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Variant icos ligand immunomodulatory proteins and related compositions and methods

A kind of immunoglobulin, variant technology, applied in the field of therapeutic composition of immune response

Pending Publication Date: 2020-09-25
ALPINE IMMUNE SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although therapeutics that can modulate IS are known, improved therapeutics are still needed

Method used

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  • Variant icos ligand immunomodulatory proteins and related compositions and methods
  • Variant icos ligand immunomodulatory proteins and related compositions and methods
  • Variant icos ligand immunomodulatory proteins and related compositions and methods

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0630] The provided implementations are:

[0631] 1. A variant ICOS ligand (ICOSL) polypeptide comprising one or more amino acid modifications in the immunoglobulin superfamily (IgSF) domain of an ICOSL reference polypeptide, wherein the ICOSL reference polypeptide is a truncated cell An extracellular domain comprising a continuous amino acid sequence and a C-terminal truncation of at least 25 amino acids with reference to the sequence of the ICOSL extracellular domain shown in SEQ ID NO:32, said continuous amino acid comprising the sequence described with reference to SEQ ID NO:32 Amino acids 1-112 of the ICOSL extracellular domain sequence shown.

[0632] 2. The variant ICOSL polypeptide of embodiment 1, wherein said variant ICOSL polypeptide exhibits an altered or identical binding to one or more extracellular domains of ICOS or CD28 as compared to said ICOSL reference polypeptide. Binding of one or more extracellular domains.

[0633] 3. The variant ICOSL polypeptide acc...

Embodiment 1

[0871] Example 1 Generation of mutant DNA constructs for the IgSF domain

[0872] Example 1 describes the generation of mutant DNA constructs of the human ICOSL IgSF domain for translation and expression on the surface of yeast as a yeast display library.

[0873] A. Degenerate library

[0874] Mutant DNA constructs encoding variants of the ECD domain of ICOSL were generated. The construct was generated based on the wild-type human ICOSL sequence shown in SEQ ID NO: 32 containing the ECD domain, SEQ ID NO: 32 is as follows:

[0875] DTQEKEVRAMVGSDVELSCACPEGSRFDLNDVYVYWQTSESKTVVTYHIPQNSSLENVDSRYRNRALMSPAGMLRGDFSLRLFNVTPQDEQKFHCLVLSQSLGFQEVLSVEVTLHVAANFSVPVVSAPHSPSQDELTFTCTSINGYPRPNVYWINKTDNSLLDQALQNDTVFLNMRGLYDVVSVLRIARTPSVNIGCCIENVLLQQNLTVGSQTGNDIGERDKITENPVSTGEKNAAT

[0876] For libraries targeting residues specific for full or partial randomization using degenerate codons, DNA encoding SEQ ID NO: 32 was purchased as a set of overlapping oligonucleotides up to 80 base pairs...

Embodiment 2

[0884] Introduction of DNA Libraries into Yeast

[0885] Example 2 describes the introduction of the ICOSL DNA library into yeast.

[0886] To introduce degenerate and 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) with Steps of electroporation-ready DNA were electroporated (Colby, D.W. et al. 2004 Methods Enzymology 388, 348-358). The only difference is that the transformed cells were grown in non-induced minimally selective SCD-Leu medium to accommodate the LEU2 selectable marker carried by the modified plasmid pBYDS03. 1 L of SCD-Leu medium consists of 14.7 g sodium citrate, 4.29 g citric acid monohydrate, 20 g dextrose, 6.7 g yeast basal nitrogen source, and 1.6 g yeast synthetic broth supplement without leucine . Filter sterilize the medium using a 0.22 µm vacuum filter unit before use.

[0887] Library sizes were determined by inoculating serial ...

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Abstract

Provided herein are immunomodulatory proteins comprising ICOSL variants and nucleic acids encoding such proteins. The immunomodulatory proteins 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 priority to U.S. Provisional Patent Application 62 / 574,161, entitled "Variant ICOS Ligand Immunomodulatory Proteins and Related Compositions and Methods," filed October 18, 2017, the contents of which are incorporated by reference in their entirety incorporated. [0003] Incorporated by reference into the sequence listing [0004] This application is filed together with the Sequence Listing in electronic form. The sequence listing was created on October 13, 2018, is 1,655,996 bytes in size, and is available as a file named 761612002240SeqList.txt. The information in the sequence listing in electronic format is incorporated by reference in its entirety. technical field [0005] The present disclosure relates to therapeutic compositions for modulating immune responses in the treatment of cancer and immunological diseases. In some aspects, the disclosure relates to specific variants of ICOS li...

Claims

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Application Information

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IPC IPC(8): C07K14/705
CPCC07K14/70532A61K39/464406A61K39/464411A61K39/4621A61K39/4631A61K2239/31A61K39/4611A61K39/464412A61K39/46434C07K2319/03C07K14/7051C12N15/85A61P35/00A61P17/00A61P11/06A61K38/00A61K47/50A61K35/54A61K38/1774C07K2319/02C07K2319/21C07K2319/30C07K2319/31C07K2319/41C07K2319/43C12N5/0681C12P21/02
Inventor L·埃文斯M·科纳克R·斯汪森
Owner ALPINE IMMUNE SCI INC
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