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Weidanz J.A.,Receptor Logic Inc | Hildebrand W.H.,The University of Oklahoma Health Sciences Center
International Reviews of Immunology | Year: 2011

The development of immunotherapies offers significant promise for clinical applications in cancer and infectious diseases. Here the authors describe a novel, integrated approach to immunotherapy that combines novel technologies to discover and target disease-specific peptide/HLA class I complexes. This unique class of markers makes the entire proteome accessible to antibody reagents and offers unsurpassed specificity for targeting cancerous and infected cells. Arm one of the three-armed approach uses an innovative technology for the efficient, direct discovery of new peptide/HLA class I markers. Arm two applies a powerful and inventive strategy to generate T-cell receptor mimics (TCRms), which are antibodies with exquisite binding specificity for peptide/HLA class I markers, and uses TCRms to validate the specific expression of markers on cancerous and infected cells. The third arm uses TCRms to target and kill diseased cells with high sensitivity and specificity. In summary, the combination of two pioneering technologies expands the repertoire of disease-specific markers that can be targeted by therapeutic antibodies and enables a powerful, integrated approach to HLA-based immunotherapy. © 2011 Informa Healthcare USA, Inc.


Patent
Receptor Logic LLC | Date: 2015-05-27

The present invention relates to a methodology of producing antibodies that recognize peptides associated with a tumorigenic or disease state, wherein the peptides are displayed in the context of HLA molecules. These antibodies will mimic the specificity of a T cell receptor (TCR) but will have higher binding affinity such that the molecules may be used as therapeutic, diagnostic and research reagents. The method of producing a T-cell receptor mimic of the present invention includes identifying a peptide of interest, wherein the peptide of interest is capable of being presented by an MHC molecule. Then, an immunogen comprising at least one peptide/MHC complex is formed, wherein the peptide of the peptide/MHC complex is the peptide of interest. An effective amount of the immunogen is then administered to a host for eliciting an immune response, and serum collected from the host is assayed to determine if desired antibodies that recognize a three-dimensional presentation of the peptide in the binding groove of the MHC molecule are being produced. The desired antibodies can differentiate the peptide/MHC complex from the MHC molecule alone, the peptide alone, and a complex of MHC and irrelevant peptide. Finally, the desired antibodies are isolated.


A methodology of producing and utilizing antibodies that recognize peptides associated with a tumorigenic or disease state, wherein the peptides are displayed in the context of HLA molecules, is disclosed. These antibodies may be utilized in therapeutic methods of mediating cell lysis.


Kim S.,University of Washington | Li J.,University of Washington | McMurtrey C.P.,The University of Oklahoma Health Sciences Center | Hildebrand W.H.,The University of Oklahoma Health Sciences Center | And 5 more authors.
Journal of Immunology | Year: 2010

The generation of a robust CD8+ T cell response is an ongoing challenge for the development of DNA vaccines. One problem encountered with classical DNA plasmid immunization is that peptides produced are noncovalently and transiently associated with MHC class I molecules and thus may not durably stimulate CD8+ T cell responses. To address this and enhance the expression and presentation of the antigenic peptide/MHC complexes, we generated single-chain trimers (SCTs) composed of a single polypeptide chain with a linear composition of antigenic peptide, β2-microglobulin, and H chain connected by flexible linkers. In this study, we test whether the preassembled nature of the SCT makes them effective for eliciting protective CD8+ T cell responses against pathogens. A DNA plasmid was constructed encoding an SCT incorporating the human MHC class I molecule HLA-A2 and the immunodominant peptide SVG9 derived from the envelope protein of West Nile virus (WNV). HLA-A2 transgenic mice vaccinated with the DNA encoding the SVG9/HLA-A2 SCT generated a robust epitope-specific CD8+ T cell response and showed enhanced survival rate and lower viral burden in the brain after lethal WNV challenge. Inclusion of a CD4+ Th cell epitope within the SCT did not increase the frequency of SVG9-specific CD8+ T cells, but did enhance protection against WNV challenge. Overall, these findings demonstrate that the SCT platform can induce protective CD8+ T cell responses against lethal virus infection and may be paired with immunogens that elicit robust neutralizing Ab responses to generate vaccines that optimally activate all facets of adaptive immunity. Copyright © 2010 by The American Association of Immunologists, Inc.


Kim S.,University of Washington | Pinto A.K.,University of Washington | Myers N.B.,University of Washington | Hawkins O.,Receptor Logic Inc | And 12 more authors.
European Journal of Immunology | Year: 2014

We used a newly generated T-cell receptor mimic monoclonal antibody (TCRm MAb) that recognizes a known nonself immunodominant peptide epitope from West Nile virus (WNV) NS4B protein to investigate epitope presentation after virus infection in C57BL/6 mice. Previous studies suggested that peptides of different length, either SSVWNATTAI (10-mer) or SSVWNATTA (9-mer) in complex with class I MHC antigen H-2Db, were immunodominant after WNV infection. Our data establish that both peptides are presented on the cell surface after WNV infection and that CD8+ T cells can detect 10- and 9-mer length variants similarly. This result varies from the idea that a given T-cell receptor (TCR) prefers a single peptide length bound to its cognate class I MHC. In separate WNV infection studies with the TCRm MAb, we show that in vivo the 10-mer was presented on the surface of uninfected and infected CD8α+CD11c+ dendritic cells, which suggests the use of direct and cross-presentation pathways. In contrast, CD11b+CD11c- cells bound the TCRm MAb only when they were infected. Our study demonstrates that TCR recognition of peptides is not limited to certain peptide lengths and that TCRm MAbs can be used to dissect the cell-type specific mechanisms of antigen presentation in vivo. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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