Dissecting cytotoxic T cell responses towards the NY‐ESO‐1 protein by peptide/MHC‐specific antibody fragments

Held, Gerhard; Matsuo, Masatsugu; Epel, Malka; Gnjatic, Sacha; Ritter, Gerd; Lee, Sang Yull; Tai, Tsin Yee; Cohen, Cyril J.; Old, Lloyd J.; Pfreundschuh, Michael; Reiter, Yoram; Hoogenboom, Hennie R.; Renner, Christoph

doi:10.1002/eji.200425297

Cited by 67 publications

(89 citation statements)

References 30 publications

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“…Human Fab antibodies were selected from a fully human Fab antibody library (kindly provided by Dyax) as previously described (24). Briefly, M-280 Dynabeads with streptavidin (Dynal) and phage particles were blocked with 2% nonfat dry milk powder (Roth) before incubation for 1 hour with HLA-B27 2 .…”

Section: Methodsmentioning

confidence: 99%

Inhibiting HLA–B27 homodimer–driven immune cell inflammation in spondylarthritis

Payeli¹,

Kollnberger²,

Belaunzaran³

et al. 2012

Arthritis & Rheumatism

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Objective. Spondylarthritides (SpA), including ankylosing spondylitis (AS), are common inflammatory rheumatic diseases that are strongly associated with positivity for the HLA class I allotype B27. HLA-B27 normally forms complexes with ␤ 2 -microglobulin (␤ 2 m) and peptide to form heterotrimers. However, an unusual characteristic of HLA-B27 is its ability to form ␤ 2 m-free heavy chain homodimers (HLA-B27 2 ), which, unlike classic HLA-B27, bind to killer cell immunoglobulinlike receptor 3DL2 (KIR-3DL2). Binding of HLA-B27 2 to KIR-3DL2-positive CD4؉ T and natural killer (NK) cells stimulates cell survival and modulates cytokine production. This study was undertaken to produce an antibody to HLA-B27 2 in order to confirm its expression in SpA and to inhibit its proinflammatory properties.Methods. We generated monoclonal antibodies by screening a human phage display library positively against B27 2 and negatively against B27 heterotrimers. Conclusion. These results demonstrate that antibody HD6 has potential for use in both the investigation and the treatment of AS and other B27-associated spondylarthritides.Positivity for HLA-B27 is strongly associated with ankylosing spondylitis (AS) and other spondylarthritides (SpA) (1-3). However, despite extensive investigation, understanding of the pathogenic role of HLA-B27 is limited (4). The canonical HLA-B27 heterotrimer structure comprises an HLA heavy chain that is noncovalently associated with a monomorphic ␤ 2 -microglobulin (␤ 2 m) light chain and a short peptide derived from self proteins, viruses, or bacteria. These heterotrimeric complexes form in the endoplasmic reticulum and egress to the cell surface, where they are recognized by CD8ϩ cytotoxic T cells through their T cell receptors (5). HLA-B27 can also form ␤ 2 m-free

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Section: Methodsmentioning

confidence: 99%

Inhibiting HLA–B27 homodimer–driven immune cell inflammation in spondylarthritis

Payeli¹,

Kollnberger²,

Belaunzaran³

et al. 2012

Arthritis & Rheumatism

Self Cite

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“…An alternative approach is the phage-display technology, which involves positive selection in the procedure (Hoogenboom et al, 1998). Using this approach, our laboratory has screened a very large human naı¨ve antibody library against a variety of recombinant human HLA-A2-peptide complexes displaying T-cell epitopes specific for antigens expressed in melanoma, prostate, breast, ovary and lung cancer (Cohen et al, 2002;Denkberg et al, 2002a;Denkberg et al, 2003;Cohen et al, 2003a;Held et al, 2004;Denkberg and Reiter, 2006).…”

Section: T-cell Receptor-like Antibodiesmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.

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“…These enabled us to screen these large libraries of such vast diversity and size in order to isolate these rare and unique TCR-like recombinant antibodies targeting human tumor and viral epitopes [21,22,[24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Using antibody phage display approaches, we have recently generated such unique molecules, coined TCR-like antibodies, against a variety of tumor and viral epitopes restricted to human HLA-A2, the most frequent MHC allele in humans. These antibodies were utilized to detect, visualize and quantitate the number of specific tumor-and viral-associated HLA-A2/peptide complexes on tumor cells, APC, and virus-infected cells [21][22][23][24][25][26].Another possible application of TCR-like antibodies is their use as targeting molecules to efficiently eliminate tumor cells due to the fact that they can mimic the unique fine specificity of T cells. This can be achieved by using the antibodies or their fragments as targeting moieties and arming them with effector modalities such as potent toxins, chemotherapeutic drugs, isotopes, or biological entities such as cytokines [27][28][29][30][31][32][33].…”

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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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Dissecting cytotoxic T cell responses towards the NY‐ESO‐1 protein by peptide/MHC‐specific antibody fragments

Cited by 67 publications

References 30 publications

Inhibiting HLA–B27 homodimer–driven immune cell inflammation in spondylarthritis

Inhibiting HLA–B27 homodimer–driven immune cell inflammation in spondylarthritis

Novel antibodies as anticancer agents

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

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