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The Tumor Targeted ...
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Hedlund, Gunnar
(författare)
The Tumor Targeted Superantigen ABR-217620 Selectively Engages TRBV7-9 and Exploits TCR-pMHC Affinity Mimicry in Mediating T Cell Cytotoxicity.
- Artikel/kapitelEngelska2013
Förlag, utgivningsår, omfång ...
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2013-10-23
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Public Library of Science (PLoS),2013
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electronicrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:lup.lub.lu.se:4194f424-4c3c-494f-bd40-071dea6e7d4d
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https://lup.lub.lu.se/record/4179754URI
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https://doi.org/10.1371/journal.pone.0079082DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
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Ämneskategori:ref swepub-contenttype
Anmärkningar
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The T lymphocytes are the most important effector cells in immunotherapy of cancer. The conceptual objective for developing the tumor targeted superantigen (TTS) ABR-217620 (naptumomab estafenatox, 5T4Fab-SEA/E-120), now in phase 3 studies for advanced renal cell cancer, was to selectively coat tumor cells with cytotoxic T lymphocytes (CTL) target structures functionally similar to natural CTL pMHC target molecules. Here we present data showing that the molecular basis for the anti-tumor activity by ABR-217620 resides in the distinct interaction between the T cell receptor β variable (TRBV) 7-9 and the engineered superantigen (Sag) SEA/E-120 in the fusion protein bound to the 5T4 antigen on tumor cells. Multimeric but not monomeric ABR-217620 selectively stains TRBV7-9 expressing T lymphocytes from human peripheral blood similar to antigen specific staining of T cells with pMHC tetramers. SEA/E-120 selectively activates TRBV7-9 expressing T lymphocytes resulting in expansion of the subset. ABR-217620 selectively triggers TRBV7-9 expressing cytotoxic T lymphocytes to kill 5T4 positive tumor cells. Furthermore, ABR-217620 activates TRBV7-9 expressing T cell line cells in the presence of cell- and bead-bound 5T4 tumor antigen. Surface plasmon resonance analysis revealed that ABR-217620 binds to 5T4 with high affinity, to TRBV7-9 with low affinity and to MHC class II with very low affinity. The T lymphocyte engagement by ABR-217620 is constituted by displaying high affinity binding to the tumor cells (KD approximately 1 nM) and with the mimicry of natural productive immune TCR-pMHC contact using affinities of around 1 µM. This difference in kinetics between the two components of the ABR-217620 fusion protein will bias the binding towards the 5T4 target antigen, efficiently activating T-cells via SEA/E-120 only when presented by the tumor cells.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Eriksson, Helena
(författare)
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Sundstedt, Anette
(författare)
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Forsberg, Göran
(författare)
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Jakobsen, Bent K
(författare)
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Pumphrey, Nicholas
(författare)
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Rödström, KarinLund University,Lunds universitet,Medicinsk strukturbiologi,Forskargrupper vid Lunds universitet,Medical Structural Biology,Lund University Research Groups(Swepub:lu)med-kir
(författare)
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Lindkvist, KarinLund University,Lunds universitet,Medicinsk strukturbiologi,Forskargrupper vid Lunds universitet,Medical Structural Biology,Lund University Research Groups(Swepub:lu)mbfy-kpe
(författare)
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Björk, Per
(författare)
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Medicinsk strukturbiologiForskargrupper vid Lunds universitet
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:PLoS ONE: Public Library of Science (PLoS)8:101932-6203
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