Methods for treating infectious diseases and tumors

A technology for infectious diseases and effects, applied in the field of treating infectious diseases and tumors, and can solve the problem of inability to respond to tumor antigens

Active Publication Date: 2011-12-14
EMORY UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to immunosuppression in patients diagnosed with cancer, the innate immune system of these patients is often unable to respond to tumor antigens

Method used

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  • Methods for treating infectious diseases and tumors
  • Methods for treating infectious diseases and tumors
  • Methods for treating infectious diseases and tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0438] Example 1: Inhibition of PD-1 using anti-PD-L1 antibodies in chronically infected mice way

[0439] Mice infected with different lymphocytic choriomeningitis viruses (LCMV) were used to study the effect of chronic viral infection on CD8+ T cell function. The Armstrong strain of lymphocytic choriomeningitis virus (LCMV) causes an acute infection that is evident within 8 days, producing long-lived, highly functional, memory-storing CD8+ T cells . In contrast, the lymphocytic choriomeningitis virus (LCMV) Cl-13 strain produces a persistent infection in the host that results in viral sepsis lasting up to 3 months. The virus persists in some indeterminate tissue, and the function of antigen-specific CD8+ T cells is attenuated. DbNP396-404 CD8+ T cells disappeared from the body when DbGP33-41 and DbGP276-286 CD8+ T cells were present but these cells did not have the ability to proliferate or secrete antiviral cytokines such as interferon ( IFN)-γ and TNF-α.

[0440] C...

Embodiment 2

[0449] Example 2: Administration of antiviral vaccines and PD-1 antagonists

[0450] A method used to boost T cell responses during persistent infection is therapeutic vaccination. The rationale for this approach is that during chronic viral infection, endogenous antigens may not be present in an optimal or immunogenic manner, and antigens delivered in the form of vaccines can provide more effective stimulation of virus-specific T and B cells . Using the chronic lymphocytic choriomeningitis virus (LCMV) model, mice were administered a recombinant vaccinia virus capable of expressing lymphocytic choriomeningitis virus (LCMV) as a therapeutic vaccine (VVGP33) GP33 epitope, resulting in a moderately enhanced CD8+ T cell response in chronically infected mice. Four of nine infected mice treated with the therapeutic vaccine showed a positive response, while none of the control mice showed a significant increase in the immune response to GP33. When therapeutic vaccination was co...

Embodiment 3

[0451] Example 3: Use of PD-1 RNA interference in chronically infected mice (RNAi) inhibits the PD-1 pathway

[0452] Ribonucleic acid interference (RNAi) can stop gene expression in mammalian cells. Long double-stranded RNAs (dsRNAs) are introduced into cells and subsequently processed into smaller quiescent RNAs (siRNAs) that target specific mRNA molecules or small groups of mRNAs. This technique is especially effective at sites where the antibody is not functional. For example, RNAi can be performed at a position where unique splice variants are capable of producing soluble forms of PD-1 and CTLA-4.

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Abstract

Disclosed herein are PD-1 antagonists useful for reducing PD-1 expression or activity in a subject. The use of such PD-1 antagonists in combination with antigens from infectious agents or tumors can enhance immune responses specific to infectious agents or tumor cells. Thus, subjects suffering from an infectious disease, such as a persistent infection, can be treated with a PD-1 antagonist. Additionally, subjects with tumors can be treated with PD-1 antagonists. In several embodiments, the subject can be treated by transplanting a therapeutically effective amount of activated T cells capable of recognizing an antigen of interest, and by administering a therapeutically effective amount of a PD-1 antagonist. Also disclosed herein are methods for testing the efficacy of a PD-1 antagonist in a subject administered the PD-1 antagonist. In some embodiments, the methods comprise measuring the proliferation of memory B cells in a sample from a subject administered a PD-1 antagonist.

Description

[0001] priority statement [0002] This application claims priority to US Provisional Patent Application Serial No. 61 / 118,570, filed November 28, 2008, which is hereby incorporated by reference. [0003] Statement of Government Support [0004] This application was made with United States Government support. , Grant Nos. RO1 AI057029, RO1 AI071852, and RO1 AI074417 awarded by the National Institutes of Health (NIH), the Government has certain rights in this invention. technical field [0005] This application relates to the application of antagonists, in particular, to the application of PD-1 antagonists for treating persistent infection and tumors, and the present invention also relates to a method for determining the effective dose of PD-1 antagonists. Background technique [0006] Immunosuppression of the host immune response plays an important role in the process of persistent infection and tumor immunosuppression. A persistent infection is an infectious disease in w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/02C12N5/0781G01N33/15A61K31/7105A61P35/00
CPCC07K16/2827C07K16/2818A61K2039/505A61K39/39C07K2317/74C07K2317/24G01N33/5052A61K2039/55516A61K39/39541A61K31/7105A61K2039/507A61P1/16A61P31/10A61P31/12A61P31/18A61P31/22A61P35/00A61P37/00Y02A50/30A61K39/001102A61K2300/00C07K16/2803C07K2317/76G01N2333/52G01N33/56966A61K39/12C12N15/1138C12N2310/14C12N2760/10034G01N33/5088G01N2800/26
Inventor R·阿梅德R·阿玛拉V·韦露K·蒂坦吉G·弗里曼
Owner EMORY UNIVERSITY
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