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Antibodies selected from combinatorial libraries block a tumor antigen that plays a key role in immunomodulation

Antibodies selected from combinatorial libraries block a tumor antigen that plays a key role in immunomodulation
Antibodies selected from combinatorial libraries block a tumor antigen that plays a key role in immunomodulation
We searched for cell-surface-associated proteins overexpressed on B cell chronic lymphocytic leukemia (CLL) to use as therapeutic antibody targets. Antibodies binding the immunosuppressive molecule CD200 were identified by cell panning of an antibody phage display library derived from rabbits immunized with primary CLL cells. B cells from 87 CLL patients exhibited 1.6- to 5.4-fold cell-surface up-regulation of CD200 relative to normal B cells. An effect of increased CD200 expression by CLL cells on the immune system was evaluated in mixed lymphocyte reactions. Addition of primary CLL but not normal B cells to macrophages and T cells downregulated the Th1 response, as seen by a 50–95% reduction in secreted IL-2 and IFN-. Antibodies to CD200 prevented downregulation of the Th1 response in most B cell CLL samples evaluated, indicating abrogation of the CD200/CD200R interaction can be sufficient to restore the Th1 response. A disease-progression-associated shift of the immune response from Th1 to Th2 has been observed in numerous cancers. Because this cytokine shift is also believed to promote the induction of regulatory T cells, reverting the immune response to Th1 through direct targeting of the cancer cells may provide therapeutic benefits in CLL by encouraging a cytotoxic T cell response.
cd200, chronic lymphocytic leukemia, immune evasion | immunotherapy
0027-8424
1041-1046
McWhirter, John R.
206422f7-49f6-4171-b636-6eb0a3003276
Kretz-Rommel, Anke
fc60d7f7-e0c2-4d8e-87b3-da0a3c1fc957
Saven, Alan
25777c2b-e4a7-49de-a8cf-66bb802c7a19
Maruyama, Toshiaki
a2bccf19-6438-49e3-ad3e-0bc4def0e945
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Mockridge, C. Ian
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Ravey, E. Prenn
22cb4eda-8497-4c10-ad71-cba11804dc9f
Qin, Fenghua
1f1d8daf-090b-4ac9-a838-8ac9f159cb8a
Bowdish, Katherine S.
eff24ad6-eb41-4b3a-8188-b5aeb26781a7
McWhirter, John R.
206422f7-49f6-4171-b636-6eb0a3003276
Kretz-Rommel, Anke
fc60d7f7-e0c2-4d8e-87b3-da0a3c1fc957
Saven, Alan
25777c2b-e4a7-49de-a8cf-66bb802c7a19
Maruyama, Toshiaki
a2bccf19-6438-49e3-ad3e-0bc4def0e945
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Mockridge, C. Ian
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Ravey, E. Prenn
22cb4eda-8497-4c10-ad71-cba11804dc9f
Qin, Fenghua
1f1d8daf-090b-4ac9-a838-8ac9f159cb8a
Bowdish, Katherine S.
eff24ad6-eb41-4b3a-8188-b5aeb26781a7

McWhirter, John R., Kretz-Rommel, Anke, Saven, Alan, Maruyama, Toshiaki, Potter, Kathleen N., Mockridge, C. Ian, Ravey, E. Prenn, Qin, Fenghua and Bowdish, Katherine S. (2006) Antibodies selected from combinatorial libraries block a tumor antigen that plays a key role in immunomodulation. Proceedings of the National Academy of Sciences, 103 (4), 1041-1046. (doi:10.1073/pnas.0510081103).

Record type: Article

Abstract

We searched for cell-surface-associated proteins overexpressed on B cell chronic lymphocytic leukemia (CLL) to use as therapeutic antibody targets. Antibodies binding the immunosuppressive molecule CD200 were identified by cell panning of an antibody phage display library derived from rabbits immunized with primary CLL cells. B cells from 87 CLL patients exhibited 1.6- to 5.4-fold cell-surface up-regulation of CD200 relative to normal B cells. An effect of increased CD200 expression by CLL cells on the immune system was evaluated in mixed lymphocyte reactions. Addition of primary CLL but not normal B cells to macrophages and T cells downregulated the Th1 response, as seen by a 50–95% reduction in secreted IL-2 and IFN-. Antibodies to CD200 prevented downregulation of the Th1 response in most B cell CLL samples evaluated, indicating abrogation of the CD200/CD200R interaction can be sufficient to restore the Th1 response. A disease-progression-associated shift of the immune response from Th1 to Th2 has been observed in numerous cancers. Because this cytokine shift is also believed to promote the induction of regulatory T cells, reverting the immune response to Th1 through direct targeting of the cancer cells may provide therapeutic benefits in CLL by encouraging a cytotoxic T cell response.

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Published date: 2006
Additional Information: Medical Sciences
Keywords: cd200, chronic lymphocytic leukemia, immune evasion | immunotherapy
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 26471
URI: http://eprints.soton.ac.uk/id/eprint/26471
ISSN: 0027-8424
PURE UUID: 51c1ed91-a684-4846-9702-b2526f41e4d0

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Date deposited: 10 Apr 2006
Last modified: 15 Jul 2019 19:14

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Contributors

Author: John R. McWhirter
Author: Anke Kretz-Rommel
Author: Alan Saven
Author: Toshiaki Maruyama
Author: C. Ian Mockridge
Author: E. Prenn Ravey
Author: Fenghua Qin
Author: Katherine S. Bowdish

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