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NK adapter compounds that bind viral antigens and methods of use

A technology for viral antigens and compounds, applied to NK adaptor compounds that bind viral antigens and fields of use

Pending Publication Date: 2022-05-13
RGT UNIV OF MINNESOTA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The X targeting domain can target, for example, viral antigens, cancer cell antigens, etc.

Method used

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  • NK adapter compounds that bind viral antigens and methods of use
  • NK adapter compounds that bind viral antigens and methods of use
  • NK adapter compounds that bind viral antigens and methods of use

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0103] 1615 Construction of Anti-HIV

[0104]Since 1615x is a platform technology, antiviral scFvs that may or may not be associated with cancer development may also be used. Synthesis and assembly of a hybrid polynucleotide encoding TriKE 1615 anti-HIV (SEQ ID NO:5) was accomplished using DNA shuffling and ligation techniques. Fully assembled polynucleotide with NcoI restriction site from 5' end to 3' end; ATG start codon; VH and VL regions of anti-CD16 scFv, i.e. fragment with 20 amino acids (PSGQAGAAASESLFVSNHAY SEQ ID NO: 1) , a modified IL-15 with a seven amino acid linker (EASGGPE SEQ ID NO:2) and an anti-HIV scFv; and finally an XhoI restriction site.

[0105] The HIV-envelope-specific, IL-15-containing trispecific killer adapter (TriKE) both reactivates NK cell killing Wounding also directs NK cell killing to HIV-infected T cells.

[0106] While advances in the efficacy and use of antiretroviral drugs have greatly improved the health and longevity of HIV-infect...

example 2

[0116] A trispecific killer adapter (TRIKE) for mesothelin targets NK cells to lung cancer

[0117] NK cells are important effectors in the treatment of hematological malignancies but have so far been less effective in treating solid tumors. Lung cancer cells are generally ineffective against NK cell killing, but we wanted to determine whether small molecules that redirect NK cell lysis to the common tumor antigen mesothelin could enhance NK cell killing in the lung cancer setting. Mesothelin is a surface protein that is overexpressed in a variety of cancers, including an aggressive cancer of the lining of the lung: mesothelioma.

[0118] Comparison of peripheral blood NK cells from healthy donors and newly diagnosed cancer patients showed that lung cancer patients maintained expression of CD16 (Fc receptor) on the cell surface, with no difference in the major subset of NK cells. Therefore, we designed a trispecific killer adapter (TriKE) consisting of a single-domain antib...

example 3

[0122] Anti-HIV / CAM16 Transient expression of BIKE and TRIKE

[0123] experimental design

[0124] For VRC01-b12CL / VRC07H G54H (see bnAbs in Table 4), we started by testing the VRCFab-based BiKE first. bNAbs take years to evolve and accumulate three times the number of mutations than other antibodies.

[0125] expression construct

[0126] For expression in mammalian cell lines, VRCOl-b12CL (light chain) was cloned into a suitable expression vector (pCoof40) together with a short linker (GGGGS2) and non-humanized CAM16. The cloning method used was Gibson assembly or the related method HiFi assembly (New England Biolabs). Humanized CAM16 BiKE was also constructed in the same manner. The VRC07H G54H plasmid was not modified. Large scale preparations of both plasmid DNAs were produced by the ZymoPURE Plasmid Maxiprep Kit (Zymo Research).

[0127] BiKE protein expression

[0128] We used suspension-adapted CHO or HEK293 cell lines (ExpiCHO / Expi293F) for high-level trans...

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Abstract

The present disclosure describes compounds that bind to NK cells and methods of using these compounds. Generally, the compounds include an NK-binding domain, a targeting domain that selectively binds to a target cell, and an NK-activating domain that operably links the NK-binding domain and the targeting domain. In illustrative embodiments, the targeting domain selectively binds to an HIV antigen.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Serial No. 62 / 906,660, filed September 26, 2019, the entire contents of which are hereby incorporated by reference in their entirety. [0003] Statement of Government Support [0004] This invention was made with government support under CA111412 and CA065493 awarded by the National Institutes of Health and CA036725, CA072669, CA077598 and CA197292 awarded by the National Cancer Institute. The government has certain rights in this invention. [0005] Incorporation of Sequence Listings [0006] The material in the accompanying Sequence Listing is hereby incorporated by reference into this application. The accompanying sequence listing text file is named GTBIO2130_1WO_Sequence_Listing.txt, was created on September 25, 2020 and is 96kb. The file can be accessed using Microsoft Word on a computer using Windows OS. Background technique ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/54C07K16/10C07K16/28
CPCC07K16/1045C07K2317/622C07K2319/33C07K2317/76C07K16/30C07K16/283C07K2317/569C07K2317/31C07K14/5443A61P31/18A61K38/00C07K2317/22C07K2319/00A61K2039/505
Inventor J·S·米勒M·费利塞斯T·伦维克D·A·瓦莱拉
Owner RGT UNIV OF MINNESOTA