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

An autoantibody, phospholipase technology, applied in biochemical equipment and methods, NGF-receptor/TNF-receptor superfamily, chemical instruments and methods, etc., can solve the problem of recurrence, disease recurrence, and lack of specificity of B cells. And other issues

Pending Publication Date: 2021-02-02
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since these treatments lack specificity for autoreactive B cells that produce serum anti-PLA2R antibodies, they may be associated with a risk of life-threatening infections
In addition, relapses may occur in patients in remission of proteinuria, and disease may 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

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0467] Four PLA2R constructs representing different domains of PLA2R were cloned into the CAAR expression system (4025.C, 4026.CF1, constructs 4027.CF12 and 4028.CF123). exist figure 1 A general schematic of the extracellular domain of PLA2R of particular interest in the present invention is illustrated in . The N-terminal domain is an immunodominant epitope recognized by patient serum antibodies. The CysR and CTLD3 domains interact to form a loop structure that can better present immunodominant epitopes; thus a construct comprising the CysR to CTLD3 domain was generated. In addition to the cysteine-rich domain, immunoreactivity of serum antibodies to C-type lectin domains 1 and 7 has also been reported.

[0468] exist Figures 2A-2G The PLA2R CAAR construct is illustrated in . All constructs use the CD8 transmembrane domain and the BBZ intracellular domain and differ in their extracellular composition.

[0469] Construct 4025.C consists of a cysteine-rich extracellular d...

Embodiment 2

[0480] Six additional PLA2R CAAR constructs were designed and generated herein. Construct C consists of a cysteine-rich domain, a CD8 hinge region, a CD8 transmembrane domain, a 4-1BB intracellular domain, and a CD3ζ signaling domain ( Figure 2A , SEQ ID NO: 25 & 26).

[0481] Construct CF1 consists of an extracellular domain including a cysteine-rich domain, a fibronectin II domain and a C-type lectin 1 domain. Construct CF1 also includes CD8 hinge region, CD8 transmembrane domain, 4-1BB intracellular domain and CD3ζ signaling domain ( Figure 2B , SEQ ID NO: 27 & 28).

[0482] Construct CF123 consists of an extracellular domain including 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 composition. Also included in the construct CF123 are the GS linker, CD8 transmembrane domain, 4-1BB intracellular domain, and CD3ζ signaling domain ( Figure 2C , SEQ ID NO: 29 & 30).

[0483] Construct CF...

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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

[0001] Cross References to Related Applications [0002] This application benefits under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 665,863, filed May 2, 2018, which is incorporated herein by reference in its entirety. Background technique [0003] Membranous nephropathy (MN) is one of the most common major causes of nephrotic syndrome in adults (up to one third of cases). About 15-25% of MN cases are secondary MN caused by drugs, infection, tumor or immune disease. The remaining 75-85% of MN cases are idiopathic, also known as primary MN. MN is caused by the formation of immune complexes in the glomeruli. Immune complexes are formed by the binding of antibodies to antigens on podocytes. Immune complexes act as activators that trigger complement-mediated lysis of glomerular epithelial cells and the release of proteases and oxidants that damage capillary walls. Up to 40% of patients with primary membranous nephropathy who do not receive immunosuppressiv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61K35/17A61K45/06C07K16/30C12N15/85
CPCC12N5/0636C12N2510/00C07K14/7051A61K48/005C12N2740/16043A61K39/0008A61P37/06A61P13/12C07K14/7056C07K14/70517C07K14/70578C07K2319/03C07K2319/40C07K14/70503C07K2319/70C07K2317/34A61K39/4611A61K39/464402A61K39/4631C12N15/62C07K14/705C12N15/85A61K48/00A61K39/0005A61K45/06C07K2319/02A61K35/17
Inventor S·吉尔J·霍根A·S·佩恩B·王
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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