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Rationally designed virus-like particles for modulation of chimeric antigen receptor (CAR)-t-cell therapy

A technology of parvovirus and DNA virus, applied in pharmaceutical composition, in medicine, can solve problems such as release syndrome, neurotoxicity, allergic reaction, etc.

Pending Publication Date: 2020-05-08
UNIVERSITY OF HEIDELBERG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the treatment of cancer, approaches such as Chimeric Antigen Receptor (CAR)-T cell therapy are promising but come with some drawbacks such as serious adverse effects including cytokine release syndrome, neurotoxicity , "targeted / non-targeted tumor" recognition, graft-versus-host disease (GVHD) and hypersensitivity

Method used

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  • Rationally designed virus-like particles for modulation of chimeric antigen receptor (CAR)-t-cell therapy
  • Rationally designed virus-like particles for modulation of chimeric antigen receptor (CAR)-t-cell therapy
  • Rationally designed virus-like particles for modulation of chimeric antigen receptor (CAR)-t-cell therapy

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Experimental program
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Effect test

Embodiment approach

[0108] In the following, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with one or more than one other aspect unless clearly indicated to the contrary. In particular, any feature indicated as preferred or advantageous may be combined with any other feature indicated as preferred or advantageous.

[0109] As mentioned in the background section, at worst, CAR T cell therapy can lead to TLS, leading to a so-called cytokine storm, a side effect due to the specific activity of CAR T cells. To reduce the consequences of increased cytokine release, treatment options include the use of anti-IL-6 antibodies or administration of corticosteroids, which can lead to inadequate treatment of primary diseases such as cancer. Therefore, it is generally desirable to prevent or at least reduce the likelihood of TLS during CAR T cell therapy. In the work leading up to the present invention, the inventors surprisingly discovered that AAV-de...

Embodiment 1

[0158] Example 1: Production and purification of wild-type AAV and NY-BR1-LCAR AAV

[0159] To generate the NY-BR1 AAV capsid insertion mutant used in this study, LCAR was inserted into the three-folded spike region of AAV as previously described (Michelfelder et al. (2011) PLoS ONE 6(8):e23101 .). Specifically, the oligonucleotide encoding the amino acid sequence LKNEQTLRADQMF was inserted into the VP1 position 588 in the AAV2 helper plasmid pMT-187-XX2 (the resulting nucleic acid encodes a modified VP1 having the amino acid sequence shown in SEQ ID NO: 4), Position T578 in the AAV5 helper plasmid pMT-rep2cap5-SfiI578 (the resulting nucleic acid encodes a modified VP1 with the amino acid sequence shown in SEQ ID NO: 5), position N590 in the AAV8 helper plasmid p5E18-VD2 / 8-Sfi590 (the resulting nucleic acid Encoding modified VP1 having the amino acid sequence shown in SEQ ID NO: 6) and position A589 in the AAV9 helper plasmid p5E18-VD2 / 9-Sfi589 (the resulting nucleic acid enc...

Embodiment 2

[0160] Example 2: Detection of NY-BR1-LCAR AAV by ELISA

[0161] Purified NY-BR1 LCAR AAV particles were coated onto well assay plate (half well). In 50 μl NaHCO at 4 °C 3 Coating was performed overnight in buffer / well. The starting concentration is 1x10 9Viral genome (VG) / ml, followed by serial 2-fold dilution of the pellet in 6 steps. After incubation, the plate was washed six times with PBS-T (1xPBS+0.05% Tween 20) at 150 μl / well. Blocking of the plate was performed by incubating for 1 hour at room temperature with 150 μl / well of blocking buffer (3% BSA, 5% sucrose in PBS-T) on a rocking device. Mouse primary antibody (NY-BR-1 No.2 - ThermoFisher order number: MA5-12645) or soluble LCAR (Morab2scFv - produced in-house) was added to each well at a final concentration of 1 μg / ml in 30 μl PBS-T, It was then incubated for 1 h at room temperature on a shaker. Thereafter, the cells were washed 3 times with PBS-T (150 µl / well). Add a secondary antibody relative to the pri...

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Abstract

The present invention relates to a modified viral structural protein (VSP) as a tool for specifically targeting a chimeric antigen receptor (CAR) expressed on cells of the immune system. The modifiedVSPs can assemble into virus like particles (VLP). Exposed areas of the VSPs are modified to comprise in a region located at the surface of a higher order structure, e.g. such as a capsomeric structure, a capsid, a VLP, a viral vector or a virus, a ligand specifically binding to a CAR (LCAR). The present invention thus, provides a modified VSP. The invention also relates to a nucleic acid encodingsaid VSP. Further, the invention relates to a capsomeric structure, a capsid, a VLP, a viral vector or a virus comprising at least one VSP. Further, the invention relates to a pharmaceutical composition comprising the VSP, the nucleic acid,the capsomeric structure, the capsid, the VLP, the viral vector or the virus comprising at least one VSP. Further, the invention relates to a VSP, a capsomericstructure, a capsid, a VLP, a viral vector or a virus for use in medicine, in particular for use in decreasing or limiting an immune response, treating or preventing tumor lysis syndrome or for treating an immune disease in a patient.

Description

[0001] The present invention relates to modified viral structural proteins (VSPs) as tools for specifically targeting chimeric antigen receptors (CARs) expressed on cells of the immune system. Modified VSPs can be assembled into virus-like particles (VLPs). The exposed region of the VSP is modified to contain a ligand that specifically binds to the CAR (LCAR) in a region located at the surface of a higher order structure such as a capsomer structure, capsid, VLP, viral vector or virus. Accordingly, the present invention provides modified VSPs. The present invention also relates to nucleic acids encoding said VSP. Furthermore, the invention relates to capsomer structures, capsids, VLPs, viral vectors or viruses comprising at least one VSP. Furthermore, the invention relates to a pharmaceutical composition comprising a VSP, a nucleic acid, a capsomer structure comprising at least one VSP, a capsid, a VLP, a viral vector or a virus. Furthermore, the invention relates to modified...

Claims

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Application Information

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IPC IPC(8): C07K14/005
CPCA61K38/00A61K35/76C07K14/005C07K2319/74C12N2750/14143A61P37/06C07K14/075C12N15/86C12N2750/14123
Inventor 帕特里克·施密特西尔克·乌里希-施密特因卡·祖尔尼格克里斯藤·多尔奥利弗·穆勒迪尔克·贾格尔
Owner UNIVERSITY OF HEIDELBERG
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