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pHLIP® peptide-mediated epitope tethering at cell surfaces

a peptide and cell surface technology, applied in the field of immunotherapy, can solve the problems of limited use of peptides, achieve the effects of enhancing the use of developed monoclonal antibodies, efficient binding, and enhancing cell recruitmen

Pending Publication Date: 2020-08-06
UNIV OF RHODE ISLAND BOARD OF TRUSTEES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent provides a solution for treating diseased tissues, such as tumors or inflamed tissues, by decorating cells with epitopes to recruit immune cells or enhance the use of monoclonal antibodies or antibodies generated through vaccination. The invention uses a strategy to position the epitope on the cell surface, which improves the recruitment of cells of the immune system. The invention also provides compositions and methods to recruit endogenous antibodies and enhance the binding of immune cells, antibodies, and antibodies generated through vaccination. The treatment targets the diseased tissue with a minimal effect on healthy tissue. Overall, this invention offers an effective and minimally invasive approach for treating diseased tissues.

Problems solved by technology

However, their use is limited by (1) the lack of adequate amounts (or any amounts) of accessible epitopes in many cancers, and (2) the emergence of resistance by selection of expression mutants not presenting proper epitopes.

Method used

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  • pHLIP® peptide-mediated epitope tethering at cell surfaces
  • pHLIP® peptide-mediated epitope tethering at cell surfaces
  • pHLIP® peptide-mediated epitope tethering at cell surfaces

Examples

Experimental program
Comparison scheme
Effect test

example 1

Small Molecule Epitope Di-nitrophenyl (DNP) to Cancer Cells by pHLIP® Promoted Cell Killing

[0161]Three different pHLIP® constructs were synthesized with a DNP—(O—(2,4-dinitrophenyl)hydroxylamine):

i) DNP-pHLIP®, where DNP-malemide was conjugated with a single Cys residue at the N-terminal of the pHLIP® peptide;

ii) DNP-PEG4-pHLIP®, where DNP-PEG4-NHS was conjugated with a single Lys residue at the N-terminal of the pHLIP® peptide; and

iii) DNP-PEG12-pHLIP®, where DNP-PEG12-NHS as conjugated with a single Lys residue at the N-terminal of pHLIP® peptide.

[0162]pHLIP® peptide with a single Cys residues used in the study for conjugation with DNP-malemide is the following: (ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: ______) pHLIP® peptide with single Lys residue and acetylated N-terminus used in the study for conjugation with DNP-PEG4-NHS and DNP-PEG12-NHS is the following: Ac-AKDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: ______)). Peptides were prepared by solid-phase synthesis. Progressions of co...

example 2

Two Peptide Epitopes by pHLIP® to Cancer Cells to Bind Two Heads of Ig Antibody

[0167]To enhance performance of antibodies and enhance immune response, it is important to promote binding of both heads of IgG with 2 epitopes coupled to the same pHLIP® peptide (see, e.g., FIG. 5B). The pHLIP® peptide with 2 Lys residues (bold and underlined) (Ac-AKQNDDQNKPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: ______)) is conjugated with excess of NHS-PEG12-malemide and NHS-PEG24-malemide linkers, purified and, pHLIP-(PEG12)2 is coupled with an HA peptide epitope (YPYDVPDYAGGGCA (SEQ ID NO: ______)). pHLIP® and HA peptides are prepared by solid-phase synthesis. Progressions of both coupling reactions and purifications are performed using reverse-phase HPLC (RP-HPLC) (the gradient: water and acetonitrile with 0.05% TFA) followed by lyophilization. The concentration of the construct is measured by absorbance at 280 nm.

[0168]PEG12 and PEG24 are be stretched for 5 nm and 10 nm, respectively. The six residues (Q...

example 3

CXCL10 Protein Chemokine Epitope by pHLIP® to Cancer Cells to Promote NK-Cells Binding

[0170]Two fusion proteins with 2 different tags (His and cMyc) are expressed and purified:

CXCL10-mucin-2x-Myc-pHLIP ®SEQ ID NO: 531mnqtailicclifltlsgiqgvplsrtvrctcisisnqpvnprslekleiipasqfcprveiiatmkkkgekrclnpeskaiknllkavskerskrspgtfekqigevkprttpaaggmdesvvlepeatgesssleptpssqeaqralgtspelptgvtgssgtrlpptpkaqdggpvgtelfrvppvstaatwqssaphqpgpslwaeaktseapstqdpstqastasspapeenapsegqrvwgqgqsprpenslereemgpvpahtdafqdwgpgsmahvsvvpvssegtpsrepvasgswtpkaeepihatmdpqrlgvlitpvpdaqaatrrqeqkliseedleqkliseedladdqnpwrayidllfptdtllldllwCXCL10-mucin-6x-His-pHLIP ®SEQ ID NO: 532mnqtailicclifltlsgiqgvplsrtvrctcisisnqpvnprslekleiipasqfcprveiiatmkkkgekrclnpeskaiknllkavskerskrspgtfekqigevkprttpaaggmdesvvlepeatgesssleptpssqeaqralgtspelptgvtgssgtrlpptpkaqdggpvgtelfrvppvstaatwqssaphqpgpslwaeaktseapstqdpstqastasspapeenapsegqrvwgqgqsprpenslereemgpvpahtdafqdwgpgsmahvsvvpvssegtpsrepvasgswtpkaeepihatmdpqrlgvlitpvpdaqaatrrqhhhhhhaddqnpwra...

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Abstract

The invention features methods and compositions for eliciting an anti-tumor response in a subject comprising administering to the subject a pHLIP® construct comprising an antibody recruiting molecule linked to one or more pHLIP® peptides by a non-cleavable linker compound. The construct increases the amount of the antibody recruiting molecule on the surface of a diseased cell.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 797,899, filed Jan. 28, 2019, the entire contents of which is incorporated herein by reference in its entirety.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH[0002]This invention was made with government support under R01 GM073857 awarded by the National Institute of General Medical Sciences of the National Institutes of Health. The government has certain rights in the invention.INCORPORATION BY REFERENCE OF SEQUENCE LISTING[0003]The contents of the sequence listing text file named “040984-512001WO_SL.txt”, which was created on Jan. 28, 2020 and is 222 kilobytes in size, is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0004]The present invention relates to immunotherapy.BACKGROUND[0005]Antibody therapies are based on the alteration of signaling, promotion of apoptosis, sequestration of growth factors, activation of the immun...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/16A61K38/20A61K38/19
CPCC07K2319/33A61K38/20A61K38/195A61K38/16A61P35/00A61P37/04A61K2121/00A61K47/00A61K47/10A61K45/05
Inventor RESHETNYAK, YANA K.ANDREEV, OLEG A.MOSHNIKOVA, ANNAENGELMAN, DONALD M.
Owner UNIV OF RHODE ISLAND BOARD OF TRUSTEES
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