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Claudin-18.2-specific immunoreceptors and T cell epitopes

A cell and cell receptor technology, applied in receptor/cell surface antigen/cell surface determinant, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, for targeting specific cell fusion, etc. Able to solve problems that have not been described, not known, etc.

Active Publication Date: 2018-04-24
BIONTECH CELL & GENE THERAPIES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to date, HLA-A*2-restricted CLDN18.2 T-cell epitopes and T-cell receptors or CARs targeting CLDN18.2 have not been described, and there is no known use of active or passive immunization methods by involving T-cells. Whether immunotherapy can target cancer cells expressing CLDN18.2 in vivo

Method used

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  • Claudin-18.2-specific immunoreceptors and T cell epitopes
  • Claudin-18.2-specific immunoreceptors and T cell epitopes
  • Claudin-18.2-specific immunoreceptors and T cell epitopes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0435] Example 1: Materials and methods

[0436] Cell Lines and Reagents

[0437] The human chronic myeloid leukemia cell line K562 (Lozzio, C.B. & Lozzio, B.B (1975), Blood 45, 321-334) stably transfected with HLA-A*0201 and used for TCR validation assays was cultured under standard conditions (Britten, C.M. et al. (2002), J. Immunol. Methods 259, 95-110) (referred to eg as K562-A2). The primary human neonatal foreskin fibroblast cell line CCD-1079Sk (ATCC No. CRL-2097) was cultured according to the manufacturer's instructions.

[0438] Peripheral blood mononuclear cells (PBMC), monocytes and dendritic cells (DC)

[0439] PBMCs were isolated from buffy coats by Ficoll-Hypaque (Amersham Biosciences, Uppsala, Sweden) density gradient centrifugation. HLA alleles were determined by PCR standard methods. Monocytes were enriched with anti-CD14 microbeads (MiltenyiBiotech. Bergisch-Gladbach, Germany). Immature DCs (iDCs) were obtained by differentiating monocytes in medium supp...

Embodiment 2

[0481] Example 2: Isolation of a high-affinity HLA-A*02-restricted murine TCR specific for claudin 18.2

[0482] We verified the immunogenic potential of CLDN18.2 in A2 / DR1 mice by repeated intranodal immunizations with IVT-RNA encoding amino acids 1-80 of CLDN18.2. The human CLDN18 gene has 2 alternative first exons, resulting in 2 protein isoforms (CLDN18.1 and CLDN18.2) that differ by 69 amino acids at the N-terminus ( Figure 4 A). Since CLDN18.1 is also expressed in normal tissues, especially the lung, we only used the N-terminal part of CLDN18.2 in order to exclusively induce CLDN18.2-specific T cell reactivity. We used splenocytes from these mice for isolation of CLDN18.2-specific T cells and subsequent cloning of the corresponding TCR genes. Splenocytes from immunized mice that successfully induced CLDN18.2-specific T cells were analyzed and analyzed ex vivo for reactivity to predicted HLA-A*02-binding CLDN18.2 peptides by an IFNγ-ELISPOT assay ( Figure 5 ).

[04...

Embodiment 3

[0487] Example 3: Generation and in vitro validation of claudin-18.2 specific CAR

[0488] We produced a second-generation CAR targeting CLDN18.2, which contains the signaling and co-stimulatory portions of CD3ζ and CD28, respectively. Deletion of the lck-binding moiety in the intracellular structure of CD28 abolishes IL2 secretion upon CAR engagement to prevent induction of regulatory T cells (Kofler D.M. et al., (2011) Molecular Therapy 19(4), 760–767). Modification of the IgG1 Fc "spacer region" domain in the extracellular part of the CAR avoids "off-target" activation and unintended initiation of innate immune responses (Hombach A. et al., (2010) Gene Therapy 17, 1206–1213 ).

[0489] To analyze the specific lysis of CLDN18.2-expressing target cells by CLDN18.2-CAR T cells, a luciferase-based cytotoxicity assay was performed. CD8+ T cells were preactivated and CD8+ T cells were transfected with IVT-RNA encoding CLDN18.2-CAR or CLDN6-specific CAR (as control). Surface ex...

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Abstract

The present invention provides Claudin-18.2-specific immunoreceptors (T cell receptors and artificial T cell receptors (chimeric antigen receptors; CARs)) and T cell epitopes which are useful for immunotherapy.

Description

[0001] invention technical field [0002] The present invention relates to the provision of claudin-18.2 (Claudin-18.2) specific immune receptors (T cell receptors and artificial T cell receptors (chimeric antigen receptors; CAR)) and T cell epitopes useful for immunotherapy. Background of the invention [0003] The evolution of the immune system has resulted in vertebrates in highly efficient networks based on two types of defense: innate and adoptive immunity. [0004] In contrast to the evolved ancient innate immune system, which relies on invariant receptors that recognize common molecular patterns associated with pathogens, adoptive immunity is based on a high degree of Specific antigen receptor and clone selection. [0005] Whereas B cells enhance the humoral immune response by secreting antibodies, T cells mediate cellular immune responses that lead to the destruction of the recognized cells. [0006] In humans and animals, T cells play a central role in cell-mediated...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K14/725C07K7/06C07K14/47A61P35/00
CPCC07K14/70539C07K14/7051C07K16/28C12N5/0636A61K39/0011A61P35/00A61P37/04C07K2317/34C07K2317/56C07K2317/565C07K2317/622C07K2317/73C07K2317/76C07K2319/02C07K2319/03C07K2319/035C07K2319/30C07K2319/33A61K2039/575A61K2039/572A61K39/4611A61K39/4631A61K39/464402A61K39/4632C07K7/06C07K14/70521C07K16/18A61K2039/5158C07K14/705
Inventor 尤格·萨因欧兹兰·图勒茨皮特拉·西蒙塔纳·奥莫科科安德里亚·布莱特克洛伊茨卡罗利娜·安娜·姆罗兹利萨·赫比驰
Owner BIONTECH CELL & GENE THERAPIES
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