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.
复制标题
DOI：
10.1007/s00262-013-1408-8
复制
发表时间：
2013-06
影响因子：
5.8
通讯作者：
Glennie, Martin J.
中科院分区：
文献类型：
--
作者：
King, Ben C.;Hamblin, Angela D.;Savage, Philip M.;Douglas, Leon R.;Hansen, Ted H.;French, Ruth R.;Johnson, Peter W. M.;Glennie, Martin J.
关键词：
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-2Kb/SI-INFEKL 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.
登录
查看更多内容
影响因子：
56.9
作者：
Morgan, Richard A.;Dudley, Mark E.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
56.9
作者：
Bargou, Ralf;Leo, Eugen;Kufer, Peter
通讯作者：
Kufer, Peter
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
45.3
作者：
Robbins, Paul F.;Morgan, Richard A.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
9.8
作者：
Ma Z;Sharp KA;Janmey PA;Finkel TH
通讯作者：
Finkel TH