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ANTIGEN-BINDING PROTEIN RECOGNIZING MAGE-A4-DERIVED PEPTIDE

Foreign code F190009753
File No. S2017-0793-C0
Posted date May 7, 2019
Country WIPO
International application number 2018JP021561
International publication number WO 2018225732
Date of international filing Jun 5, 2018
Date of international publication Dec 13, 2018
Priority data
  • P2017-111157 (Jun 5, 2017) JP
Title ANTIGEN-BINDING PROTEIN RECOGNIZING MAGE-A4-DERIVED PEPTIDE
Abstract [Problem] To provide CAR T cells that can be used in CAR infusion therapy in which a cancer-specific intracellular antigen is used.
[Solution] The problem is solved by CAR T cells for cancer therapy provided with an antibody that recognizes a MAGE-A4-derived peptide and an HLA-A2 complex, wherein the antibody has a VH amino acid sequence of SEQ ID NO: 36 and a VL amino acid sequence of SEQ ID NO: 38. In this case, the antibody preferably is provided with an amino acid sequence of SEQ ID NO: 32.
Outline of related art and contending technology BACKGROUND ART
Current, malignant tumor is greater than 30% cause of death, cause of death in developed countries in the first position. Medical advances also the presence of cancer cure, there are many cancers are difficult to treat. Make the new cancer therapy development, a problem of an emergency. As a method of treating cancer, surgery, chemotherapy, radiation therapy and treatment of the three major, or a combination thereof as the main treatment is performed. In recent years, cancer immunotherapy treatment is referred to as the development of the fourth, non-invasive and the height of the effect has attracted attention. Immunotherapy, vaccine therapy mainly, antibody therapy, cells are classified into 3 of the infusion therapy. Cell transfusion therapy is, in response to a cancer-specific cytotoxic T cell-derived T cell receptor gene (T cell receptor: TCR) was introduced at the outside of the lymphocytes of patients after T-cell receptor gene to the infusion therapy diaphramatic lymphocytes, and antigen recognition site of the intracellular signaling molecules as scFv CD3 ζ as chimeric (chimeric antigen receptor antigen receptor bound: CAR) is introduced into the patient's peripheral blood lymphocytes is to treat the infusion. These treatments, antigen-specific lymphocyte receptor gene which has a method for producing a large number in a short time by a variety of cancer can be specific to the patient and the treatment T cells.
TCR gene therapy infusion, peptide MHC complexes (peptide-MHC complex: pMHC) to kill a cancer to recognize since the system, safe and effective treatment and, is currently under development in the world. However, it is the killer T cell clones can be used to isolate a problem that it is very difficult. On the other hand, the advantages of the CAR transfusion therapy and the next 3 points. (1) A single chain antibody (scFv) T cell receptor (TCR) and co-stimulatory molecules and signaling domain CAR T cells are introduced, different from the original T cells, cancer antigen-MHC-independent can be destroyed, and can be adapted to a wide range of patient has an advantage of T cells, (2) as well as CD8 positive, CD4 positive T cells or T cells can be applied also to the non inherits, (3) antibody reactivity for comparison with the TCR, a high affinity. Indeed, CAR therapy, anti-CD19 antibody was used as a therapy to a patient of leukemia and lymphoma CAR extremely high clinical efficacy has been reported (Non-Patent Document 1: for the document, are shown at the end). CD19 Molecule is expressed on the cell B, cell loss B supplemented immunoglobulin can be addressed. In general, to use antigen expressed only in cancer cells is ideal. However, such cell surface antigens, there is a problem that the current is not missing.
On the other hand, the molecules existing within the cell, cancer and testis antigen, such as a specific cancer neoantigen is reported. However, a specific cancer antigen cells will be used in transfusion therapy CAR, has not been known. In view of such circumstances, inventors of the present invention, peptide antigens and MHC complex intracellular antibodies that recognize isolated, using antibodies, immune therapy CAR considered practical applications. Peptide MHC specific antibodies that recognize complex, only a limited number of successful has been reported (Non-Patent Document 2) does not. Peptide MHC complexes to obtain antibodies that specifically recognize specific, specific kill the cancer cells can be made to a CAR-T cells if, for the treatment can be remarkably made. Peptide MHC complexes CAR is recognized, the CAR-T cells within CAR-T cells and at the same time the infusion to specifically recognize peptides can be administered, CAR-T cell proliferation antigen presenting cells can be expected.
Scope of claims (In Japanese)[請求項1]
以下の(A)または(B)のポリペプチドを含み、HLA-A2-MAGE-A4複合体を抗原として認識する抗原結合性タンパク質:
 (A)配列番号36のVH(重鎖可変領域)のアミノ酸配列と、配列番号38のVL(軽鎖可変領域)のアミノ酸配列とを含むポリペプチド;
 (B)配列番号36のVH(重鎖可変領域)のアミノ酸配列と90%以上の相同性を持つアミノ酸配列と、配列番号38のVL(軽鎖可変領域)のアミノ酸配列と90%以上の相同性を持つアミノ酸配列とを含むポリペプチド。

[請求項2]
VHとVLとの間に、以下の(C)または(D)のポリペプチドを含む請求項1に記載の抗原結合性タンパク質:
 (C)配列番号37のsc(一本鎖)のアミノ酸配列を含むポリペプチド;
 (D)配列番号37のsc(一本鎖)のアミノ酸配列と90%以上の相同性を持つアミノ酸配列を含むポリペプチド。

[請求項3]
請求項1または2に記載のものであって、配列番号32のアミノ酸配列、または配列番号32のアミノ酸配列と90%以上の相同性を持つアミノ酸配列を含むポリペプチドである抗原結合性タンパク質。

[請求項4]
抗原結合性タンパク質が、Fab、Fab'、F(ab') 2、Fvまたは一本鎖Fv(scFv)である請求項1~3のいずれか一つに記載の抗原結合性タンパク質。

[請求項5]
請求項1~4のいずれか一つに記載の抗原結合性タンパク質をコードする核酸。

[請求項6]
請求項5に記載の核酸を含むベクター。

[請求項7]
請求項1~4のいずれか一つに記載の抗原結合性タンパク質とシグナル伝達タンパク質の細胞内ドメインを含むキメラ抗原受容体。

[請求項8]
シグナル伝達タンパク質がCD3zeta(CD3ζ)鎖または共刺激分子CD(GITR)のいずれかである請求項7に記載のキメラ抗原受容体。

[請求項9]
更にCD28の細胞内ドメインまたはGITRの細胞内ドメインのいずれかを含む請求項8に記載のキメラ抗原受容体。

[請求項10]
請求項7~9のいずれか一つに記載のキメラ抗原受容体をコードする核酸。

[請求項11]
請求項10に記載の核酸を含むベクター。

[請求項12]
請求項7~9のいずれか一つに記載のキメラ抗原受容体を発現する細胞。

[請求項13]
請求項12に記載の細胞を有効成分として含有する医薬組成物。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • MIE UNIVERSITY
  • Inventor
  • SHIKU, Hiroshi
  • AKAHORI, Yasushi
  • KATO, Yuya
  • MIYAHARA, Yoshihiro
IPC(International Patent Classification)
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