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Compositions and methods of phospholipase a2 receptor chimeric autoantibody receptor t cells

a technology of phospholipase a2 receptor and chimeric autoantibody, which is applied in the direction of drug composition, immunology disorders, peptides, etc., can solve the problems of life-threatening infections, disease can recur, and relapse, and achieves high affinity for autoantibody-based bcrs, limited toxicity to healthy cells, and induces killing of b cells

Pending Publication Date: 2021-04-01
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a cell that can target and kill B cells that produce autoantibodies, while being safe towards healthy cells. This is achieved by expressing a specific molecule called a CAAR on the cell surface. The technical effect is a more precise and targeted treatment for autoimmune diseases.

Problems solved by technology

However, since these treatments lack specificity for the autoreactive B cells that produce the serum anti-PLA2R antibody, they can be associated with risk of life-threatening infections.
Moreover, relapse can occur in patients who achieve remission in proteinuria, and disease can recur after kidney transplantation.

Method used

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  • Compositions and methods of phospholipase a2 receptor chimeric autoantibody receptor t cells
  • Compositions and methods of phospholipase a2 receptor chimeric autoantibody receptor t cells
  • Compositions and methods of phospholipase a2 receptor chimeric autoantibody receptor t cells

Examples

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experimental examples

[0232]The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0233]Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

[0234]The Materials and Methods used in the performance of the experiments disclose...

example 1

[0257]Four PLA2R constructs representing different domains of the PLA2R were cloned into a CAAR expression system (4025.C, 4026.CF1, Construct 4027.CF12 and 4028.CF123). The general schematics of the extracellular domains of PLA2R of particular interest in the invention are illustrated in FIG. 1. The N terminal domain is an immunodominant epitope that is recognized by patient serum antibodies. The CysR and CTLD3 domain interact to form a ring-like structure that may better present immunodominant epitopes; hence constructs including the CysR through CTLD3 domains were generated. In addition to the cysteine-rich domain, serum antibody immunoreactivity to the C-type lectin domains 1 and 7 has also been reported.

[0258]The PLA2R CAAR constructs illustrated in FIGS. 2A-2G. All constructs use the CD8 transmembrane domain and BBZ intracellular domain and differ in their extracellular composition.

[0259]Construct 4025.C was comprised of a cysteine rich extracellular domain, a CD8 hinge region...

example 2

[0269]Six additional PLA2R CAAR constructs were designed and generated herein. Construct C was comprised of a cysteine rich domain, a CD8 hinge region, a CD8 transmembrane domain, a 4-1BB intracellular domain and CD3 zeta signaling domain (FIG. 2A, SEQ ID NOs: 25 & 26).

[0270]Construct CF1 was comprised of an extracellular domain comprising a cysteine rich domain, a fibronectin II domain, and a C-type lectin 1 domain. Construct CF1 also included a CD8 hinge region, a CD8 transmembrane domain, a 4-1BB intracellular domain and CD3 zeta signaling domain (FIG. 2B, SEQ ID NOs: 27 & 28).

[0271]Construct CF123 was comprised of an extracellular domain comprising a cysteine rich domain, a fibronectin II domain, a C-type lectin 1 domain, a C-type lectin 2 domain, and a C-type lectin 3 domain. Also included in construct CF123 was a GS linker, a CD8 transmembrane domain, a 4-1BB intracellular domain and CD3 zeta signaling domain (FIG. 2C, SEQ ID NOs: 29 & 30).

[0272]Construct CF1237 was comprised ...

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Abstract

The invention includes compositions comprising at least one chimeric autoantibody receptor (CAAR) specific for an anti-phospholipase A2 receptor (PLA2R) autoantibody-based B cell receptor, polynucleotides encoding the CAAR, vectors comprising a polynucleotide encoding the CAAR, and recombinant T cells comprising the CAAR. The invention also includes methods of making a genetically modified cell, e.g., a genetically modified T cell, expressing a PLA2R-CAAR wherein the expressed CAAR comprises a PLA2R extracellular domain.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]The present application is entitled to priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 665,863 filed May 2, 2018, which is hereby incorporated by reference in its entirety herein.BACKGROUND OF THE INVENTION[0002]Membranous nephropathy (MN) is among the most common primary causes of nephrotic syndrome in adults (up to one-third of cases). About 15-25% of membranous nephropathy cases are secondary membranous nephropathy, caused by drugs, infections, tumors, or immune diseases. The remaining 75-85% of membranous nephropathy cases are idiopathic, also called primary membranous nephropathy. MN is caused by immune complex formation in the glomerulus. The immune complexes are formed by binding of antibodies to antigens on the podocyte. The immune complex serves as an activator that triggers complement-mediated lysis of glomerular epithelial cells and the release of proteases and oxidants damaging capillary walls. U...

Claims

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Application Information

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IPC IPC(8): C07K14/705C07K14/725A61K35/17
CPCC07K14/7056C07K14/70517C07K14/70578C07K2319/02A61K35/17C07K2319/03C07K14/7051C12N5/0636C12N2510/00A61K48/005C12N2740/16043A61K39/0008A61P37/06A61P13/12C07K2319/40C07K14/70503C07K2319/70C07K2317/34A61K39/4611A61K39/464402A61K39/4631C12N15/62C07K14/705C12N15/85A61K48/00A61K39/0005A61K45/06
Inventor GILL, SAARHOGAN, JONATHANPAYNE, AIMEE S.WANG, BAOMEI
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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