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Cd79-specific chimeric antigen receptor

A chimeric antigen receptor and CD79 technology, which is used to target specific cell fusion, receptor/cell surface antigen/cell surface determinants, specific peptides, etc., can solve the problem of decreased density of CD22 sites

Pending Publication Date: 2020-12-22
AUTOLUS LIMIED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a clinical trial using a CD22 CAR showed that although a complete response was initially observed in 73% of patients, relapse was observed after 6 months, which was associated with decreased CD22 site density

Method used

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  • Cd79-specific chimeric antigen receptor
  • Cd79-specific chimeric antigen receptor
  • Cd79-specific chimeric antigen receptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0746] Example 1: Production of single domain antibodies specific for CD79a or CD79b

[0747] To generate single domain antibodies (dAbs) specific for CD79a or CD79b, llamas were immunized with combinations of CD79a or CD79b derived peptides and DNA.

[0748] Sera were isolated from immunized animals before and after each immunization to follow the immune response to the immunogen.

[0749] Approximately 200 ml of blood samples were taken from the immunized alpacas and centrifuged through a Ficoll discontinuous gradient to obtain an enriched lymphocyte population. Total RNA was isolated from these cells by acid guanidinium thiocyanate extraction. Following first-strand cDNA synthesis, DNA fragments encoding the variable segment of the heavy chain and part of the long or short hinge region are amplified by PCR. The amplified pool of single domain antibody sequences was digested with restriction enzymes PstI and NotI and ligated into the phagemid vector pSOS11.

[0750]Afte...

Embodiment 2

[0752] Example 2: Generation of dAbs specific for CD79a or CD79b CAR

[0753] A second generation CAR was designed with 41BB and CD3 zeta endodomains and an antigen binding domain comprising an anti-CD79a or anti-CD79b dAb as described in Example 1. Primary human T cells from normal donors were transduced with retroviral vectors expressing the anti-CD79 CAR or an irrelevant EGFRvIII CAR as a negative control. The ability of cells to kill CD79-expressing target cells was studied using flow cytometry.

[0754] T cell proliferation was measured after 72 hours of co-culture, and the release of cytokines such as IFNγ and IL-2 was measured after 24 hours of co-culture with CD79-expressing target cells.

Embodiment 3

[0755] Example 3: Using CD79 CAR for Antigen Negative Escape

[0756] NALM6 cells (i.e., B-ALL cell line) were engineered into different clones by retroviral transduction and CrispR / Cas9 editing to obtain the following phenotypes:

[0757] - CD19+CD22+CD79+, or

[0758] - CD19+CD22-CD79+, or

[0759] - CD19-CD22+CD179+, or

[0760] - CD19-CD22-CD79+.

[0761] These clones were also engineered to express firefly luciferase.

[0762] NSG mice were implanted with wild-type NALM6 cells, the above clones or their mixtures by tail vein injection. Mice were administered human T cells transduced to express CD19 CAR, CD22 CAR, CD19OR CD22 CAR or CD19 OR CD22OR CD79 CAR by tail vein injection. Xenograft responses to CAR T cells were initially determined by bioluminescent imaging. Mice were sacrificed at fixed time points and the residual NALM6 population was studied by flow cytometry.

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Abstract

The present invention provides a chimeric antigen receptor (CAR) which specifically binds CD79. It further provides a nucleic acid sequence and a vector encoding said CAR. It further provides a cell which expresses said CAR at the cell surface.

Description

[0001] field of invention [0002] The present invention relates to chimeric antigen receptors (CARs) that specifically bind cluster of differentiation 79 (CD79). Cells and agents useful in the treatment of B cell malignancies are also contemplated. [0003] Background of the invention [0004] Several immunotherapeutic agents have been described for cancer treatment, including therapeutic monoclonal antibodies (mAbs), immunoconjugated mAbs, radioconjugated mAbs, and bispecific T cell engagers. Typically, these immunotherapeutics target a single antigen: for example, Rituximab targets CD20; Myelotarg targets CD33; and Alemtuzumab targets CD52. [0005] Chimeric antigen receptors are proteins that, in their usual form, graft the specificity of monoclonal antibodies (mAbs) to the effector functions of T cells. They generally take the form of type I transmembrane domain proteins with an antigen-recognizing amino-terminus, a spacer, and a transmembrane domain, all linked to compl...

Claims

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Application Information

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IPC IPC(8): A61P35/02A61K48/00A61K35/17C07K16/28
CPCA61K48/005C07K16/2896C07K2319/33A61P35/02C12N15/902C12N2740/10043C12N5/0636A61K2239/13A61K39/464411A61K2239/31A61K39/464412A61K39/4631A61K39/464413A61K39/4611A61P35/00A61K35/17A61K38/00C07K14/7051C07K16/2803C12N15/625C12N15/86
Inventor M.普勒S.科尔多巴S.托马斯S.奥诺哈M.费拉里
Owner AUTOLUS LIMIED
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