Search

JP-2026076157-A - Human mesothelin chimeric antigen receptor and its use

JP2026076157AJP 2026076157 AJP2026076157 AJP 2026076157AJP-2026076157-A

Abstract

[Problem] To provide compositions and methods for treating diseases related to mesothelin expression. [Solution] The present invention relates to a method for providing an immune response in a patient by administering immune effector cells that have been engineered to express a chimeric antigen receptor (CAR) containing, for example, an antibody (e.g., scFv) that specifically targets mesothelin. In particular, the present invention relates to the use of immune effector cells, such as T cells or NK cells, engineered to express an antibody, for example, a CAR containing an antigen-binding fragment thereof, for treating cancers associated with the expression of mesothelin (or MSLN). [Selection Diagram] None

Inventors

  • グレゴリー・ビーティ
  • ボリス・エンヘルス
  • ニーラジャ・イダマカンティ
  • カール・エイチ・ジューン
  • アンドレアス・レーヴ
  • ソン・ホイジュエン
  • チーロン・ウー

Assignees

  • ノバルティス アーゲー
  • ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア

Dates

Publication Date
20260511
Application Date
20251224
Priority Date
20131219

Claims (20)

  1. an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR) comprising: i) an antibody or antibody fragment containing a human anti-mesothelin binding domain; ii) a transmembrane domain; and iii) an intracellular signal transduction domain containing a stimulating domain, wherein the anti-mesothelin binding domain comprises one or more light chain complementarity-determining regions 1 (LC CDR1), 2 (LC CDR2), and 3 (LC CDR3) containing the amino acid sequences listed in Table 5, and one or more heavy chain complementarity-determining regions 1 (HC CDR1), 2 (HC CDR2), and 3 (HC CDR3) containing the amino acid sequences listed in Table 4.
  2. The isolated nucleic acid molecule according to claim 1, comprising LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequence shown in Table 5.
  3. The isolated nucleic acid molecule according to claim 1, comprising HC CDR1, HC CDR2, and HC CDR3, each containing the amino acid sequence shown in Table 4.
  4. The isolated nucleic acid molecule according to claim 1, comprising LC CDR1, LC CDR2, and LC CDR3 containing the amino acid sequences listed in Table 5, and HC CDR1, HC CDR2, and HC CDR3 containing the amino acid sequences listed in Table 4.
  5. The isolated nucleic acid molecule according to claim 1, wherein the anti-mesothelin binding domain contains one of the amino acid sequences of the light chain variable region listed in Table 2.
  6. The isolated nucleic acid molecule according to claim 1, wherein the anti-mesothelin binding domain contains one of the amino acid sequences of the heavy chain variable region listed in Table 2.
  7. The isolated nucleic acid molecule according to claim 1, wherein the anti-mesothelin binding domain contains an amino acid sequence from any of the light chain variable regions listed in Table 2 and any of the heavy chain variable regions listed in Table 2.
  8. An isolated nucleic acid molecule according to any one of claims 1 to 7, wherein the anti-mesothelin binding domain is scFv.
  9. An isolated nucleic acid molecule according to any one of claims 1 to 8, wherein the anti-mesothelin binding domain includes an amino acid sequence having at least one, two, or three modifications to the amino acid sequence of the light chain variable region shown in Table 2, but the number of modifications does not exceed 30, 20, or 10, or a sequence having 95-99% identity with the amino acid sequence shown in Table 2.
  10. An isolated nucleic acid molecule according to any one of claims 1 to 9, wherein the anti-mesothelin binding domain includes an amino acid sequence having at least one, two, or three modifications to the amino acid sequence of the heavy chain variable region shown in Table 2, but the number of modifications does not exceed 30, 20, or 10, or a heavy chain variable region having 95-99% identity with the amino acid sequence shown in Table 2.
  11. An isolated nucleic acid molecule according to any one of claims 1 to 10, wherein the encoded anti-mesothelin binding domain comprises a sequence selected from the group consisting of SEQ ID NOs: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, and 62, or sequences having 95-99% identity with these.
  12. An isolated nucleic acid molecule according to any one of claims 1 to 11, wherein the nucleic acid sequence encoding the anti-mesothelin binding domain includes a sequence selected from the group consisting of SEQ ID NOs: 87; SEQ ID NOs: 88; SEQ ID NOs: 89; SEQ ID NOs: 90; SEQ ID NOs: 91; SEQ ID NOs: 92; SEQ ID NOs: 93; SEQ ID NOs: 94; SEQ ID NOs: 95; SEQ ID NOs: 96; SEQ ID NOs: 97; SEQ ID NOs: 98; SEQ ID NOs: 99; SEQ ID NOs: 100; SEQ ID NOs: 101; SEQ ID NOs: 102; SEQ ID NOs: 103; SEQ ID NOs: 104; SEQ ID NOs: 105; SEQ ID NOs: 106; SEQ ID NOs: 107; SEQ ID NOs: 108; SEQ ID NOs: 109; and SEQ ID NOs: 110, or sequences having 95-99% identity with these.
  13. An isolated nucleic acid molecule according to any one of claims 1 to 12, wherein the encoded CAR comprises a transmembrane domain containing a transmembrane domain of a protein selected from the group consisting of the alpha, beta, or zeta chain of a T cell receptor, and CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.
  14. An isolated nucleic acid molecule according to any one of claims 1 to 13, wherein the encoded transmembrane domain contains the sequence of SEQ ID NO: 6.
  15. An isolated nucleic acid molecule according to any one of claims 1 to 14, wherein the encoded transmembrane domain includes at least one, two, or three modifications to the amino acid sequence of SEQ ID NO: 6, but the number of modifications does not exceed 20, 10, or 5, or a sequence having 95-99% identity with the amino acid sequence of SEQ ID NO: 6.
  16. An isolated nucleic acid molecule according to any one of claims 1 to 15, wherein the nucleic acid sequence encoding the transmembrane domain includes the sequence of SEQ ID NO: 17 or a sequence having 95-99% identity thereto.
  17. An isolated nucleic acid molecule according to any one of claims 1 to 16, wherein the encoded anti-mesothelin-binding domain is connected to a transmembrane domain by a hinge region.
  18. The isolated nucleic acid molecule according to claim 17, wherein the encoded hinge region includes sequence number 2 or a sequence having 95-99% identity thereto.
  19. The isolated nucleic acid molecule according to claim 17, wherein the nucleic acid sequence encoding the hinge region includes the sequence of SEQ ID NO: 13 or a sequence having 95-99% identity thereto.
  20. Furthermore, an isolated nucleic acid molecule according to any one of claims 1 to 19, comprising a sequence encoding a co-stimulatory domain.

Description

This application claims priority under International Application PCT/CN2013/089979 filed December 19, 2013, International Application PCT/CN2014/082610 filed July 21, 2014, and International Application PCT/CN2014/090509 filed November 6, 2014, and incorporates the entire contents of each of these applications herein by reference. Field of Invention The present invention relates to T cells engineered to express a chimeric antigen receptor (CAR) for treating diseases generally associated with mesothelin expression. Background of the Invention Mesothelin was originally identified by Pastan et al. as a tumor-associated antigen because its expression is limited in normal tissues but overexpressed in tumors. Chang K, et al., Cancer Res. 1992;52(1):181-186 and Chang K, et al. Proc Natl Acad Sci USA. 1996;93(1):136-140. The mesothelin gene encodes a precursor 71 kDa protein, which, when processed, produces mesothelin, a 40 kDa protein fixed to the cell membrane by glycosylphosphatidylinositol (GPI) binding, and a 31 kDa amino-terminal detached fragment called megakaryocyte-enhancing factor (MPF). Both fragments contain an N-glycosylation site. A soluble splice variant of a 40 kDa carboxyl-terminal fragment, called "soluble mesothelin/MPF-related," has been found in the serum of patients with pancreatic ductal adenocarcinoma (PDA). Johnston, F, et al. Clinical Cancer Research. 2009;15(21):6511. Mesothelin is currently being studied as both a therapeutic target and a biomarker for disease activity and treatment response. Argani P, et al. Clin Cancer Res. 2001;7(12):3862-3868. Mesothelin is a differentiation antigen that is also present in normal tissues. Using the mouse anti-human mesothelin antibody K1 developed by Pastan's group, strong K1 reactivity, though at lower levels than typically seen in malignant tissues, has been detected in mesothelial cells lining the peritoneal cavity, pleural cavity, and pericardial cavity. Chang K, et al., Cancer Res. 1992;52(1):181-186. Weak K1 reactivity has been detected in the fallopian canal epithelium, tracheal basal epithelium, and tonsil epithelium. Mesothelin has also been found in all layers of the cornea. Jirsova K, et al. Experimental eye research. 2010;91(5):623-629. However, K1 responsiveness has not been detected in most normal tissues, including the liver, kidneys, spleen, bone marrow, lymph nodes, thymus, myocardium, tongue, skeletal muscle, skin, cerebral cortex, cerebellum, spinal cord, peripheral nerves, pituitary gland, adrenal gland, salivary gland, mammary gland, thyroid gland, parathyroid gland, testis, prostate, epididymis, cervical epithelium, lung parenchyma, esophagus, small intestinal epithelium, colonic epithelium, bladder epithelium, and gallbladder epithelium. Chang K, et al., Cancer Res. 1992;52(1):181-186. Mesothelin is overexpressed in most primary pancreatic adenocarcinomas, while its expression in benign pancreatic tissue is rare and weak. (Argani P, et al. Clin Cancer Res. 2001;7(12):3862-3868). Epithelial malignant pleural mesothelioma (MPM) invariably expresses mesothelin, but sarcomatoid MPM does not. Most serous epithelial ovarian cancers and associated primary peritoneal cancers express mesothelin. Mesothelin is a target of the innate immune response in ovarian cancer and has been proposed as a target for cancer immunotherapy. Bracci L, et al. Clin Cancer Res. 2007;13(2 Pt 1):644-653; Moschella F, et al. Cancer Res. 2011;71(10):3528-3539; Gross G, et al. FASEB J. 1992;6(15):3370-3378; Sadelain M, et al. NatRevCancer. 2003;3(1):35-45; Muul LM, et al. Blood. 2003;101(7):2563-2569; Yee C, et al. Proc Natl Acad Sci U S A. 2002;99(25):16168-16173. The presence of mesothelin-specific cytotoxic lymphocytes (CTLs) in patients with pancreatic cancer correlates with overall survival. Thomas AM, et al. J Exp Med. 2004;200:297-306. Furthermore, Pastan and collaborators used soluble antibody fragments of anti-mesothelin antibodies conjugated to an immunotoxin for the treatment of cancer patients with mesothelin-positive tumors. This approach demonstrated sufficient safety and some clinical activity in pancreatic cancer. Hassan R, et al. Cancer Immun. 2007;7:20 and Hassan R, et al. Clin Cancer Res. 2007;13(17):5144-5149. In ovarian cancer, this treatment strategy resulted in a minor response in one patient and stable disease in a second patient according to RECIST criteria, along with complete resolution of ascites. Chang K, et al., Cancer Res. 1992;52(1):181-186Chang K, et al. Proc Natl Acad Sci USA. 1996;93(1):136-140Johnston, F, et al. Clinical Cancer Research. 2009;15(21):6511Argani P, et al. Clin Cancer Res. 2001;7(12):3862-3868Jirsova K, et al. Experimental eye research. 2010;91(5):623-629Bracci L, et al. Clin Cancer Res. 2007;13(2 Pt 1):644-653Moschella F, et al. Cancer Res. 2011;71(10):3528-3539Gross G, et al. FASEB J. 1992;6(15):3370-3378Sadelain M, et al. NatRevCancer. 2003;3(1):35-45Muul LM, et al. Blood. 2003;101(7):2563-2569Yee C, et al. Pr