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Cd22-specific t cell receptors and adoptive t cell therapy for treatment of b cell malignancies

A specific, host cell-based technology for use in immunotherapy to address relapse and other issues

Pending Publication Date: 2021-07-23
MAX DELBRUECK CENT FUER MOLEKULARE MEDIZIN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, downregulation of surface expression of the target antigen is a major limitation of all antibody-based strategies, including CARs.
Despite high cost, relapse occurs in at least 50% of treated patients

Method used

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  • Cd22-specific t cell receptors and adoptive t cell therapy for treatment of b cell malignancies
  • Cd22-specific t cell receptors and adoptive t cell therapy for treatment of b cell malignancies
  • Cd22-specific t cell receptors and adoptive t cell therapy for treatment of b cell malignancies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Example 1: Generation of CD22-specific TCRs

[0095] T cells were negatively selected against self-antigens in the thymus to avoid autoimmune disease. To obtain CD22-specific TCRs, we used mouse models transgenic for the human TCRα and TCR b loci (Li et al., 2010, Nat. Med. 16, 1029-35) and available for appropriate epitope expression. Human HLA-A*02:01 transgene to generate murine T cells. Following immunization by gene gun with non-cognate human CD22 cDNA, we obtained specific immune responses against CD22, which were tested by co-culturing blood or splenocytes with NIH3T3 cells expressing human HLA-A2 and CD22. Further assessment of reactive T cells using a peptide library spanning CD22 and in silico predicted nonamers revealing the specificity of the peptide. Hassan et al. also described this epitope and eluted it from LCL (2013, MolCell Proteomics 12(7), 1829-43). The TCRs described here were isolated from mice inoculated four times with full-length CD22 DNA gen...

Embodiment 2

[0096] Example 2: CD22 TCR confers reactivity to CD22 expressing cell lines and primary tumor cells.

[0097] CD22 TCR reactivity was tested against recombinant and native CD22 expressing cells. Following TCR transduction, human peripheral blood lymphocytes (hPBL) were co-matched with two renal cell carcinoma cell lines expressing the full-length form of CD22 or a truncated molecule that lacked the transmembrane and intracellular sequences but still contained the epitope co-cultivate. The second version of CD22 is expressed only inside the cell. After 18-20 hours, the supernatants of the co-cultures were tested for secreted IFNγ by ELISA. CD22 TCR-transduced hPBL recognized two renal cell carcinoma cell lines expressing CD22 in full length or in the intracellular form ( figure 2 a). To further test the recognition of cells that naturally express CD22, CD22 TCR-transduced hPBLs were co-cultured with a panel of B cell lines from different malignancies ( figure 2 b-d). Ex...

Embodiment 3

[0099] Example 3: CD22 TCR delays tumor growth in a xenograft mouse model

[0100] To test the ability of CD22 TCR-transduced hPBL to kill tumor cells in vivo, NOG mice were injected with the pre-ALL B cell line Nalm6 transduced with firefly luciferase and the isogenic marker CD90.1, and four days later treated with hPBL deal with. Tumor growth was measured by firefly luciferase signaling, and blood was analyzed for the isogenic marker CD90.1 expressed by tumor cells as well as transferred T cells by CD8 and TCRvβ chain staining. CD22 TCR-transduced hPBL-transferred mice had a median survival of 53±7 days, while untreated or untransduced hPBL-transferred mice survived only 30±3 days or 28±0 days, respectively ( Figure 4 ).

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Abstract

The present invention is directed to the field of immunotherapy, in particular, adoptive T cell therapy or T cell receptor (TCR) gene therapy of cancer, in particular, of B cell lymphoma or B cell leukemia. The invention provides a nucleic acid encoding TCR alpha or beta chain constructs of TCR constructs capable of specifically binding to a peptide of SEQ ID NO: 1, derived from the lineage specific antigen CD22, in the context of HLA-A2 and to subsequently lyse CD22-positive cells. The invention further provides a corresponding protein and host cell, e.g., a CD8+ T cell, pharmaceutical compositions comprising the same, and therapeutic use for treatment of B cell lymphoma or B cell leukemia, such as diffuse large B-cell lymphoma (DLBCL).

Description

technical field [0001] The present invention relates to the field of immunotherapy, in particular adoptive T cell therapy or T cell receptor (TCR) gene therapy for cancer. The present invention provides a nucleic acid encoding at least one TCR alpha or TCR beta chain construct of a TCR construct capable of interacting with a B-cell lineage-specific antigen derived in the context of HLA-A*02:01 The peptide represented by SEQ ID NO: 1 of CD22 specifically binds. The present invention also provides corresponding proteins expressing said TCR construct and host cells (preferably CD8 + T cells), and the medical use of such nucleic acids, proteins or host cells, especially in the prevention and / or treatment of CD22-positive B-cell lymphoma or B-cell leukemia, so that CD22-positive cell surface and Expressed in the cytoplasm. Background technique [0002] B cell-derived tumors remain one of the leading causes of death in the Western world. In Germany, approximately 1,500-2,000 n...

Claims

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Application Information

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IPC IPC(8): C07K14/725C07K16/30
CPCC07K14/7051C07K16/30C07K2317/565A61P35/00A61K38/00C07K14/70596C07K14/71
Inventor T·布兰肯斯坦A·佩祖托S·莱茵
Owner MAX DELBRUECK CENT FUER MOLEKULARE MEDIZIN
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