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Cell penetrating protein-antibody conjugates and methods of use thereof

A conjugate and cell technology, applied in biochemical equipment and methods, antibodies, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve the problem that antibody therapy can only target extracellular molecules, etc. question

Active Publication Date: 2022-03-04
CITY OF HOPE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current antibody therapy can only target extracellular molecules

Method used

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  • Cell penetrating protein-antibody conjugates and methods of use thereof
  • Cell penetrating protein-antibody conjugates and methods of use thereof
  • Cell penetrating protein-antibody conjugates and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] Example 1. Generation of bispecific antibodies by hybridization of attached DNA oligos

[0217] As described in more detail below, the present invention demonstrates that conjugation of double-stranded phosphorothioated DNA oligonucleotides to antibodies enables the antibodies to penetrate cells, recognize and bind intracellular antigens. Furthermore, Applicants demonstrate that this strategy enables the generation of cell-penetrating bispecific antibodies capable of recognizing and binding two intended intracellular target proteins. For example, Applicants show that sense and antisense linking of phosphorothioated DNA oligonucleotides to anti-STAT3 and anti-NFkB (p65) antibodies allows hybridization of selected nucleic acid sequences. After the hybridization procedure is complete, the bound antibody is purified by expected increased molecular weight compared to a single IgG-antibody ( figure 1 ).

[0218] Anti-STAT3-anti-STAT3 or anti-NFkB-anti- Formation of NFkB. ...

Embodiment 2

[0220] Example 2. Recognition of intracellular antigens STAT3 and NFkB(p65) by cell-penetrating bispecific antibodies

[0221] Human lymphoma Ly3 cells were incubated with single antibodies raised against STAT3 or NFkB (p65) modified with phosphorothioated single-stranded (ss) DNA oligomers to achieve recognition of intracellular targets ( figure 2 ). Since NFkB(p65) IgG is modified with phosphorothioated sense ssDNA-oligomers, and STAT3 IgG is modified with phosphorothioated antisense ssDNA-oligomers, Applicants conclude that the nucleic acid sequence is not critical for intracellular delivery. Crucially, the intracellular delivery is a prerequisite for the recognition of intracellular antigens.

[0222] However, incubation of human lymphoma Ly3 cells with bispecific anti-STAT3-anti-NFκB(p65) linked together by hybridizing phosphorothioated dsDNA oligonucleotides resulted in intracellular STAT3 protein and NFkB(p65) protein simultaneous identification.

[0223] All modifi...

Embodiment approach 1

[0226] Embodiment 1: A cell penetrating conjugate comprising a phosphorothioate nucleic acid linking a first non-cell penetrating protein to a second protein, wherein said phosphorothioate nucleic acid enhances said first non-cell penetrating protein and said first non-cell penetrating protein. Intracellular delivery of the second protein described above.

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Abstract

The present aspect provides cell penetrating conjugates. The conjugate includes the non-cell-penetrating protein linked by a phosphorothioate nucleic acid, wherein the phosphorothioate nucleic acid enhances intracellular delivery of the non-cell-penetrating protein. The invention also provides methods and kits comprising the conjugates provided herein.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 62 / 202,006, filed August 6, 2015, which is hereby incorporated by reference in its entirety and for all purposes. [0003] Statement Regarding Rights to Inventions Under Federally Sponsored Research and Development [0004] This invention was made with support under Grant Number R01CA122976 provided by the National Institutes of Health and National Cancer Institute. The government has certain rights in this invention. [0005] Background of the invention [0006] Compared to other types of drugs such as small molecule drugs, antibodies have proven to be an effective drug form due to their ease of production, specificity, and biological durability. Current antibody therapies can only target extracellular molecules. However, many important targets for disease therapy and disease diagnosis are intracellular. For example, many transcription factors such as...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/00A61K38/14A61K39/00A61K47/00
CPCA61K38/00A61K38/14C07K16/00A61K2039/505C07K2317/77A61P35/00C12N15/11C12N2310/315C12N2310/3513C12N2310/18C07K16/18C07K16/468C07K2317/31A61K47/6843A61K47/6889A61K47/6851A61K47/6871A61K47/549A61K47/6879C07K16/30C07K16/40C07K2317/24C07K2317/40C07K2317/622
Inventor A·赫尔曼H·于
Owner CITY OF HOPE
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