Secretable variant immunomodulatory proteins and engineered cell therapy

A technology for immunoregulatory proteins and immune cells, applied in the field of preparation and use of such protein compositions

Pending Publication Date: 2019-10-18
ALPINE IMMUNE SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although some agents that can modulate IS are known, there is still a need for improved therapeutics

Method used

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  • Secretable variant immunomodulatory proteins and engineered cell therapy
  • Secretable variant immunomodulatory proteins and engineered cell therapy
  • Secretable variant immunomodulatory proteins and engineered cell therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0402] Among other things, the provided implementations are:

[0403] 1. An immunomodulatory protein comprising at least one non-immunoglobulin affinity modified immunoglobulin superfamily (IgSF) domain comprising one of the wild-type IgSF domains or multiple amino acid substitutions, where:

[0404] said at least one affinity-modified IgSF domain specifically binds at least one cell surface cognate binding partner of a wild-type IgSF domain;

[0405] The immunomodulatory protein does not comprise a transmembrane domain; and

[0406] The immunomodulatory protein is not conjugated to a half-life extending moiety.

[0407] 2. The immunomodulatory protein of embodiment 1, wherein said half-life extending moiety is a multimerization domain.

[0408] 3. The immunomodulatory protein of embodiment 1 or 2, wherein said half-life extending moiety is an Fc domain.

[0409] 4. The immunomodulatory protein of any one of embodiments 1 to 3, wherein said immunomodulatory protein further...

Embodiment 1

[0686] Generation of mutant DNA constructs of the IgSF domain

[0687] Example 1 describes the generation of mutant DNA constructs of human CD80, CD86, ICOSL and NKp30 IgSF domains for translation and expression on the surface of yeast as yeast display libraries. The following examples illustrate the binding and activity of affinity-modified domains of exemplary IgSF proteins in the form of Fc fusions; the affinity-modified domains are expected to interact with secretable immunomodulatory proteins or transmembrane proteins as described. Immunomodulatory protein linkage.

[0688] A. Degenerate library

[0689] Libraries that are fully or partially randomized with degenerate codons are used to target specific residues of a target protein, such as the specific mixed base set encoding various amino acid substitutions, human CD80 (SEQ ID NO: 28), ICOSL (SEQ ID NO: 32) and NKp30 (SEQ ID NO: 54) encoding DNA was obtained as a collection of overlapping oligonucleotides up to 80 base...

Embodiment 2

[0695] Introduction of DNA library into yeast

[0696] Example 2 describes the introduction of CD80, CD86, ICOSL and NKp30 DNA libraries into yeast.

[0697]To introduce degenerate random library DNA into yeast, electroporation-competent cells of yeast strain BJ5464 (ATCC.org; ATCC No. 208288) were prepared and run on a Gene Pulser II (Biorad, USA) using a method obtained from a method essentially as described. Electroporation-ready DNA from the above steps was electroporated (Colby, D.W. et al. 2004 Methods Enzymology 388, 348-358). The only difference was that transformed cells were grown in non-inducible minimally selective SCD-Leu medium to accommodate the LEU2 selectable marker carried by the modified plasmid pBYDS03.

[0698] Library size was determined by plating serial dilutions of freshly recovered cells onto SCD-Leu agar plates, after which library size was extrapolated from the number of single colonies from the plating that generated at least 50 colonies / plate. ...

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Abstract

Provided are immunomodulatory proteins, nucleic acids encoding such immunomodulatory proteins, cells engineered to express the immunomodulatory proteins and infections agents containing nucleic acid encoding the immunomodulatory proteins. In some embodiments, the immunomodulatory proteins are secretable. In some embodiments, the immunomodulatory proteins are transmembrane proteins that are surfaceexpressed. The immunomodulatory proteins, engineered cells and infectious agents provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 410,827, filed October 20, 2016, entitled "Secretable Variant Immunomodulatory Proteins and Engineered Cell Therapy," filed on 3 / 2017 U.S. Provisional Application No. 62 / 475,210, titled "Secretable Variant Immunomodulatory Proteins and Engineered Cell Therapy," filed July 22 and titled July 27, 2017 Priority to U.S. Provisional Application No. 62 / 537,921 for "Secretable Variant Immunomodulatory Proteins and Engineered Cell Therapy," the contents of each of which are incorporated by reference in their entirety incorporated. [0003] Incorporated by reference to the sequence listing [0004] This application is filed with a sequence listing in electronic format. The sequence listing is provided as a file named 761612001440SeqList.TXT created on October 19, 2017, which is 3,524,332 bytes in size. The information in the sequence listing in electronic format is inc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/12A61K38/17C07K14/47C07K14/705C12N15/86
CPCC07K14/70503C07K14/70532A61P29/00A61P35/00A61P37/02A61P37/04C07K2319/03C07K14/7051A61K39/0011A61K2039/5156A61K2039/5158Y02A50/30C12N5/0634C12N5/0636C12N5/0639A61K35/17A61K38/1774C12N2770/36141C07K2319/02A61K38/177A61K45/06C07K14/70517C07K14/70521C07K14/70596C07K2319/30C07K2319/33C12N5/0637
Inventor R·斯旺森M·科尔纳克尔
Owner ALPINE IMMUNE SCI INC
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