Chimeric antigen receptors targeting b-cell maturation antigen

A technology of B cells and cells, which is applied in the field of CAR that specifically binds mature antigens of B cells, malignant cell-related diseases, treatment of B cell lymphoma and leukemia, and transformation of immune cells to express BCMA-specific CAR on their surface, which can solve the problem Drug resistance and other issues

Active Publication Date: 2018-05-01
PFIZER INC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, multiple myeloma remains incurable and almost all patients develop resistance to these drugs and eventually relapse

Method used

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  • Chimeric antigen receptors targeting b-cell maturation antigen
  • Chimeric antigen receptors targeting b-cell maturation antigen
  • Chimeric antigen receptors targeting b-cell maturation antigen

Examples

Experimental program
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preparation example Construction

[0221] Provided herein are methods for preparing immune cells for immunotherapy. In some embodiments, the method comprises introducing a CAR according to the invention into immune cells and expanding the cells. In some embodiments, the present invention relates to a method for engineering immune cells, comprising: providing cells and expressing at least one CAR as described above on the surface of the cells. Methods of engineering immune cells are described, for example, in PCT Patent Application Publication Nos. WO / 2014 / 039523, WO / 2014 / 184741, WO / 2014 / 191128, WO / 2014 / 184744, and WO / 2014 / 184143, the entire contents of which are hereby incorporated by reference. into this article. In some embodiments, the method comprises: transfecting a cell with at least one polynucleotide encoding a CAR as described above, and expressing the polynucleotide in the cell.

[0222] In some embodiments, polynucleotides are present in lentiviral vectors for stable expression in cells.

[0223] ...

Embodiment 1

[0306] Example 1: Determination of Kinetics and Affinity of BCMA / Human IgG Interaction at 25°C and / or 37°C

[0307] This example measures the kinetics and affinities of various anti-BCMA antibodies at 25°C and 37°C.

[0308]All experiments were performed on a Bio-Rad Proteon XPR36 surface plasmon resonance biosensor (Bio-Rad, Hercules, CA). A batch of anti-BCMA antibodies was prepared using the amine coupling method on a Bio-Rad GLC sensor chip similar to that described in Abdiche, et al., Anal. Biochem. 411, 139-151 (2011). The fixed analysis temperature was 25° C., and the running buffer was HBS-T+ (10 mM HEPES, 150 mM NaCl, 0.05% Tween-20, pH 7.4). Channels were activated in the analyte (horizontal) direction by injecting a mixture of 1 mM ECD and 0.25 mM NHS at a flow rate of 30 μL / min for 3 minutes. IgG was immobilized on the activation site by injecting 20 μg / ml IgG in 30 μg / ml 10 mM acetate buffer (pH 4.5) for 1.5 minutes in the ligand (perpendicular) direction. Th...

Embodiment 2

[0323] Example 2: BCMA-specific CAR-T cells

[0324] This example illustrates the functional activity of BCMA-specific CAR-T cells against BCMA-positive (BCMA+) tumor cells.

[0325] Among all BCMA-specific CAR molecules generated, 8 were selected for further activity testing based on affinity for BCMA, cross-reactivity between human BCMA and cynomolgus BCMA, and epitope. The CAR molecules tested included: P5A, P5AC1, P5AC16, PC1, PC1C12, COM22, P6DY, and P6AP. Three different constructs were designed: version 1 (v1) including the FcγRIIIα hinge, version 2 (v2) including the CD8α hinge, and version 3 (v3) including the IgG1 hinge. Chimeric antigen receptors (CARs) shown in Table 5 were prepared and used and evaluated for their degranulation activity on BCMA+ cells. The degranulation activity of each transiently expressed CAR was determined in human T cells.

[0326] Table 5: Exemplary BCMA-specific CARs

[0327]

[0328]

[0329]

[0330]

[0331]

[0332] ...

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Abstract

The invention provides Chimeric Antigen Receptors (CARs) that specifically bind to BCMA (B-Cell Maturation Antigen). The invention further relates to engineered immune cells comprising such CARs, CAR-encoding nucleic acids, and methods of making such CARs, engineered immune cells, and nucleic acids. The invention further relates to therapeutic methods for use of these CARs and engineered immune cells for the treatment of a condition associated with malignant cells expressing BCMA (e.g., cancer).

Description

field of invention [0001] The present invention relates to chimeric antigen receptors (CARs). CARs are able to exploit the properties of the ligand-binding domain to redirect the specificity and reactivity of immune cells to a selected target. In particular, the present invention relates to a CAR that specifically binds a B-cell maturation antigen (BCMA-specific CAR). The invention also relates to polynucleotides encoding BCMA-specific CARs and isolated cells expressing BCMA-specific CARs on their surface. The present invention also relates to a method for engineering immune cells to express BCMA-specific CAR on their surface. The invention is particularly beneficial for the treatment of B cell lymphomas and leukemias. The present invention also relates to immune cells comprising BCMA-specific CARs (BCMA-specific CAR-T cells), compositions comprising BCMA-specific CAR-T cells, and the use of the BCMA-specific CAR-T cells for treatment and expression of BCMA Methods for dis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00A61K35/17A61P37/04A61P35/00
CPCA61K35/17C07K14/7051C07K2317/565C07K2317/56C07K2319/03C07K2319/02C07K16/28C12N15/85C12N5/0636C12N5/0646A61P35/00C12N2510/02C07K2319/33A61K38/00C07K16/2878C07K14/70517C07K14/70578A61K31/7076A61K2039/505C07K2317/73C07K2317/92C07K2317/622A61P35/02A61P37/04A61K39/0011A61K2039/5156C12N5/10C07K2317/569C12N15/63C07K16/2896C07K16/2863C12N2510/00A61K39/4631A61K39/464417A61K39/46
Inventor T·C-C·国J·F·查帕罗里格斯B·J·萨苏R·加莱托B·A·博尔达伊保尔C·A·佐默T·J·范布拉尔科T·C·佩特尔A·拉吉帕尔P·迪沙托A·朱莱拉J·瓦尔顿
Owner PFIZER INC
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