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Immunomodulatory fusion proteins and uses thereof

a technology of immunomodulatory fusion and fusion proteins, which is applied in the direction of peptide/protein ingredients, genetically modified cells, immunological disorders, etc., can solve the problems of incomplete remission, inability to fully remit, and inability to fully remit, and achieve the effect of increasing immune cell activity

Inactive Publication Date: 2018-02-15
FRED HUTCHINSON CANCER RES CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent is about a fusion protein that contains an extracellular component with a binding domain that specifically targets a target molecule, an intracellular component with a signaling domain that can deliver a stimulatory signal to a lymphocyte, and a hydrophobic component that connects the extracellular and intracellular components. The length of the fusion protein is designed to match the distance between membranes in an immunological synapse. The fusion protein can be used to deliver inhibitory signals or to enhance the immune response.

Problems solved by technology

This form of adoptive T cell therapy with tumor infiltrating lymphocytes can be technically cumbersome and leads to complete remission in only a minor fraction of patients with melanoma and is rarely effective in other cancers (Besser et al., Clin.

Method used

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  • Immunomodulatory fusion proteins and uses thereof
  • Immunomodulatory fusion proteins and uses thereof
  • Immunomodulatory fusion proteins and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

CD200R-CD28 Fusion Protein Constructions

[0187]Exemplary fusion proteins as described herein are illustrated using schematic representations in FIG. 1A. Exemplary fusion proteins include immunomodulatory fusion proteins (IFPs) comprised of the extracellular domain of CD200R or a portion thereof, and an intracellular signaling domain of CD28 or a portion thereof (FIG. 1A, constructs I-V). The hydrophobic component may be comprised of the transmembrane domain of either CD200R (FIG. 1A, construct I) or CD28 (FIG. 1A, constructs II-V), or portions thereof. In some exemplary CD200R-CD28 fusion proteins, the hydrophobic component comprises the transmembrane domain of CD28 and the extracellular component further comprises an extracellular portion of CD28, particularly an extracellular cysteine residue adjacent to the hydrophobic component (e.g., FIG. 1A construct III, CD200R-CD28Cys; construct IV, CD200R-3aas-CD28Cys; and construct V, CD200R-9aas-CD28Cys). The extracellular component may co...

example 2

Transgenic Expression of CD200R-CD28 Constructs

[0190]A preclinical mouse model for disseminated leukemia, based on the murine C57BL / 6 Friend virus-induced erythroleukemia (FBL) and TCRgag transgenic mice, was used to determine if CD200R-CD28 chimeric receptors can improve T cell function.

[0191]TCR transgenic mice were generated to produce CD8+ T cells specific for the gag epitope (TCRgag). C57BL / 6 (B6) mice were purchased from the Jackson Laboratory. TCRgag transgenic mice express a TCR transgene specific for the Friend virus gag epitope in CD8+ T cell (Ohlen et al., J. Immunol. 166: 2863-2870, 2001). All animal studies performed were approved under the University of Washington Institutional Animal Care and Use Committee protocol (Protocol #2013-01). The murine B6 Friend virus induced erythroleukemia (FBL) expresses the F-MuLV encoded gag epitope (peptide CCLCLTVFL).

[0192]CD200R-CD28 chimeric constructs based on murine genes were inserted into the pMP71 retroviral vector and used to...

example 3

CD200R-CD28 Constructs Promote In Vitro Proliferation, Accumulation, and Effector Function of Transduced T Cells

[0195]The CD200R-CD28 constructs described in Examples 1 and 2 were assessed for their abilities to promote proliferation, accumulation, and effector function of TCRgag T cells.

[0196]Expansion of Effector Cells In Vitro

[0197]TCRgag effector cells were generated in vitro as previously described (Stromnes et al., J. Clin. Invest. 120: 3722-34, 2010). Irradiated antigen presenting splenocytes (5×106), irradiated FBL (3×106), and TCRgag tg cells (106) were cultured together with IL-2 (50 U / mL) in 10 mL of culture media (IMDM supplemented with non-essential amino acids, 2 μM glutamine, 100 U / mL penicillin / streptomycin, 10% FBS, and 50 μM 2-mercapatoethanol). T cells were restimulated weekly and assessed by flow cytometry 5-7 days after the last stimulation.

[0198]In Vitro T Cell Proliferation Assay

[0199]TCRgag T cells were transduced as in Example 2. To assess T cell proliferati...

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Abstract

The present disclosure relates to immunomodulatory fusion proteins containing an extracellular binding domain and an intracellular signaling domain, wherein binding of a target can generate a modulatory signal in a host cell, such as a T cell. The present disclosure also relates to uses of immune cells expressing such immunomodulatory fusion proteins to treat certain diseases, such as cancer or infectious disease.

Description

STATEMENT REGARDING SEQUENCE LISTING[0001]The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 360056_433WO_SEQUENCE_LISTING.txt. The text file is 286 KB, was created on Mar. 4, 2016, and is being submitted electronically via EFS-Web.BACKGROUND[0002]T cell-based immunotherapies began to be developed when tumor-reactive T cells were found among a population of tumor-infiltrating lymphocytes (TILs) (Clark et al., Cancer Res. 29:705, 1969). One strategy, known as adoptive T cell transfer, in some contexts involves the isolation of tumor infiltrating lymphocytes pre-selected for tumor-reactivity, clonal expansion of the tumor-reactive T cells induced by anti-CD3 and anti-CD28 antibodies in the presence of IL-2, and finally infusing the expanded cell population back to the tumor-bearing patient (together with che...

Claims

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Application Information

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IPC IPC(8): C07K14/705A61K35/17C12N5/0783C07K14/725
CPCC07K14/70596C07K14/7051C07K14/70521C07K14/70578C07K14/70507C07K14/70503A61K35/17C12N5/0637C12N5/0638C07K2319/74C07K2319/03A61K38/00A61K48/00C12N2510/00C07K14/70517C12N5/0636A61P31/04A61P31/12A61P35/00A61P37/02A61P37/06A61K39/4632A61K39/464453A61K39/464402A61K39/4611
Inventor ODA, SHANNON K.GREENBERG, PHILIP D.SCHMITT, THOMAS M.
Owner FRED HUTCHINSON CANCER RES CENT
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