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Tn-muc1 chimeric antigen receptor (CAR) t cell therapy

A chimeric antigen receptor, antigen technology, applied in the direction of antibody medical components, NGF-receptor/TNF-receptor superfamily, receptors/cell surface antigens/cell surface determinants, etc.

Pending Publication Date: 2021-11-16
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most importantly, most of the identified and best studied tumors express cell surface antigens that are also expressed by normal tissues, which leads to non-specific targeting of CAR T cells (off-target activity)
Second, solid tumors often have an immunosuppressive tumor microenvironment that may inhibit the activity of CAR T cells once the cells reach the tumor and recognize the antigen
Third, the persistence of antitumor responses is highly correlated with the persistence of adoptively-transferred cells, and the optimal persistence of CAR T cells in solid tumors has not yet matched the persistence observed in hematopoietic malignancies. sexual match

Method used

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  • Tn-muc1 chimeric antigen receptor (CAR) t cell therapy
  • Tn-muc1 chimeric antigen receptor (CAR) t cell therapy
  • Tn-muc1 chimeric antigen receptor (CAR) t cell therapy

Examples

Experimental program
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Effect test

Embodiment 1

[0645] Example 1: Gene expression analysis of MUC1 and associated glycosyl transferase in breast cancer - breast cancer sample TCGA gene expression analysis

[0646]One known mechanism for abnormal O-glycosylation on the surface of the tumor is a mutation or apparent genetic silence of the associated glycosyl transferase, but also proposes another mechanism: excessive expression of glycin, such as MUC1, thus Sato the cytochrome machine. The study of TN-MUC1 expression analysis in breast cancer is initiated by interrogating whether MUC1 or any direct O-glycosyltransferase (and molecular companion protein C1Galt1c1) has different gene expression in group samples of TCGA. . When the patient is layered according to the race, lymph node, transfer state, or the overall cancer phase, the gene expression is not different (all P> 0.05). The expression of MUC1 varies from tumor phase, of which T1 and T2 tumors are expressed below T3 and T4 tumor expression (P <0.001). In addition to the T...

Embodiment 2

[0647] Example 2: MUC1 and associated glycosyl transferase in breast cancer cell line and matching normal and breast cancer tissue Genetic expression analysis in the product

[0648] The gene expression of MUC1 and associated O-glycosyl transferase was analyzed in several commercially available breast cancer cell lines having different HR or HER2 expression states. The MCF10A is an HR-non-invasive breast epithelial cell line. MCF7 is HR + Her2 - Breast cancer cell line. BT20, MDA-MB-231 and MDA-MB-453 are HR-HER2-breast cancer cell lines. All B3GNT6 (MFC 0.04), C1Galt1 (MFC 0.07) and C1Galt1C1 (0.44) of C1Galt1 (0.44) were low, and MUC1 (142.85) and ST6Galnac1 (61.06) were highly expressed. Figure 2A This is consistent with the two mechanisms of abnormal O-glycan expression. Similarly, the B3GNT6 (MFC 0.16) of breast tumor samples is low and the expression of MUC1 (MFC 31.62) is high compared to matching normal breast tissue. Figures 7A-7C . C1Galt1 (MFC 0.93), C1Galt1C1 (MFC 0....

Embodiment 3

[0649] Example 3: TN-MUC1 glycosyl epitope specifically expressed in breast cancer rather than in adjacent normal breast tissue Specific expression - Immunohistochemistry (IHC) analysis in normal and malignant breast tissue

[0650] Use 5E5 anti-TN-MUC1 antibody to quantify TN-MUC1 sugar graphs by IHC ( Figure 3A with 3B . There is a normal adjacent breast tissue in 7 in 52 breast tumor tissue slices. Tumor epithelial cells were strongly dyed by TN-MUC1, while adjacent normal breast epithelial cells were lacking on TN-MUC1 staining or under a significantly lower H fraction. The average H fraction of tumor tissue was 183.8 ± 95.7, and the average H fraction of normal breast tissue was 34.9 ± 32.8 (P 0.05).

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Abstract

Various TnMUC1-specific chimeric antigen receptors (CARs), nucleic acids encoding the same, and methods of using the same, are provided. Compositions and methods comprising a TnMUC1-specific CAR for treating MUC1-associated cancer in a subject in need thereof are provided.

Description

[0001] Cross-reference related application [0002] The priority of US Temporary Patent Application No. 62 / 824, 532, filed on July 31, 2019, this application, according to 35 USC §119 (E), is submitted to the US Temporary Patent Application No. 62 / 824, 532, and July 31, 2019. All content is incorporated herein by reference. [0003] technical background [0004] The chimeric antigen receptor (Car) T cell is modified by the gene to identify the specific tumor-associated antigen and then kill the effects of immune cells of tumor cells. Although the success of Car T therapy has led to approving blood system malignant tumors, Car T therapy is still uncertain in treating solid tumors (such as breast cancer). Car T Therapy has several obstacles in solid tumors. Most importantly, most of the identified and studied the cell surface antigen expressed by the most sufficient tumor is also expressed by normal tissue, which results in non-specific targeting (delative activity) of CAR T cells. Se...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/30A61K35/17C12N5/078
CPCA61K31/7076A61P35/00A61K31/675C07K14/7051C07K14/70578C07K14/70507C07K14/70517C07K2319/00C07K2319/02C07K2319/03C07K2319/33C07K16/3092C07K2317/622A61K39/4631A61K2239/55A61K39/4611A61K2239/38A61K2239/31A61K2239/54A61K39/46447A61K39/464412A61K2239/49A61K2239/59A61K2239/48A61K2300/00A61K35/17C07K14/70596A61K45/06
Inventor A·D·波西C·H·祝恩
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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