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Anti-garp protein and uses thereof

Inactive Publication Date: 2016-09-01
ARGENX BVBA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention relates to a protein that can bind to Glycoprotein A Repeats Previous (GARP) in the presence of TGF-β. This protein can be an antibody or an antibody fragment, such as a whole antibody, a humanized antibody, a single chain antibody, a dimeric single chain antibody, a Fv, a Fab, an affibody, an avian antibody, a nanobody, or an antibody mimetic. The protein can also bind to a conformational epitope of GARP that is complexed with latent TGF-β. The invention also includes the use of these proteins for inhibiting TGF-β signaling and treating diseases associated with TGF-β.

Problems solved by technology

Insufficient Treg function results in autoimmune pathology, while excessive Treg function may inhibit anti-tumor immune responses in cancer patients.
However, antibodies against hTGF-β were not found promising.

Method used

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  • Anti-garp protein and uses thereof
  • Anti-garp protein and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

New Monoclonal Antibodies Directed Against Human GARP (Anti-hGARP Monoclonals)

[0324]DBA / 2 or Balb / c mice were immunized with murine P1HTR cells transfected with human GARP. Sera from immunized mice were tested for the presence of anti-hGARP antibodies, by screening for binding to hGARP-expressing BW cells by FACS. Splenocytes from mice with high titers of anti-hGARP antibodies were fused to SP2 / neo cells. Hybridomas were selected in HAT medium and cloned under limiting dilution. Supernatants of + / −1600 hybridoma clones were screened by FACS for the presence of antibodies binding to hGARP-expressing BW cells. Thirty-eight clones producing anti-hGARP monoclonal antibodies were identified in this screening. Nine clones were selected and amplified for large scale-production and purification of nine new anti-hGARP monoclonals (MHGARP1 to 9).

[0325]As shown in FIG. 1, MHGARP1 to 9 bind to murine BW5147 cells transfected with hGARP, but not to untransfected cells. MHGARP1 to 9 also bind 293...

example 2

MHGARP8, but None of 12 Other Anti-hGARP Monoclonals, Inhibits Active TGF-β Production by Human Treg Cells

[0327]A human Treg clone (1E+06 cells / ml) was stimulated in serum-free medium with coated anti-CD3 (1 μg / ml) and soluble anti-CD28 (1 μg / ml) antibodies, in the presence or absence of 20 μg / ml of an anti-hGARP monoclonal antibody. Thirteen anti-hGARP monoclonals were tested in this assay: the above mentioned nine new monoclonals (MHGARP1 to 9), and commercially available antibody clones Plato-1 (Enzo Life Sciences, catalog No. ALX-804-867), 272G6 (Synaptic Systems, catalog No. 221 111), 50G10 (Synaptic Systems, catalog No. 221 011) and 7B11 (BioLegend, catalog No. 352501). Cells were collected after 24 hours, lysed and submitted to SDS-PAGE under reducing conditions. Gels were blotted on nitrocellulose membranes with the iBlot system (Life Technologies). After blocking, membranes were hybridized with primary antibodies directed against phosphorylated SMAD2 (pSMAD2, Cell Signaling...

example 3

MHGARP8, but not Other Anti-hGARP mAbs, Recognizes a Conformational Epitope that Requires the Presence of TGF-β

Mapping the Regions Recognized by Anti-hGARP Monoclonals

[0329]Murine BW5147 T cells were electroporated with plasmids encoding the HA-tagged proteins schematized in FIG. 3, part A, corresponding to hGARP, mGARP or mGARP / hGARP chimeras. Stable clones selected in neomycin were stained with biotinylated anti-hGARP antibodies (anti-hGARP1 to 9) and streptavidin-PE, with the commercial anti-hGARP antibody (clone Plato-1) and a secondary anti-mIgG2b-AF488, or with an anti-HA antibody and secondary anti-mouse IgG1-AF488. Histograms are gated on live cells. Black histograms show signals on untransfected BW cells, white histograms show signals on BW cells expressing the HA-tagged hGARP, and grey histograms show signals on BW cells expressing HA-tagged mGARP or mGARP / hGARP chimeras.

[0330]Parental BW5147 T cells (BW non-transfected) or clones stably transfected with hGARP alone (BW+hG...

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Abstract

The present invention relates to a protein binding to GARP in the presence of TGF-β and uses thereof.

Description

RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Application No. 62 / 111,429, filed on Feb. 3, 2015, the contents of which are hereby incorporated herein by reference in their entirety. This application is also a continuation-in-part of U.S. Non-Provisional application Ser. No. 14 / 908,368, filed on Jan. 28, 2016, which is a 371 of International Patent Application No. PCT / EP2014 / 066650, filed Aug. 1, 2014, which claims priority to EP Patent Application No. 14167425.9 filed May 7, 2014, EP Patent Application No. 13178958.8 filed Aug. 1, 2013 and U.S. Provisional Patent Application No. 61 / 861,008 filed Aug. 1, 2013. The contents of each of these related applications are hereby incorporated by reference in their entireties.FIELD OF INVENTION[0002]The present invention relates to human anti-GARP protein that inhibits TGF-β signaling. The present invention also relates to the treatment of immune disorders and diseases such as cancer.BACKGROUND OF INVENTION[0...

Claims

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Application Information

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IPC IPC(8): C07K16/28A61K39/395A61K45/06C07K16/22
CPCC07K16/2863C07K16/22A61K39/39558A61K45/06C07K2317/55C07K2317/76C07K2317/33A61K2039/505C07K2317/34A61P9/00A61P9/10A61P25/00A61P29/00A61P31/00A61P35/00A61P37/04C07K16/28C07K16/2875C07K16/30C07K2317/22C07K2317/24C07K2317/31C07K2317/32C07K2317/41C07K2317/515C07K2317/54C07K2317/565C07K2317/569C07K2317/622C07K2317/624C07K2317/626C07K2317/92
Inventor LUCAS, SOPHIEVAN DE WONING, SEBASTIANSAUNDERS, MICHAELDE HAARD, HANSDE BOECK, GITTECOULIE, PIERRE
Owner ARGENX BVBA
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