LIGAND RECOGNITION BY Αβ T CELL RECEPTORS

Davis, Mark M.; Boniface, J. Jay; Reich, Ziv; Lyons, Daniel S.; Hampl, Johannes; Arden, Bernhard; Chien, Yueh‐hsiu

doi:10.1146/annurev.immunol.16.1.523

Cited by 849 publications

(722 citation statements)

References 85 publications

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Section: Discussionmentioning

confidence: 99%

“…Positions 2 and 9 in MHC-binding peptides, termed anchor sites, react with specific sites in the groove of HLA. These positions play a major role in determining the binding of the peptide to the MHC molecule [56][57][58][59][60][61][62][63].Modification of amino acids that are different from the consensus residues in anchor positions is a known strategy to improve the affinity of tumor-derived T cell epitopes to MHC. In many cases, T cells generated to enhanced modified epitopes recognize the wild-type peptide as well, but this does not exclude the possibility that alterations in the MHC-peptide conformation may occur as a result of such modifications.…”

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confidence: 99%

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Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

et al. 2008

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MHC class I molecules are important components of immune surveillance. There are no available methods to directly visualize and determine the quantity and distribution of MHC/ peptide complexes on individual cells or to detect such complexes on antigen-presenting cells in tissues. MHC-restricted recombinant antibodies with the same specificity of T cell receptors (TCR) may become a valuable tool to address these questions. They may also serve as valuable targeting molecules that mimic the specificity of cytotoxic T cells. We isolated by phage display a panel of human recombinant Fab antibodies with peptidespecific, MHC-restricted TCR-like reactivity directed toward HLA-A2-restricted T cell epitopes derived from a novel antigen termed TCRc alternative reading frame protein (TARP) which is expressed on prostate and breast cancer cells. We have characterized one of these recombinant antibodies and demonstrated its capacity to directly detect specific HLA-A2/ TARP T cell epitopes on antigen-presenting cells that have complexes formed by naturally occurring active intracellular processing of the antigen, as well as on the surface of tumor cells. Moreover, by genetic fusion we armed the TCR-like antibody with a potent toxin and demonstrated that it can serve as a targeting moiety killing tumor cells in a peptide-specific, MHC-restricted manner similar to cytotoxic T lymphocytes. Key words: Immunotoxin Á MHC Á Recombinant antibody Á T-cell receptor IntroductionMost patients with metastatic prostate and breast cancers are provided with the limited benefits from standard chemo-and hormone-based therapies. During the recent years, much effort has been invested in developing new approaches, such as immunotherapy, to improve the therapeutic abilities, by combining the tumor specificity of cell-mediated immunity with the freedom from toxic chemotherapies.Recent immunotherapy approaches employ the principle that CD8 + CTL recognize and kill tumor cells that display peptides from tumor-associated antigens presented by MHC class I molecules. Several tumor antigens and HLA allele-specific peptides from prostate cancer-associated antigens have been identified as CD8 + T cell epitopes, including HLA-A2-binding peptides derived from prostate-specific antigen (PSA) [1,2], prostate-specific membrane antigen (PSMA) [3], prostate stem cell antigen (PSCA) [4,5], and prostate acid phosphatase 6, which are all now components of current vaccine trials [5][6][7][8][9][10][11].Identification of new tumor-specific antigens is an essential step for the successful development of immunotherapy ap- [12][13][14]. One of these, T cell receptor gamma alternate reading frame protein (TARP), is expressed on breast and prostate cancer cells [15,16]. It was shown that TARP was expressed on >90% of cancer specimens examined [9,15]. In order to define new breast and prostate CD8 + T cell tumor antigens, two wild-type HLA-A2 epitopes from TARP were identified [17]. The wild-type sequences were also improved by sequence modifications to produce epitopeenha...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

et al. 2008

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“…16 However, binding of T-cell receptors to their target MHCI/peptide complex is known to have low affinity. 39 This may allow the scTCR-containing virions to escape from the endosome. Alternatively, binding of the virus particles to the HLA-A1/MAGE-A1 complex may have resulted in a distinct internalization, that is, differing from the normal HAdV-5 internalization via clathrin-coated vesicles.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus targeting to HLA-A1/MAGE-A1-positive tumor cells by fusing a single-chain T-cell receptor with minor capsid protein IX

et al. 2008

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“…The fact that a specific interaction between phage and TCR can be detected suggests that a multivalent display of P/MHC on phage was achieved, since interactions between a TCR and MHC monomers are not detectable [1]. Background interaction was evaluated in the same experiment using OVA-wt/H-2K b phage (described above) as an irrelevant control.…”

Section: Vsv-wt/h-2k B Phage and Vsv-l1/h-2k B Phage Specifically Binmentioning

confidence: 99%

“…The affinity of this interaction is inherently weak [1,2], making it difficult to study. Soluble noncovalent complex of peptide and MHC (P/MHC) tetramer technology [3] has enabled the generation of tools capable of stabilizing this interaction and rendering its detection possible.…”

Section: Introductionmentioning

confidence: 99%

Phage‐displayed libraries of peptide/major histocompatibility complexes

et al. 2004

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Characterizing peptide epitopes targeted by major histocompatibility complex (MHC)-restricted T cells of unknown specificity would have broad implications. In this article we introduce and validate an original phage-displayed library of noncovalent complexes of peptide and MHC (P/MHC). We show that soluble MHC molecules associate with peptides presented by a phage, thereby resulting in the formation of multivalent P/MHC phages. Complex formation is stabilized by the interaction of the soluble partner (MHC) with two components, peptide and g 2-microglobulin, both of which are covalently linked to the phage. As proof of concept, we have used this strategy to express peptide libraries in the context of H-2K b . Using monoclonal antibody 25D (specific for ovalbumin/H-2K b ) as a template to screen the library, we were able to select a variant epitope functionally and structurally related to the wild-type peptide. Interaction studies between monoclonal antibody 25D and cells suggest that the variant peptide has been selected on the basis of a decreased dissociation rate between the peptide/H-2K b complex and its ligand. A weak agonist of the N15 TCR (vesicular stomatitis virus/H-2K b -specific) was also isolated from another P/MHC library. This strategy opens up new perspectives for antigen discovery and the manipulation of T cell responses.

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LIGAND RECOGNITION BY Αβ T CELL RECEPTORS

Cited by 849 publications

References 85 publications

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

Adenovirus targeting to HLA-A1/MAGE-A1-positive tumor cells by fusing a single-chain T-cell receptor with minor capsid protein IX

Phage‐displayed libraries of peptide/major histocompatibility complexes

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