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Methods and compositions useful in generating non canonical CD8+ T cell responses

A cell and cytomegalovirus technology, applied in the field of CD8+ immune response, can solve the problems of virus disappearance, CD4 not observed, and SIV-specific antibody response not occurring

Inactive Publication Date: 2018-05-22
OREGON HEALTH & SCI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although RhCMV-protected rhesus macaques showed periodic low-level "blips" of viremia, no CD4 + Memory T cell depletion, absence of SIV-specific antibody responses, and subsequent viral nucleic acid becoming nearly unquantifiable over time, with replication-competent virus disappearing from tissues of protected animals

Method used

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  • Methods and compositions useful in generating non canonical CD8+ T cell responses
  • Methods and compositions useful in generating non canonical CD8+ T cell responses
  • Methods and compositions useful in generating non canonical CD8+ T cell responses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0155] Example 1. Induction of MHC-E-restricted CD8 by rhesus cytomegalovirus vaccine vector lacking UL128 and UL130 but containing UL40 and US28 genes + T cells.

[0156] It was previously demonstrated that RhCMV / SIV vectors drive alternative SIV-specific CD8 + T cell responses, which are quite different from typical responses produced by conventional vaccine formats, and even from SIV infection itself (Hansen, S.G. et al., Science 340, 1237874 (2013), which is incorporated herein by reference).

[0157] Although RhCMV / SIV-induced CD8 + T cell responses are MHC-II restricted CD8 + T cell populations are present predominantly, but remaining CD8 restricted + The molecules of T cells (those inhibited by the pan-MHC-I blocking antibody W6 / 32) remain unknown.

[0158]In particular, administration of 68-1 RhCMV / gag vectors resulted in targeting of SIVmac239Gag in rhesus macaques vaccinated with each RhCMV / gag vector 273-287 (Gag 15-mer #69) and Gag 477-491 (Gag 15-mer #1...

Embodiment 2

[0184] Example 2 - Target peptide specific CD8 in the context of MHC-E + production of T cells

[0185] T cell receptors that recognize target peptides from antigens in the case of classically polymorphic MHC-Ia molecules can be used to transfect autologous T cells for immunotherapy of diseases such as cancer or infectious diseases. A major obstacle to this approach is the diversity of MHC-Ia in the population, which limits the use of a given TCR to MHC-Ia-matched patients. By generating target peptides that recognize antigen-derived peptides (e.g., peptides from tumor antigens and peptides from pathogens) in the context of non-classical, non-polymorphic MHC-E molecules, MHC matching becomes obsolete and the resulting TCR Can be used on all patients.

[0186] CD8 recognizing MHC-E / peptide complexes in nature + T cells are rare, and there are currently no reliable methods to generate such T cells against target antigens such as tumor antigens, antigens from pathogens, tiss...

Embodiment 3

[0187] Example 3 - Broadly targeted CD8 restricted by major histocompatibility complex E + T cell response

[0188] Major histocompatibility complex (MHC)-E is a highly conserved, ubiquitous, non-canonical MHC-Ib molecule with limited polymorphisms that is involved in NK cell reactivity primarily through interaction with NKG2 / CD94 receptors adjustment. Here, among all protein antigens tested, rhesus macaques sensitized with Rh157.5 / .4 gene-deleted RhCMV vectors uniquely shifted MHC-E function to present highly diverse peptide epitopes to CD8α / β + T cells, about 4 different epitopes per 100 amino acids. Since MHC-E is upregulated on HIV / SIV and other persistent virally infected cells to evade NK cell activity, MHC-E restricts CD8 + The ability of T cell responses to exploit the potential of pathogen immune evasion to adapt may make these unconventional responses very effective.

[0189] Adaptive cellular immunity against intracellular pathogens is the recognition of CD8 ...

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Abstract

Methods of inducing a CD8+ T cell response to a heterologous antigen in which at least 10% of the CD8+ T cells are MHC-E restricted are disclosed. The method involves immunizing with a CMV vector thatdoes not express UL128 and UL130 proteins. Also disclosed are recombinant CMV vectors comprising nucleic acids encoding a heterologous protein antigen, a UL40 protein, and a US28 protein but that donot express an active UL128 and UL130 protein. Also disclosed are recombinant CMV vectors comprising nucleic acids encoding a heterologous protein antigen, but that do not express an active UL40 protein, UL128 protein, UL130 protein, and optionally a US28 protein. Also disclosed are recombinant CMV vectors comprising nucleic acids encoding a heterologous protein antigen, but that do not express anactive US28 protein, UL128 protein, UL130 protein, and optionally a UL40 protein.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 114,203, filed February 10, 2015, U.S. Provisional Application No. 62 / 196,520, filed July 24, 2015, and U.S. Provisional Application No. 62 / 196,520, filed September 18, 2015 Priority interest in .62 / 220,703, each of which is incorporated herein by reference in its entirety. technical field [0003] In general, the art is the use of CMV vectors in immunizations. More specifically, the art is to generate CD8 + immune response. More specifically, the art is to generate T cells with receptors restricted by MHC-E, including CD8 + . [0004] Statement of Government Support [0005] This invention was made with US Government support under Grant No. P01 AI094417 awarded by the National Institutes of Health. The US Government has certain rights in this invention. Background technique [0006] A rhesus cytomegalovirus (RhCMV) vaccine vector (RhCMV / SIV) expressing...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/86C12N5/10A61K35/17A61P35/00A61P31/00A61P37/02
CPCA61K35/17C12N5/0636C12N15/86C12N2710/16143A61K39/4632A61K39/4611A61K39/464838C12Q1/68A61K2039/5256A61K2039/53A61K2039/57C12N9/0093C12N15/00A61K39/12A61K2039/5252C12N2740/15034C12Y117/04001A61P31/00A61P31/06A61P31/12A61P31/14A61P31/18A61P31/20A61P31/22A61P33/00A61P35/00A61P35/02A61P37/02A61P37/04A61P37/06Y02A50/30A61K48/00C12N2710/16111C12N2710/16162A61K39/21A61K39/245A61K2039/5158A61K2039/575C12N7/00C12N2710/16134C12N2740/15043
Inventor 克劳斯·弗吕路易斯·皮克斯克特·汉森约纳·萨夏丹尼尔·马卢利
Owner OREGON HEALTH & SCI UNIV
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