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
June 2013
King, Ben C.
aee5fe5f-fc9c-4cc1-8a11-08f099d20a1d
Hamblin, Angela D.
1c6da054-f1e8-4e58-a180-1c99b4f0a33a
Savage, Philip M.
eea178be-7195-4a66-abd5-24b9f4b06bb0
Douglas, Leon R.
049b5f33-6870-4773-ae34-663489b472ba
Hansen, Ted H.
dab738fa-2068-49fa-bf6b-c095e6d6a512
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Johnson, Peter W.M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
King, Ben C., Hamblin, Angela D., Savage, Philip M., Douglas, Leon R., Hansen, Ted H., French, Ruth R., Johnson, Peter W.M. and Glennie, Martin J.
(2013)
Antibody-peptide-MHC fusion conjugates target non-cognate T cells to kill tumour cells.
Cancer Immunology Immunotherapy, 62 (6), .
(doi:10.1007/s00262-013-1408-8).
(PMID:23604105)
Abstract
Attempts to generate robust anti-tumour cytotoxic T lymphocyte (CTL) responses using immunotherapy are frequently thwarted by exhaustion and anergy of CTL recruited to tumour. One strategy to overcome this is to retarget a population of virus-specific CTL to kill tumour cells. Here, we describe a proof-of-principle study using a bispecific conjugate designed to retarget ovalbumin (OVA)-specific CTL to kill tumour cells via CD20. A single-chain trimer (SCT) consisting of MHCI H-2K(b)/SIINFEKL peptide/beta 2 microglobulin/BirA was expressed in bacteria, refolded and chemically conjugated to one (1:1; F2) or two (2:1; F3) anti-hCD20 Fab' fragments. In vitro, the [SCT × Fab'] (F2 and F3) redirected SIINFEKL-specific OT-I CTL to kill CD20(+) target cells, and in the presence of CD20(+) target cells to provide crosslinking, they were also able to induce proliferation of OT-I cells. In vivo, activated OT-I CTL could be retargeted to kill [SCT × Fab']-coated B cells from hCD20 transgenic (hCD20 Tg) mice and also EL4 and B16 mouse tumour cells expressing human CD20 (hCD20). Importantly, in a hCD20 Tg mouse model, [SCT × Fab'] administered systemically were able to retarget activated OT-I cells to deplete normal B cells, and their performance matched that of a bispecific antibody (BsAb) comprising anti-CD3 and anti-CD20. [SCT × Fab'] were also active therapeutically in an EL4 tumour model. Furthermore, measurement of serum cytokine levels suggests that [SCT × Fab'] are associated with a lower level of inflammatory cytokine release than the BsAb and so may be advantageous clinically in terms of reduced toxicity.
This record has no associated files available for download.
More information
Published date: June 2013
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 353481
URI: http://eprints.soton.ac.uk/id/eprint/353481
ISSN: 0340-7004
PURE UUID: 5be01f94-fc02-4dd6-8a73-a4c05d4bc35a
Catalogue record
Date deposited: 10 Jun 2013 10:44
Last modified: 15 Mar 2024 02:58
Export record
Altmetrics
Contributors
Author:
Ben C. King
Author:
Angela D. Hamblin
Author:
Philip M. Savage
Author:
Leon R. Douglas
Author:
Ted H. Hansen
Author:
Ruth R. French
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics