Targeted immunotolerance

A technology targeting parts and immune cells, applied in immunoglobulin, targeting specific cell fusion, allergic diseases, etc., can solve side effects and other problems

Pending Publication Date: 2020-04-14
PANDION THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In both cases, broadly active immunosuppressive drugs used against pathogenic immune responses have severe side effects

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1076] Example 1: Agonizing HLA-targeted PD-1 of therapeutic compounds.

[1077] Engineering of PD-1 Agonist Therapeutics Targeting HLA

[1078] Binding domains specific for HLA-A2 were obtained by cloning the variable regions of Ig heavy and light chains from BB7.2 hybridoma (ATCC) and converting into single chain Ab (scFv). The activity and specificity of the scFv can be confirmed by assessing the binding of BB7.2 to cells expressing HLA-A2 compared to cells expressing other HLA-A alleles. The minimal PD-L1 residues required for PD-1 binding activity were identified by systematically evaluating the 3′ and 5′ amino acid requirements of the PD-L1 IgV domain corresponding to amino acids 68–114. The expression construct was designed, and the protein was synthesized and purified, and the PD-1 binding activity was tested by Biacore. The minimum essential amino acids required for PD-1 binding by the PD-L1 IgGV domain are referred to as PD-L1-IgV. To generate BB7.2 scFv and PD-L1...

Embodiment 2

[1082] Example 2: CD39 and / or CD73 as effector domains generate purinergic halides surrounding target cell types or tissues

[1083] Catalytically active fragments of CD39 and / or CD73 are fused to the targeting domain. After binding and accumulation at the target site, CD39 phosphohydrolyzes ATP to AMP. After binding and accumulation at the target site, CD73 dephosphorylates extracellular AMP to adenosine. Soluble catalytically active forms of CD39 suitable for use herein have been found to circulate in human and murine blood, see eg Yegutkin et al. FASEB J. 2012 Sep;26(9):3875-83. Soluble recombinant CD39 fragments are also described in Inhibition of platelet function by recombinant soluble ecto-ADPase / CD39, Gayle, et al., J Clin Invest. 1998 May 1;101(9):1851-1859. Suitable CD73 molecules include soluble forms of CD73 that can be shed from endothelial cell membranes by proteolytic cleavage or by hydrolysis of the GPI anchor by shear stress, see e.g. Refs: Yegutkin G, Bodin...

Embodiment 3

[1085] Example 3: Measuring antibody-induced PD-1 signaling.

[1086] Jurkat cells stably express 2 constructs, 1) human PD-1 polypeptide fused to b-galactosidase, which can be referred to as "enzyme donor"; and 2) SHP fused to b-galactosidase -2 polypeptides, which may be referred to as "enzyme receptors". PD-1 antibodies are contacted with cells, and when PD-1 is engaged, SHP-2 is recruited to PD-1. The enzyme acceptor and enzyme donor form a fully active b-galactosidase that can be assayed. This assay can be used to show the activation of PD-1 signaling.

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PUM

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Abstract

Methods and compounds for conferring site-specific or local immune privilege.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 510,586, filed May 24, 2017, U.S. Provisional Application No. 62 / 510,816, filed May 25, 2017, U.S. Provisional Application No. 62 / 558,175, filed September 13, 2017 and priority to U.S. Provisional Application No. 62 / 595,352 filed December 6, 2017, each of which is hereby incorporated by reference in its entirety. technical field [0003] Embodiments provided herein relate, for example, to methods and compositions for local or targeted immune immunity. Background technique [0004] Examples of unwanted immune responses (eg, as in rejecting transplanted tissues or in autoimmune disorders) constitute a major health problem for millions of people worldwide. The long-term outcome of organ transplantation is often characterized by chronic rejection and eventual failure of the transplanted organ. More than two dozen autoimmune disorders are known, affecting virtual...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/20A61K39/395C07K14/55
CPCC07K16/2803C07K16/2818C07K16/2833A61K2039/505C07K2317/31C07K2317/52C07K2317/622C07K2317/64C07K2317/70C07K2317/73C07K2317/75C07K2319/00C07K2317/21C07K2319/75A61P37/06C07K14/55C07K2317/524C07K2317/71C07K2319/30C07K2319/33A61P1/04A61P29/00A61P31/12A61P3/10C07K16/2827C07K14/70532C07K19/00A61K38/00A61K39/3955C07K16/246C07K2317/30C07K2317/41
Inventor 乔安妮·L·瓦伊尼内森·希金森-斯科特
Owner PANDION THERAPEUTICS INC
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