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pHLIP-MEDIATED INTRACELLULAR DELIVERY OF IMMUNO-STIMULATORY COMPOUNDS

An immunostimulatory compound technology, applied in the field of pHLIP®-mediated intracellular delivery of immunostimulatory compounds, can solve the problem that drugs cannot effectively pass through the cell membrane

Pending Publication Date: 2022-01-18
RHODE ISLAND COUNCIL ON POSTSECONDARY EDUCATION +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another limitation is that these drugs tend to be polar molecules that do not cross cell membranes efficiently

Method used

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  • pHLIP-MEDIATED INTRACELLULAR DELIVERY OF IMMUNO-STIMULATORY COMPOUNDS
  • pHLIP-MEDIATED INTRACELLULAR DELIVERY OF IMMUNO-STIMULATORY COMPOUNDS
  • pHLIP-MEDIATED INTRACELLULAR DELIVERY OF IMMUNO-STIMULATORY COMPOUNDS

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] described in this article Peptides and U.S. Patent Nos. 9,814,781 and 9,289,508 (incorporated herein by reference) and U.S. Patent Publication Nos. 20180117183, 20180064648, 20180221500, 20180117183, 20180064648, 201602565150, 915 No. 20150051153, No. 20120142042, No. 20120039990, and No. 20080233107, each of which is incorporated herein by reference.

[0124] STING is known in the literature, but the use of STING agonists has been hampered by problems with cellular delivery. Figures 13 to 16 show illustrative - Linker - cargo construct, eg, with cargo as an immunostimulatory compound. As mentioned above, the delivery of charged molecules across cell membranes is difficult to achieve. Constructs disclosed herein, for example, - Linker - cargo construct that mediates targeting of cancer and immune cells (due to the low pH of their isosurfaces) and avoids or minimizes overall autoimmune responses to STING agonists (eg, cGAMP). The problems of targeting cargoes suc...

Embodiment 2

[0166] Example 2: Mediated tumor targeting and cytoplasmic delivery of CDN

[0167] pHLIP-CDN (cyclic dinucleotide), STING agonist, such as pHLIP-S-S-cGAMP (schematic diagram below), was synthesized and purified by CheminPharma, Inc. STING agonists are linked via a self-sacrificing linker to The C-terminal membrane insert of the peptide, and its unmodified form is released into the cytoplasm, which can effectively activate the STING pathway

[0168]

[0169] Chemical structure of the pHLIP-S-S-cGAMP conjugate, where cGAMP is linked to (A) at The Cys of the peptide or (B) is located in the acetylation Peptide Lys.

[0170] pHLIP-S-S-cGAMP was tested on B16-Blue ISG and B16-Blue ISG-KO-STING cells (Invitrogen). B16-Blue ISG is a murine melanoma cell stably transfected with the secreted embryonic alkaline phosphatase (SEAP) gene under the control of the interferon-inducible ISG54 promoter enhanced by the polymeric interferon-stimulated response element (ISRE) Tie( ...

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Abstract

The invention features a composition comprising an immuno-stimulatory compound and a pHLIP peptide, e.g., an immunostimulatory compound that comprises a cyclic purine dinucleotide, which binds to a stimulator of interferon genes (STING) such as a cGAMP cyclic compound inside a cell.

Description

[0001] related application [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 797,893, filed January 28, 2019, under 35 U.S.C. § 119(e), the entire contents of which are incorporated herein by reference. [0003] Statement of Federally Funded Research [0004] This invention was made with government support under award R01 GM073857 from the National Institute of General Medical Sciences, National Institutes of Health. The US Government has certain rights in this invention. [0005] Sequence Listing Incorporated by Reference [0006] The content of the text file of the sequence listing named "040984-511001WO_SL.txt." was created on January 28, 2020, and its size is 94,882 bytes, the entirety of which is incorporated herein by reference. technical field [0007] The present invention relates to immunotherapy. Background technique [0008] Traditional approaches to cancer treatment use toxic agents that do not discriminate well between norma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00C07K14/00C09K11/06A61K47/64A61K47/42A61K47/65A61P35/00
CPCA61K47/42A61K47/64A61P35/00A61K9/0019A61K39/39A61P37/04
Inventor Y·K·列舍特尼亚克O·A·安德烈耶夫D·M·恩格尔曼A·莫申科瓦J·迪肯
Owner RHODE ISLAND COUNCIL ON POSTSECONDARY EDUCATION
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