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Compositions and methods for targeting mutant ras

A technology of mutant and composition, applied in the field of compositions and methods for targeting mutant RAS, can solve the problem of no RAS oncoprotein and the like

Pending Publication Date: 2021-11-09
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Unfortunately, there are no effective pharmacological inhibitors of RAS oncoproteins

Method used

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  • Compositions and methods for targeting mutant ras
  • Compositions and methods for targeting mutant ras
  • Compositions and methods for targeting mutant ras

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0539] Example 1: Identification of mRAS neoantigens

[0540] As described here, various computational and proteomic studies were performed to identify mRAS neoantigens and their interactions with HLA types. figure 1 is a schematic depicting a discovery strategy for mutant RAS epitopes, in which a computer model is used to predict the affinity of mRAS peptides for MHC, followed by experiments to measure the affinity / stability of the interaction and detect the peptides by mass spectrometry.

[0541] A computer study was conducted to predict mRAS neoantigens using antigen.garnish software, which analyzes human or mouse DNA missense mutations, insertions, deletions and fusions and predicts neoepitopes computationally using 7 efficient algorithms . The model exports neoepitopes by MHC I / II binding affinity. For example, if figure 2 As shown, the model was used to predict a 9-10-mer neoepitope containing a mutation at a position corresponding to G12 in RAS.

[0542] Such as ...

Embodiment 2

[0548] Example 2: Evaluation of Immunogenicity of mRAS

[0549] Experiments were performed to assess the immunogenicity of mRAS peptide-MHC recognition as described herein. Such as Figure 11 As indicated, PMBCs were isolated and stimulated from normal donors selected for HLA type (HLA-A02, HLA-A03, HLA-A11 and HLA-B07). Experiments using the IFN-γ ELISPOT assay were performed to assess CD8+ T cell responses. Summary of mRAS CTL responses as Figure 12 as well as Figure 13A-Figure 13F shown.

[0550] Additional experiments using pMHC multimer staining were performed on T cell cultures to identify mRAS-specific T cells ( Figure 14 ). Experiments also showed that mRAS T cell responses were highly specific ( Figure 15 ). Experiments using various doses of B7-G12R were used to demonstrate the observed response with high affinity ( Figure 16 ).

[0551] Experiments were also performed to examine whether the B7-G12R CTL response could kill the G12R+PDA cell line. Su...

Embodiment 3

[0553] Example 3: Development of mRAS-specific TCR therapy

[0554] As described herein, experiments were performed to design TCR therapies targeting specific mRAS peptides in the context of specific HLA types.

[0555] Such as Figure 18 As indicated, T cells observed to bind A11-G12V and B7-G12R mRAS peptide-HLA type complexes were sorted, expanded, and subjected to TCRα / β sequencing. Two distinct CD8+ T cell clones were identified as HLA-A*11:01-restricted G12V-specific T cells: (1) TRAV39 / TRBV20-1 and TRAV12-1 / TRBV28 were observed.

[0556] Based on the sequencing, lentiviral constructs called TCR831 and TCR833 were designed ( Figure 19 ). TCR831 contains TRAV39 and TRBV20-1, while TCR833 contains TRAV12-1 and TRBV28. Both constructs contain the T2A linker domain and the EF1α promoter. Similarly, additional constructs were designed, termed TCR896, TCR897, TCR847 and TCR864, as Figure 20 summarized. Figure 20 RAS mutation sensitivity, HLA restriction, α-chain an...

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Abstract

This invention relates to compositions and methods of treating cancer associated with mutant RAS. In certain aspects, the invention relates to antigenic RAS peptide fragments and T-cell receptors that bind to specific mutant RAS peptide fragments in the context of specific HLA types.

Description

[0001] Citations to related applications [0002] This application claims priority to U.S. Provisional Patent Application Serial No. 62 / 796,733, filed January 25, 2019, which is hereby incorporated by reference in its entirety. Background technique [0003] Somatic mutations have been identified as common drivers of tumorigenesis. Activating point mutations in the Ras gene were the first somatic point mutations identified in human cancer. RAS mutations are the most common somatic mutations found in human cancers, and they contribute to the pathogenesis of a variety of highly prevalent malignancies, including lung, colorectal, and pancreatic ductal adenocarcinomas. Mutant RAS is an attractive target for the treatment of cancer because it is considered a driver mutation uniquely expressed by cancer cells and important for tumor growth and survival. These mutations usually involve codon 12 of the RAS protein, and the amino acid changes are highly conserved, most commonly caused...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17A61K39/04A61K39/385A61K39/39A61K39/395A61K45/00
CPCA61K35/17A61K31/7088C07K14/82C07K14/7051C07K16/2833C07K16/40C07K16/32C07K2317/33C07K2317/73A61K39/001164A61K2039/5156A61K2039/5158A61K2039/5154C07K2317/32C07K2317/34A61K38/08A61K39/00A61P35/00C07K7/06C12N15/62A61K2039/505C07K2319/00A61K39/385A61K39/39
Inventor 阿达姆·贝尔罗伯特·冯德海德杰拉尔德·里内特比阿特丽斯·卡雷诺
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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