KR20220136876A - Transformed professional antigen presenting cells specifically binding to antigen containing chimeric antigen receptor(CAR) and uses thereof - Google Patents
Transformed professional antigen presenting cells specifically binding to antigen containing chimeric antigen receptor(CAR) and uses thereof Download PDFInfo
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Abstract
Description
본 발명은 키메릭 항원 수용체(CAR)를 포함하는 형질전환된 항원 특이적 전문적 항원표출세포로서, 구체적으로 상기 키메릭 항원 수용체는 programmed death-ligand 1 (PD-L1)에 특이적으로 결합하는 항원 결합 도메인을 포함하는, 상기 세포를 유효성분으로 포함하는 세포 치료제 또는 암의 치료용 약학적 조성물에 관한 것이다.The present invention provides a transformed antigen-specific professional antigen-presenting cell comprising a chimeric antigen receptor (CAR), wherein the chimeric antigen receptor is an antigen that specifically binds to programmed death-ligand 1 (PD-L1). It relates to a cell therapeutic agent or a pharmaceutical composition for the treatment of cancer comprising the cell as an active ingredient, including a binding domain.
전문적 항원표출세포(professional antigen presenting cell)에는 대식세포(macrophage), 수지상세포(dendritic cell), 미감작 B 세포(naive B cell)가 포함된다(Makala et al., 2004). 대식세포와 수지상세포는 항원을 인식하면 식작용(phagocytosis)에 의해 항원을 잘게 부수고, 대식세포와 수지상세포에서 발현하는 주조직적합성(major histocompatibility complex, MHC) 항원은 항원 결정부(epitope)를 T 세포(T cell)에 전달한다(Kambayashi and Laufer, 2014). 미감작 B 세포(naive B cell)의 경우는 B 세포 수용체(B cell receptor, membrane bound IgM)에 의해 항원을 인식하고, 그 후 항원을 잘게 부수어 미감작 B 세포에서 발현하는 주조직적합성(major histocompatibility complex, MHC) 항원은 항원 결정부(epitope)를 T 세포(T cell)에 전달한다(Kambayashi and Laufer, 2014). 전문적 항원표출세포는 또한 주조직적합성(major histocompatibility complex, MHC) 항원에 의한 항원 결정부 전달과 동시자극신호(co-stimulatory signal) 전달에 의해 미감작 T 세포(naive T cell)를 작동 T 세포(effector T cell)로 활성화시킨다(Kambayashi and Laufer, 2014). 전문적 항원표출세포는 그 외에도 다양한 사이토카인(cytokine)과 케모카인(chemokine)을 분비하여, 염증 반응을 유발하거나 다른 면역세포의 활성을 유발한다(Kambayashi and Laufer, 2014). 따라서, 효과적인 면역 반응은 전문적 항원표출세포의 활성화에 의해 시작되며, 전문적 항원표출세포의 활성화 없이는 효과적인 면역 반응이 유발되지 않는다(Makala et al., 2004). Professional antigen presenting cells include macrophages, dendritic cells, and naive B cells (Makala et al., 2004). When macrophages and dendritic cells recognize antigens, they break down antigens by phagocytosis, and major histocompatibility complex (MHC) antigens expressed in macrophages and dendritic cells transfer the antigenic determinant (epitope) to T cells. (T cell) (Kambayashi and Laufer, 2014). In the case of naive B cells, the antigen is recognized by the B cell receptor (membrane bound IgM), and then the antigen is crushed and expressed in the naïve B cells (major histocompatibility). complex, MHC) antigen delivers epitope to T cells (Kambayashi and Laufer, 2014). Professional antigen-presenting cells also induce naive T cells by transduction of antigenic determinants by major histocompatibility complex (MHC) antigens and co-stimulatory signal transduction into effector T cells ( effector T cells) (Kambayashi and Laufer, 2014). In addition, the specialized antigen-expressing cells secrete various cytokines and chemokines to induce an inflammatory response or activate other immune cells (Kambayashi and Laufer, 2014). Therefore, an effective immune response is initiated by activation of professional antigen-presenting cells, and an effective immune response cannot be induced without activation of professional antigen-presenting cells (Makala et al., 2004).
최근에는 전문적 항원표출세포의 활성을 유발하여 종양을 치료하는 방법이 고안되었다. 즉, 종양 특이적 항원을 암 환자 유래 전문적 항원표출세포에 처리하고, 다시 종양 특이적 항원에 의해 활성화된 전문적 항원표출세포를 암 환자의 몸에 넣어주는 방법이다(van Willigen et al., 2018). 암 환자에 이식된 활성화된 전문적 항원표출세포는 직접적으로 종양 세포를 표적하는 세포독성 T 세포(cytotoxic T lymphocytes, CTL)와 자연살생세포(natural killer cell, NK cell)의 활성을 유발하여, 종양 세포를 죽이게 된다(Galluzzi et al., 2018; Lu et al., 2020). Recently, a method for treating tumors by inducing the activation of specialized antigen-expressing cells has been devised. That is, it is a method in which tumor-specific antigens are treated with cancer patient-derived specialized antigen-expressing cells, and then, professional antigen-expressing cells activated by tumor-specific antigens are put into the cancer patient's body (van Willigen et al., 2018). . Activated specialized antigen-expressing cells implanted in cancer patients induce the activation of cytotoxic T lymphocytes (CTL) and natural killer cells (NK cells) that directly target tumor cells, thereby causing tumor cells (Galluzzi et al., 2018; Lu et al., 2020).
하지만, 이러한 면역 요법의 가장 큰 해결해야할 과제는 종양 특이적인 항원이 지금까지 그렇게 많이 발견되지 않았다는 것이다. 따라서, 최근에는 암의 세포 표면에서 발현하는 단백질을 인식하는 항체의 단일사슬 Fv 단편(single-chain variable fragment, scFv) 부분을 CD3 제타(zeta) 또는 다른 단백질의 세포질내 신호전달 도메인(cytoplasmic signaling domain)에 접목시킨 키메릭 항원 수용체(chimeric antigen receptor, CAR)를 세포독성 T 세포와 자연살생세포에 발현시켜, 암의 세포 표면에서 발현하는 단백질을 인식하여 전달되는 신호 전달에 의해 세포독성 T 세포와 자연살생세포의 암 특이적 활성을 유발하는 새로운 항암 치료 방법이 도입되었다. 즉, 키메릭 항원 수용체를 T 세포 또는 자연살생세포에 접목시키면, 암특이적 항원을 인식하는 전문적 항원표출세포에 의한 신호 전달과 관계없이 scFv의 특정 항원 인지만으로 T 세포 또는 자연살생세포의 항암 작용을 활성화시킬 수 있으며, 또한 HLA type에 제한적이지 않아 많은 사람들이 보편적으로 사용할 수 있는 보다 효율적인 치료 방법으로 이용할 수 있다. 실제로, 이러한 키메릭 항원 수용체 발현 T 세포나 자연살생세포는 여러 암에서 효능을 보이고 있다(Holzinger et al., 2016; Pettitt et al., 2018; Wang et al., 2020). However, the biggest challenge for such immunotherapy is that tumor-specific antigens have not been discovered so far. Therefore, recently, a single-chain variable fragment (scFv) portion of an antibody that recognizes a protein expressed on the cell surface of cancer has been replaced with CD3 zeta or the cytoplasmic signaling domain of another protein. ) grafted onto the chimeric antigen receptor (CAR) is expressed in cytotoxic T cells and natural killer cells to recognize proteins expressed on the surface of cancer cells and to communicate with cytotoxic T cells by signal transduction. A new anticancer treatment method that induces cancer-specific activity of natural killer cells has been introduced. That is, when the chimeric antigen receptor is grafted onto T cells or natural killer cells, the anticancer action of T cells or natural killer cells only by recognizing specific antigens of scFv regardless of signal transduction by specialized antigen-expressing cells that recognize cancer-specific antigens. In addition, since it is not limited to HLA type, it can be used as a more efficient treatment method that can be used universally by many people. Indeed, these chimeric antigen receptor-expressing T cells or natural killer cells have shown efficacy in several cancers (Holzinger et al., 2016; Pettitt et al., 2018; Wang et al., 2020).
한편, programmed death-ligand 1 (PD-L1 또는 CD274 또는 B7-H1)은 40 kDa의 내재성 막 단백질(integral membrane protein)이며, 다양한 암종(malignant cells)과 골수유래 면역억제 세포(myeloid-derived suppressor cells, MDSCs) 또는 면역세포에서 관찰된다(Iwai et al., 2002; Blank et al., 2004; Von Knethen and Brune, 2019). 특히 암세포는 PD-L1을 과발현하여 종양 항원 특이적 T 세포(tumor antigen-specific T cells)의 공격을 회피하게 된다 (Okazaki and Honjo, 2007; Markham, 2016; Cao et al., 2019). 즉, 암세포가 PD-L1을 과발현하면, 종양 항원 특이적으로 활성화된 T 세포에서 발현되는 PD-L1의 수용체인 PD-1과 결합하고, PD-L1 / PD-1 신호전달을 통하여 종양 항원 특이적 T 세포의 활성을 억제하게 된다(Okazaki and Honjo, 2007; Markham, 2016; Cao et al., 2019). 이에 따라, PD-L1 / PD-1 신호전달을 억제할 수 있는 중화항체(면역관문 억제제, immune checkpoint inhibitor)가 개발되었고, 이러한 중화항체가 암을 좀 더 효과적으로 제거 할 수 있는 치료제로 각광 받고 있다(Sznol and Chen, 2013; Homet Moreno et al., 2015). 지금까지 PD-L1을 발현하는 암종은 흑색종(melanoma), 폐암(lung cancer), 육종(Sarcoma), 신장암(renal-cell carcinoma), 림프종(lymphoma), 직장암(colorectal cancer), 위암(gastric cancer), 식도암(esophageal cancer), 진행된 고형암(advanced solid tumor), 유방암(breast cancer), 두경부암(head and neck cancer), 난소암(ovarian cancer), 전립선암(prostate cancer) 등이 있다(Zhang et al., 2020). On the other hand, programmed death-ligand 1 (PD-L1 or CD274 or B7-H1) is a 40 kDa integral membrane protein, and is used in various types of malignant cells and myeloid-derived suppressor cells. cells, MDSCs) or immune cells (Iwai et al., 2002; Blank et al., 2004; Von Knethen and Brune, 2019). In particular, cancer cells overexpress PD-L1 to evade attack by tumor antigen-specific T cells (Okazaki and Honjo, 2007; Markham, 2016; Cao et al., 2019). That is, when cancer cells overexpress PD-L1, it binds to PD-1, a receptor for PD-L1 expressed in tumor antigen-specifically activated T cells, and is specific for tumor antigens through PD-L1/PD-1 signaling. It inhibits the activity of enemy T cells (Okazaki and Honjo, 2007; Markham, 2016; Cao et al., 2019). Accordingly, neutralizing antibodies (immune checkpoint inhibitors) that can inhibit PD-L1/PD-1 signaling have been developed, and these neutralizing antibodies are attracting attention as therapeutic agents that can more effectively remove cancer. (Sznol and Chen, 2013; Homet Moreno et al., 2015). Carcinomas expressing PD-L1 so far have been melanoma, lung cancer, sarcoma, renal-cell carcinoma, lymphoma, colorectal cancer, and gastric cancer. cancer, esophageal cancer, advanced solid tumor, breast cancer, head and neck cancer, ovarian cancer, prostate cancer, etc. (Zhang) et al., 2020).
또한, programmed death 1(PD-1 또는 CD279)은 288개의 아미노산으로 구성된 1형 막 단백질(membrane protein)이며, T 세포가 활성화될 때 세포 표면에 발현하는 면역 글로불린(Ig) 수퍼 패밀리(immunoglobulin superfamily)에 속하는 내재성 막 단백질(integral membrane protein)이다(Ishida et al., 1992). 활성화된 T 세포에서 발현되는 PD-1은 그 리간드인 PD-L1과 결합하여, T 세포의 활성을 억제시키는 것으로 알려져 있다(Syn et al., 2017). In addition, programmed death 1 (PD-1 or CD279) is a
현재, 키메릭 항원 수용체를 발현하는 변형된 단핵세포/대식세포 (한국공개특허 제10-2018-0028533)나 키메릭 항원 수용체(한국공개특허 제10-2017-0090506호)를 이용한 CAR-T 세포 또는 CAR-NK 세포를 이용한 항암 치료 요법에 관한 문헌은 있으나 세포 내 신호전달 도메인을 강화하여 PD-1의 세포외 도메인을 포함한 키메릭 항원 수용체를 발현하는 전문적 항원표출세포를 이용한 면역 항암 치료제에 대해서는 기재된 바 없다.Currently, CAR-T cells using a modified monocyte/macrophage expressing a chimeric antigen receptor (Korean Patent Application Laid-Open No. 10-2018-0028533) or a chimeric antigen receptor (Korean Patent Application Laid-Open No. 10-2017-0090506) Alternatively, there is literature on anticancer therapy using CAR-NK cells, but for immunotherapy using specialized antigen-expressing cells that enhance intracellular signaling domains and express chimeric antigen receptors including the extracellular domain of PD-1, has not been described
이러한 배경 하에, 본 발명자들은 전문적 항원표출세포의 기능과 키메릭 항원 수용체의 기능을 접목시킨 새로운 치료 방법을 고안하였다. 즉, 종양 세포 표면 단백질을 리간드(ligand)로 인식할 수 있는 수용체와 리간드를 인식한 후, 키메릭 항원 수용체에 의해 전문적 항원표출세포의 활성을 유발할 수 있는 신규 키메릭 신호전달 도메인을 고안하였고, 이러한 키메릭 신호전달 도메인에 의해 활성화된 전문적 항원표출세포가 암에 대한 세포독성 능력을 가질 수 있다는 것을 증명하였다. 즉, 사람의 PD-L1과 PD-1의 결합이 가능하다는 점을 이용하여 PD-1의 세포외 도메인, 톨유사수용체-2(toll-like receptor 2, TLR-2)의 막관통 도메인, TLR-3의 세포 내 도메인, TLR-4의 세포 내 도메인, IgE 수용체 gamma chain (Fcε receptor I gamma chain, FcεRIγ) 또는 IgG 수용체 2A alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα) 또는 IgE 수용체 beta chain (Fcε receptor I beta chain, FcεRIβ)의 면역수용체 타이로신 기반 활성화 모티프(immunoreceptor tyrosine-based activation motif, ITAM)를 소단위(subunit)로 하여, 3개의 ITAM을 링커(linker)로 연결시킨 신규 합성 세포 내 신호 전달 도메인과 결합한 재조합 단백질을 발현하는 키메릭 항원 수용체 발현 대식세포를 제작하였다. 이때 대식세포에서 발현하는 PD-1의 세포 외 도메인은 PD-L1을 인지하여 PD-L1을 발현하는 특정 암세포와 결합 시, 이들 대식세포 내부로 활성화 신호를 전달해 줄 수 있고, 결국 이러한 신호는 대식세포를 활성화시켜 PD-L1을 발현하는 암에 대한 세포독성을 가질 수 있게 한다. 실제로, 상기 대식세포가 PD-L1을 발현하는 세포에 특이적으로 세포독성 능력이 있음을 체외 실험을 통해 확인하였다. Under this background, the present inventors devised a new treatment method that grafts the function of the professional antigen-presenting cell and the function of the chimeric antigen receptor. That is, after recognizing a receptor and a ligand that can recognize a tumor cell surface protein as a ligand, a novel chimeric signaling domain that can induce the activity of a specialized antigen-presenting cell by the chimeric antigen receptor was designed, It was demonstrated that professional antigen-presenting cells activated by such a chimeric signaling domain can have cytotoxicity against cancer. That is, the extracellular domain of PD-1, the transmembrane domain of toll-like receptor 2 (TLR-2), the TLR by taking advantage of the fact that human PD-L1 and PD-1 are capable of binding. Intracellular domain of -3, Intracellular domain of TLR-4, IgE receptor gamma chain (Fcε receptor I gamma chain, FcεRIγ) or IgG receptor 2A alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα) or IgE receptor beta chain (Fcε A novel synthetic intracellular signal transduction domain in which three ITAMs are linked by a linker using the immunoreceptor tyrosine-based activation motif (ITAM) as a subunit of receptor I beta chain, FcεRIβ) A chimeric antigen receptor-expressing macrophage expressing a recombinant protein bound to was prepared. At this time, the extracellular domain of PD-1 expressed in macrophages recognizes PD-L1 and, when combined with a specific cancer cell expressing PD-L1, can deliver an activation signal into these macrophages, and eventually these signals are Activating phagocytes allows them to have cytotoxicity against cancers expressing PD-L1. In fact, it was confirmed through an in vitro experiment that the macrophages have specific cytotoxicity to cells expressing PD-L1.
따라서 본 발명의 목적은 키메릭 항원 수용체(CAR)를 포함하는 형질전환된 세포로서, 상기 키메릭 항원 수용체는 PD-L1에 특이적으로 결합하는 항원 결합 도메인, 막관통 도메인 및 세포 내 신호전달 도메인을 포함하며, 상기 세포는 표적화된 효과기 활성을 갖는 항원 특이적 전문적 항원표출세포로서 대식세포, 수지상세포 또는 미감작 B 세포(naive B cell)를 포함하는, 형질전환된 세포를 제공하는 것이다.Accordingly, an object of the present invention is a transformed cell comprising a chimeric antigen receptor (CAR), wherein the chimeric antigen receptor has an antigen binding domain, a transmembrane domain and an intracellular signaling domain that specifically binds to PD-L1. Including, the cell is to provide a transformed cell, including a macrophage, dendritic cell or naive B cell (naive B cell) as an antigen-specific professional antigen-presenting cells having a targeted effector activity.
본 발명의 다른 목적은 상기 형질전환된 세포를 유효성분으로 포함하는 세포 치료제 또는 PD-L1을 발현하는 암세포를 사멸시키는 암의 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for the treatment of cancer that kills cancer cells expressing PD-L1 or a cell therapeutic agent comprising the transformed cells as an active ingredient.
상기와 같은 본 발명의 목적을 달성하기 위해서, 본 키메릭 항원 수용체(CAR)를 포함하는 형질전환된 세포로서, 상기 키메릭 항원 수용체는 PD-L1에 특이적으로 결합하는 항원 결합 도메인, 막관통 도메인 및 세포 내 신호전달 도메인을 포함하며, 상기 세포는 표적화된 효과기 활성을 갖는 항원 특이적 전문적 항원표출세포로서 대식세포, 수지상세포 또는 미감작 B 세포(naive B cell)를 포함하는, 형질전환된 세포를 제공한다.In order to achieve the object of the present invention as described above, as a transformed cell comprising the present chimeric antigen receptor (CAR), the chimeric antigen receptor has an antigen binding domain that specifically binds to PD-L1, a transmembrane domain and an intracellular signaling domain, wherein the cell comprises a macrophage, dendritic cell or naive B cell as an antigen-specific professional antigen-presenting cell having a targeted effector activity. provide cells.
또한, 본 발명은 상기 형질전환된 세포를 포함하는, 세포 치료제 또는 PD-L1을 발현하는 암세포를 사멸시키는 암의 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for the treatment of cancer including the transformed cells, which kills a cell therapeutic agent or a cancer cell expressing PD-L1.
본 발명의 일실시 예에 있어서, 상기 키메릭 항원 수용체(CAR)의 항원 결합 도메인은 상기 PD-L1에 특이적으로 결합하는 PD-1의 세포외 도메인일 수 있다.In one embodiment of the present invention, the antigen-binding domain of the chimeric antigen receptor (CAR) may be an extracellular domain of PD-1 that specifically binds to the PD-L1.
본 발명의 일실시 예에 있어서, 상기 막관통 도메인은 TLR-2일 수 있다.In one embodiment of the present invention, the transmembrane domain may be TLR-2.
본 발명의 일실시 예에 있어서, 상기 세포 내 신호전달 도메인은 TLR-3, TLR-4, IgE 수용체 gamma chain (Fcε receptor I gamma chain, FcεRIγ), IgG 수용체 2A alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα), IgE 수용체 beta chain (Fcε receptor I beta chain, FcεRIβ)의 면역수용체 타이로신 기반 활성화 모티프(ITAM) 또는 이들의 조합일 수 있다.In one embodiment of the present invention, the intracellular signaling domain is TLR-3, TLR-4, IgE receptor gamma chain (Fcε receptor I gamma chain, FcεRIγ), IgG receptor 2A alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα), an immunoreceptor tyrosine-based activation motif (ITAM) of the IgE receptor beta chain (Fcε receptor I beta chain, FcεRIβ), or a combination thereof.
상기 PD-L1을 발현하는 암종은 흑색종(melanoma), 폐암(lung cancer), 육종(Sarcoma), 신장암(renal-cell carcinoma), 림프종(lymphoma), 직장암(colorectal cancer), 위암(gastric cancer), 식도암(esophageal cancer), 진행된 고형암(advanced solid tumor), 유방암(breast cancer), 두경부암(head and neck cancer), 난소암(ovarian cancer) 및 전립선암(prostate cancer)으로 이루어진 군으로부터 선택될 수 있다.The PD-L1 expressing carcinoma is melanoma, lung cancer, sarcoma, renal-cell carcinoma, lymphoma, colorectal cancer, gastric cancer ), esophageal cancer, advanced solid tumor, breast cancer, head and neck cancer, ovarian cancer and prostate cancer to be selected from the group consisting of can
본 발명에 따른 형질전환된 세포는 전문적 항원표출세포가 항원에 특이적으로 결합할 때, 전문적 항원표출세포의 활성을 유발하는 강화된 키메릭 신호전달 도메인을 제공한다. 이에 대한 예시로, PD-1의 세포외 도메인과 전문적 항원표출세포의 신호 전달에 중요한 작용을 하는 TLR-3, TLR-4 및 IgE 수용체 gamma chain (Fcε receptor I gamma chain, FcεRIγ) 또는 IgG 수용체 2A alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα) 또는 IgE 수용체 beta chain (Fcε receptor I beta chain, FcεRIβ)의 면역수용체 타이로신 기반 활성화 모티프(ITAM)를 소단위(subunit)로 하여, 3개의 ITAM을 링커(linker)로 연결시킨 신규 합성 세포 내 신호 전달 도메인을 포함하는 재조합 단백질로서, 이를 과발현시킬 수 있는 벡터로 형질전환된 전문적 항원표출세포의 경우 PD-L1을 발현하는 암종에 특이적으로 세포독성을 갖는다. 따라서, 본 발명에 의한 키메릭 항원 수용체를 과발현하는 전문적 항원표출세포는 PD-L1을 발현하는 암종 치료를 위한 면역세포 치료제로서 유용하게 사용될 수 있다.The transformed cell according to the present invention provides an enhanced chimeric signaling domain that induces the activity of the professional antigen-presenting cell when the professional antigen-presenting cell specifically binds to an antigen. As an example, TLR-3, TLR-4, and IgE receptor gamma chain (Fcε receptor I gamma chain, FcεRIγ) or IgG receptor 2A, which play an important role in the signal transduction of the extracellular domain of PD-1 and specialized antigen-presenting cells Using the immunoreceptor tyrosine-based activation motif (ITAM) of the alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα) or the IgE receptor beta chain (Fcε receptor I beta chain, FcεRIβ) as a subunit, three ITAMs are linkers ), a recombinant protein comprising a novel synthetic intracellular signal transduction domain linked to, and has specific cytotoxicity to PD-L1-expressing carcinoma in the case of professional antigen-expressing cells transformed with a vector capable of overexpressing it. Therefore, the specialized antigen-expressing cell overexpressing the chimeric antigen receptor according to the present invention can be usefully used as an immune cell therapeutic agent for the treatment of PD-L1-expressing carcinoma.
도 1은 본 발명의 일 실시예에 따른 키메릭 항원 수용체를 발현시키는 각 도메인의 cDNA 구역 중 하나의 형태를 나타낸 모식도이다.
도 2는 본 발명의 일 실시예에 따른 키메릭 항원 수용체를 발현시키는 각 도메인의 cDNA 구역 중 하나의 형태를 나타낸 모식도이다.
도 3은 본 발명의 일 실시예에 따른 키메릭 항원 수용체를 발현시키는 각 도메인의 cDNA 구역 중 하나의 형태를 나타낸 모식도이다.
도 4는 본 발명의 일 실시예에 따른 키메릭 항원 수용체를 발현시키는 각 도메인의 cDNA 구역 중 하나의 형태를 나타낸 모식도이다.
도 5는 본 발명의 일 실시예에 따른 렌티바이럴 벡터 중 하나의 형태를 나타낸 모식도이다.
도 6은 본 발명의 일 실시예에 따른 렌티바이럴 벡터 중 하나의 형태를 나타낸 모식도이다.
도 7은 본 발명의 일 실시예에 따른 렌티바이럴 벡터 중 하나의 형태를 나타낸 모식도이다.
도 8은 본 발명의 일 실시예에 따른 렌티바이럴 벡터 중 하나의 형태를 나타낸 모식도이다.
도 9는 본 발명의 일 실시예에 따른 전문적 항원표출세포 표면에 발현하는 키메릭 항원 수용체 중 하나의 형태를 나타낸 모식도이다.
도 10은 본 발명의 일 실시예에 따른 전문적 항원표출세포 표면에 발현하는 키메릭 항원 수용체 중 하나의 형태를 나타낸 모식도이다.
도 11은 본 발명의 일 실시예에 따른 전문적 항원표출세포 표면에 발현하는 키메릭 항원 수용체 중 하나의 형태를 나타낸 모식도이다.
도 12는 본 발명의 일 실시예에 따른 전문적 항원표출세포 표면에 발현하는 키메릭 항원 수용체 중 하나의 형태를 나타낸 모식도이다.
도 13은 본 발명에서 제공하는 키메릭 항원 수용체의 타겟인 PD-L1을 발현하는 암세포(PD-L1 positive cell)에서 PD-L1의 발현량을 유세포 분석을 이용해 측정한 결과를 나타낸 도이다.
도 14는 본 발명의 일 실시예에 따른 발현 벡터 4종을 렌티바이러스 시스템을 이용하여 형질도입시킨 전문적 항원표출세포들에서의 GFP의 발현 비율을 비교한 결과를 나타낸 도이다.
도 15는 본 발명의 일 실시예에 따른 발현 벡터 4종을 렌티바이러스 시스템을 이용하여 형질도입시킨 전문적 항원표출세포들이 PD-L1을 인식하는지 여부를 유세포 분석을 이용해 나타낸 도이다.
도 16은 본 발명의 일 실시예에 따른 4 종의 키메릭 항원 수용체 또는 공벡터를 형질도입시킨 전문적 항원표출세포를 작동 세포(effector cell)로 하여 PD-L1을 발현하는 암세포(Raji cell)에 대한 세포독성을 공배양 후 24시간이 경과된 때에 측정한 결과를 나타낸 도이다.
도 17은 본 발명의 일 실시예에 따른 4 종의 키메릭 항원 수용체 또는 공벡터를 형질도입시킨 전문적 항원표출세포를 작동 세포(effector cell)로 하여 PD-L1을 발현하는 암세포(Raji cell)에 대한 세포독성을 공배양 후 48시간이 경과된 때에 측정한 결과를 나타낸 도이다.1 is a schematic diagram showing the form of one of the cDNA regions of each domain expressing a chimeric antigen receptor according to an embodiment of the present invention.
2 is a schematic diagram showing the form of one of the cDNA regions of each domain expressing a chimeric antigen receptor according to an embodiment of the present invention.
3 is a schematic diagram showing the form of one of the cDNA regions of each domain expressing a chimeric antigen receptor according to an embodiment of the present invention.
4 is a schematic diagram showing the form of one of the cDNA regions of each domain expressing a chimeric antigen receptor according to an embodiment of the present invention.
5 is a schematic diagram showing the form of one of the lentiviral vectors according to an embodiment of the present invention.
6 is a schematic diagram showing the form of one of the lentiviral vectors according to an embodiment of the present invention.
7 is a schematic diagram illustrating a form of one of lentiviral vectors according to an embodiment of the present invention.
8 is a schematic diagram showing the form of one of the lentiviral vectors according to an embodiment of the present invention.
9 is a schematic diagram showing the form of one of the chimeric antigen receptors expressed on the surface of a professional antigen-expressing cell according to an embodiment of the present invention.
10 is a schematic diagram showing the form of one of the chimeric antigen receptors expressed on the surface of a professional antigen-expressing cell according to an embodiment of the present invention.
11 is a schematic diagram showing the form of one of the chimeric antigen receptors expressed on the surface of a professional antigen-expressing cell according to an embodiment of the present invention.
12 is a schematic diagram showing the form of one of the chimeric antigen receptors expressed on the surface of a professional antigen-expressing cell according to an embodiment of the present invention.
13 is a diagram showing the results of measuring the expression level of PD-L1 in cancer cells (PD-L1 positive cells) expressing PD-L1, a target of the chimeric antigen receptor provided in the present invention, using flow cytometry.
14 is a diagram showing the result of comparing the expression ratio of GFP in professional antigen-expressing cells transduced with four types of expression vectors according to an embodiment of the present invention using a lentiviral system.
15 is a diagram showing, using flow cytometry, whether professional antigen-expressing cells transduced with four types of expression vectors according to an embodiment of the present invention using a lentiviral system recognize PD-L1.
16 is an effector cell using professional antigen-expressing cells transduced with four types of chimeric antigen receptors or empty vectors according to an embodiment of the present invention to cancer cells (Raji cells) expressing PD-L1. It is a diagram showing the result of measuring the cytotoxicity of the co-culture when 24 hours have elapsed.
FIG. 17 is an example of a PD-L1-expressing cancer cell (Raji cell) using professional antigen-expressing cells transduced with four types of chimeric antigen receptors or empty vectors according to an embodiment of the present invention as effector cells. It is a diagram showing the results of measuring the cytotoxicity of the cells when 48 hours have elapsed after the co-culture.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
본 발명은 하나의 양태로서, 키메릭 항원 수용체(CAR)를 포함하는 형질전환된 세포로서, 상기 키메릭 항원 수용체는 PD-L1(programmed death-ligand 1)에 특이적으로 결합하는 항원 결합 도메인, 막관통 도메인 및 세포 내 신호전달 도메인을 포함하며, 상기 세포는 표적화된 효과기 활성을 갖는 항원 특이적 전문적 항원표출세포로서 대식세포, 수지상세포 또는 미감작 B 세포(naive B cell)를 포함하는, 형질전환된 세포를 제공한다.In one aspect, the present invention provides a transformed cell comprising a chimeric antigen receptor (CAR), the chimeric antigen receptor comprising an antigen binding domain that specifically binds to PD-L1 (programmed death-ligand 1); A transmembrane domain and an intracellular signaling domain, wherein the cell comprises a macrophage, dendritic cell or naive B cell as an antigen-specific professional antigen-presenting cell having a targeted effector activity. transformed cells are provided.
본 발명의 일 실시예에 따른 키메릭 항원 수용체 단백질은 기능적 동등물을 포함할 수 있다. '기능적 동등물'이란 아미노산의 부가, 치환, 또는 결실의 결과, 상기 키메릭 항원 수용체 단백질의 아미노산 서열과 적어도 70% 이상, 바람직하게는 80% 이상, 더욱 바람직하게는 90% 이상, 더더욱 바람직하게는 95% 이상의 서열 상동성을 갖는 것으로, 실질적으로 동질의 생리활성을 나타내는 단백질을 말한다. '실질적으로 동질의 생리활성'이란 PD-L1에 특이적으로 결합할 수 있는 활성을 가진 것을 의미한다.The chimeric antigen receptor protein according to an embodiment of the present invention may include a functional equivalent. "Functional equivalent" means at least 70% or more, preferably 80% or more, more preferably 90% or more, even more preferably the amino acid sequence of the chimeric antigen receptor protein as a result of the addition, substitution, or deletion of amino acids. refers to a protein having a sequence homology of 95% or more and exhibiting substantially homogeneous physiological activity. 'Substantially homogenous physiological activity' means having an activity capable of specifically binding to PD-L1.
본 발명은 또한 키메릭 항원 수용체의 단편, 유도체 및 유사체(analogues)를 포함한다. 본원에 사용된, 용어 '단편', '유도체' 및 '유사체'는 본 발명의 키메릭 항원 수용체 단백질과 실질적으로 같은 생물학적 기능 또는 활성을 보유하는 폴리펩티드를 말한다. 본 발명의 단편, 유도체 및 유사체는 (i) 하나 이상의 보존적(conservative) 또는 비보존적 아미노산 잔기(바람직하게는 보존적 아미노산 잔기)가 치환된 폴리펩티드(상기 치환된 아미노산 잔기는 유전 암호에 의해 암호화될 수도, 되지 않을 수도 있다) 또는 (ⅱ) 하나 이상의 아미노산 잔기에서 치환기(들)를 가지는 폴리펩티드, 또는 (ⅲ) 또 다른 화합물(폴리펩티드의 반감기를 연장할 수 있는 화합물, 예를 들면 폴리에틸렌 글리콜)과 결합된 성숙 폴리펩티드로부터 유래된 폴리펩티드, 또는 (ⅳ) 부가적인 아미노산 서열(예를 들면, 선도 서열, 분비 서열, 상기 폴리펩티드를 정제하는데 사용된 서열, 프로테이노젠(proteinogen) 서열 또는 융합 단백질)과 결합된 상기 폴리펩티드로부터 유래된 폴리펩티드일 수 있다. 본 발명에 정의된 상기 단편, 유도체 및 유사체는 당업자에 잘 알려져 있다.The present invention also includes fragments, derivatives and analogues of chimeric antigen receptors. As used herein, the terms 'fragment', 'derivative' and 'analog' refer to a polypeptide that retains substantially the same biological function or activity as the chimeric antigen receptor protein of the present invention. Fragments, derivatives and analogs of the present invention may comprise (i) polypeptides in which one or more conservative or non-conservative amino acid residues (preferably conservative amino acid residues) are substituted, wherein the substituted amino acid residues are encoded by the genetic code. may or may not be) or (ii) a polypeptide having substituent(s) at one or more amino acid residues, or (iii) another compound (a compound capable of extending the half-life of the polypeptide, such as polyethylene glycol); a polypeptide derived from the associated mature polypeptide, or (iv) an additional amino acid sequence (eg, a leader sequence, a secretion sequence, a sequence used to purify the polypeptide, a proteinogen sequence, or a fusion protein); It may be a polypeptide derived from said polypeptide to which it is bound. The fragments, derivatives and analogs as defined herein are well known to those skilled in the art.
본 발명에서 programmed death-ligand 1 (PD-L1 또는 CD274 또는 B7-H1)은 다양한 암종(malignant cells)에서 발견된다. 지금까지 PD-L1을 발현하는 암종은 흑색종(melanoma), 폐암(lung cancer), 육종(Sarcoma), 신장암(renal-cell carcinoma), 림프종(lymphoma), 직장암(colorectal cancer), 위암(gastric cancer), 식도암(esophageal cancer), 진행된 고형암(advanced solid tumor), 유방암(breast cancer), 두경부암(head and neck cancer) 또는 난소암(ovarian cancer), 전립선암(prostate cancer)이 있으나, 이에 제한되는 것은 아니다. In the present invention, programmed death-ligand 1 (PD-L1 or CD274 or B7-H1) is found in various malignant cells. Carcinomas expressing PD-L1 so far have been melanoma, lung cancer, sarcoma, renal-cell carcinoma, lymphoma, colorectal cancer, and gastric cancer. cancer, esophageal cancer, advanced solid tumor, breast cancer, head and neck cancer or ovarian cancer, prostate cancer, but limited thereto it's not going to be
본 발명에서 "키메릭 신호전달 도메인"은 원하는 리간드에 결합하여 리간드-수용체 반응을 통해 전문적 항원표출세포의 활성화를 유도하고 해당 리간드를 발현하는 세포를 공격할 수 있도록 하기 위해 전문적 항원표출세포에 발현시키기 위한 융합 단백질을 의미할 수 있다. 곧, 전문적 항원표출세포에 발현 시 리간드에 결합하여 이들 세포들의 활성화를 유도하는 단백질이라고 볼 수 있다. 따라서, 본 발명에서 제공하는 신규 키메릭 신호전달 도메인은 모든 항원-항체 반응을 포함한 모든 리간드-수용체 반응을 이용한 전문적 항원표출세포의 활성화를 유도할 수 있는 범용적 의미의 신규 키메릭 신호전달 도메인을 제공한다. In the present invention, "chimeric signaling domain" binds to a desired ligand, induces activation of professional antigen-presenting cells through ligand-receptor reaction, and is expressed in specialized antigen-expressing cells to attack cells expressing the ligand It may mean a fusion protein for In other words, when expressed in specialized antigen-expressing cells, it can be seen as a protein that binds to a ligand and induces activation of these cells. Therefore, the novel chimeric signaling domain provided by the present invention is a novel chimeric signaling domain in a general sense that can induce the activation of professional antigen-presenting cells using all ligand-receptor reactions including all antigen-antibody reactions. to provide.
즉, 상기 키메릭 항원 수용체는 전문적 항원표출세포에 발현 시 항원에 결합하여 이들 세포들의 활성화를 유도하는 단백질이라고 볼 수 있다. 이를 통해 면역 반응을 일으키고자 하는 세포에 특이적인 항원을 인식하는 단백질일 수 있으며, 상기 면역 반응을 일으키고자 하는 세포는 특정 조직에 존재하거나 병변을 일으킨 조직을 이루는 세포를 의미할 수 있다.That is, the chimeric antigen receptor can be regarded as a protein that binds to an antigen and induces activation of these cells when expressed in professional antigen-expressing cells. Through this, it may be a protein recognizing an antigen specific to a cell to cause an immune response, and the cell to cause an immune response may refer to a cell existing in a specific tissue or constituting a tissue causing a lesion.
상기 키메릭 항원 수용체(CAR)의 항원 결합 도메인은 상기 PD-L1에 특이적으로 결합하는 PD1의 세포외 도메인일 수 있다. 상기 PD1의 세포외 도메인은 서열번호 1 또는 이와 95% 이상의 상동성을 나타내는 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되는 것은 아니다.The antigen binding domain of the chimeric antigen receptor (CAR) may be an extracellular domain of PD1 that specifically binds to the PD-L1. The extracellular domain of PD1 may consist of SEQ ID NO: 1 or an amino acid sequence having 95% or more homology thereto, but is not limited thereto.
상기 항원 결합 도메인은 신호전달을 증폭하기 위해 PD1의 세포외 도메인 한 쌍을 인간 이뮤노글로불린 G1 중쇄 불변 영역(IgG1 heavy chain constant region)에 각각 연결시킨 이합체(dimer) 형태일 수 있으나, 이에 제한되는 것은 아니다.The antigen binding domain may be in the form of a dimer in which a pair of extracellular domains of PD1 are linked to a human immunoglobulin G 1 heavy chain constant region (IgG 1 heavy chain constant region) in order to amplify signal transduction, respectively. It is not limited.
상기 인간 이뮤노글로불린 G1 중쇄 불변 영역(IgG1 heavy chain constant region)은 서열번호 2 또는 이와 95% 이상의 상동성을 나타내는 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되는 것은 아니다.The human immunoglobulin G 1 heavy chain constant region (IgG 1 heavy chain constant region) may consist of SEQ ID NO: 2 or an amino acid sequence showing 95% or more homology thereto, but is not limited thereto.
본 발명의 키메릭 항원 수용체의 일 구성요소인 세포내 신호전달 도메인은 항원 결합 도메인에 결합에 의해 면역 세포의 면역반응을 활성화시키는 부위를 의미한다. 상기 신호전달 도메인은 TLR-3, TLR-4, 타이로신 기반 활성화 모티프(ITAM) 또는 이들의 조합일 수 있다. 바람직한 일 구현예에서, 상기 신호전달 도메인은 TLR-3-TLR-4의 구성에 ITAM을 소단위(subunit)로 하여 링커(linker)로 연결시킨 형태일 수 있으며, 상기 ITAM은 한 개 이상이 연결된 형태일 수 있으며, 바람직하게는 3개가 연결된 형태일 수 있으나, 이에 제한되는 것은 아니다.The intracellular signaling domain, which is one component of the chimeric antigen receptor of the present invention, refers to a site that activates an immune response of an immune cell by binding to an antigen-binding domain. The signaling domain may be TLR-3, TLR-4, tyrosine-based activation motif (ITAM), or a combination thereof. In a preferred embodiment, the signaling domain may be in the form of connecting ITAM as a subunit to the structure of TLR-3-TLR-4 with a linker, wherein one or more ITAMs are linked may be, and preferably may be in the form of three connected, but is not limited thereto.
상기 ITAM은 IgE 수용체 gamma chain (Fcε receptor I gamma chain, FcεRIγ), IgG 수용체 2A alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα) 또는 IgE 수용체 beta chain (Fcε receptor I beta chain, FcεRIβ)의 면역수용체 타이로신 기반 활성화 모티프일 수 있으나, 이에 제한되는 것은 아니다.The ITAM is based on immunoreceptor tyrosine of IgE receptor gamma chain (Fcε receptor I gamma chain, FcεRIγ), IgG receptor 2A alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα) or IgE receptor beta chain (Fcε receptor I beta chain, FcεRIβ) It may be an activation motif, but is not limited thereto.
상기 TLR-3은 서열번호 3 또는 이와 70% 이상, 바람직하게는 80% 이상, 더욱 바람직하게는 90% 이상, 더더욱 바람직하게는 95% 이상의 서열 상동성을 갖는 것으로, 서열번호 3으로 표시되는 아미노산 서열과 실질적으로 동등한 기능을 나타내는 아미노산 서열로 이루어질 수 있고; 상기 TLR-4는 서열번호 4 또는 이와 70% 이상, 바람직하게는 80% 이상, 더욱 바람직하게는 90% 이상, 더더욱 바람직하게는 95% 이상의 서열 상동성을 갖는 것으로, 서열번호 4로 표시되는 아미노산 서열과 실질적으로 동등한 기능을 나타내는 아미노산 서열로 이루어질 수 있고; 상기 ITAM은 서열번호 5; 서열번호 6; 또는 서열번호 7로 표시되는 아미노산 서열과 실질적으로 동등한 기능을 나타내는 아미노산 서열로 이루어질 수 있다.The TLR-3 is SEQ ID NO: 3 or more than 70%, preferably 80% or more, more preferably 90% or more, even more preferably 95% or more sequence homology thereto, and the amino acid represented by SEQ ID NO: 3 may consist of an amino acid sequence exhibiting a function substantially equivalent to the sequence; The TLR-4 is SEQ ID NO: 4 or more than 70%, preferably 80% or more, more preferably 90% or more, even more preferably 95% or more sequence homology thereto, and the amino acid represented by SEQ ID NO: 4 may consist of an amino acid sequence exhibiting a function substantially equivalent to the sequence; The ITAM is SEQ ID NO: 5; SEQ ID NO: 6; Alternatively, it may consist of an amino acid sequence exhibiting a function substantially equivalent to the amino acid sequence represented by SEQ ID NO: 7.
상기 링커는 서열번호 8로 표시되는 아미노산 서열과 실질적으로 동등한 기능을 나타내는 아미노산 서열로 이루어질 수 있다.The linker may consist of an amino acid sequence having a function substantially equivalent to that of the amino acid sequence represented by SEQ ID NO: 8.
본 발명의 막관통 도메인 (Transmembrane domain)은 PD-1의 세포외 도메인과 보조자극, 필수 신호전달 도메인을 세포막 사이로 연결하는 부위이며, 세포내 신호 전달 도메인은 항원 결합 도메인의 결합에 의해 면역 세포의 면역반응을 활성화시키는 부위를 의미한다.The transmembrane domain of the present invention is a site that connects the extracellular domain of PD-1 and the costimulatory and essential signaling domains between the cell membrane, and the intracellular signaling domain is the antigen-binding domain of the immune cell. It refers to a site that activates an immune response.
본 발명의 키메릭 항원 수용체의 일 구성요소인 막관통 도메인은 CD28, CD3 엡실론, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154 및 TLR-2로 이루어진 군으로부터 선택되는 단백질의 막관통 도메인을 포함하는 것일 수 있다. 바람직하게는, 상기 막통과 도메인은 TLR-2일 수 있고, 이는 서열번호 9 또는 이와 95% 이상의 상동성을 나타내는 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되는 것은 아니다.One component of the transmembrane domain of the chimeric antigen receptor of the present invention is CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154 and a transmembrane domain of a protein selected from the group consisting of TLR-2. Preferably, the transmembrane domain may be TLR-2, which may consist of SEQ ID NO: 9 or an amino acid sequence showing 95% or more homology thereto, but is not limited thereto.
상기 항원 결합 도메인은 신호 펩타이드를 포함할 수 있으며, 상기 신호 펩타이드는 TLR-4 신호 펩타이드일 수 있으며, 서열번호 10 또는 이와 95% 이상의 상동성을 나타내는 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되는 것은 아니다.The antigen-binding domain may include a signal peptide, and the signal peptide may be a TLR-4 signal peptide, and may consist of SEQ ID NO: 10 or an amino acid sequence showing 95% or more homology thereto, but is limited thereto not.
본 발명에서 사용되는 벡터는 당 분야에 공지된 벡터를 다양하게 사용할 수 있고, 상기 항원 수용체를 생산하고자 하는 숙주세포의 종류에 따라 프로모터 (promoter), 종결자 (terminator), 인핸서 (enhancer) 등과 같은 발현조절 서열, 막 표적화 또는 분비를 위한 서열 등을 적절히 선택하고 목적에 따라 다양하게 조합할 수 있다. 본 발명의 벡터는 플라스미드 벡터, 코즈미드 벡터, 박테리오 파아지 벡터 및 바이러스 벡터 등을 포함하나 이에 제한되지 않는다. 적합한 벡터는 프로모터, 오퍼레이터, 개시코돈, 종결코돈, 폴리아데닐화 시그널 및 인핸서 같은 발현 조절 엘리먼트 외에도 막 표적화 또는 분비를 위한 시그널 서열 또는 리더 서열을 포함하며 목적에 따라 다양하게 제조될 수 있다.The vector used in the present invention may use a variety of vectors known in the art, and may include a promoter, a terminator, an enhancer, etc., depending on the type of host cell to produce the antigen receptor. Expression control sequences, sequences for membrane targeting or secretion, etc. can be appropriately selected and variously combined according to the purpose. The vector of the present invention includes, but is not limited to, a plasmid vector, a cosmid vector, a bacteriophage vector, and a viral vector. Suitable vectors include a signal sequence or leader sequence for membrane targeting or secretion in addition to expression control elements such as promoter, operator, start codon, stop codon, polyadenylation signal and enhancer, and may be prepared in various ways depending on the purpose.
본 발명에서는 바람직한 일 예로서, 렌티-바이러스용 벡터를 사용할 수 있으며, 본 발명의 하기 실시예에서는 pCDH-CMV-MCS-EF1-copGFP 벡터(렌티-바이러스용 벡터)를 사용하였다(도 5 내지 도 8 참조).In the present invention, as a preferred example, a lenti-virus vector can be used, and in the following examples of the present invention, pCDH-CMV-MCS-EF1-copGFP vector (lenti-virus vector) was used ( FIGS. 5 to 5 ). 8).
또한, 본 발명의 PD-L1에 특이적으로 결합하는 키메릭 항원 수용체를 상기 벡터를 통해 세포에 도입하여 세포를 형질전환시킬 수 있다. 상기 세포는 세포독성 T 세포(cytotoxic T cell)와 NK 세포, 종양 침윤 림프구, B 세포, NK 세포, 또는 NKT 세포일 수 있으며, 바람직하게는, 전문적 항원표출세포인 대식세포, 수지상세포, 미감작 B 세포(naive B cell) 일 수 있다. 일부 실시 양태에서, 상기 세포는 골수, 말초혈액, 말초혈액단핵세포 또는 제대혈로부터 얻거나 제조될 수 있다. 일부 실시양태에서, 세포는 인간 세포이다.In addition, the cell can be transformed by introducing the chimeric antigen receptor that specifically binds to PD-L1 of the present invention into the cell through the vector. The cells may be cytotoxic T cells and NK cells, tumor infiltrating lymphocytes, B cells, NK cells, or NKT cells. It may be a naive B cell. In some embodiments, the cells may be obtained or prepared from bone marrow, peripheral blood, peripheral blood mononuclear cells or umbilical cord blood. In some embodiments, the cell is a human cell.
본 발명의 일 구현예로서, 상기 기술한 벡터를 이용하여 PD-L1에 특이적으로 결합하는 키메릭 항원 수용체를 전문적 항원표출세포에 형질전환시킬 수 있다.As an embodiment of the present invention, a chimeric antigen receptor that specifically binds to PD-L1 can be transformed into specialized antigen-expressing cells using the vector described above.
상기와 같이 본 발명의 키메릭 항원 수용체가 도입되어 형질전환된 세포는 PD-L1을 항원으로 인식하고 이와 강하게 결합하는 특징을 가진다.As described above, the cells transformed by introducing the chimeric antigen receptor of the present invention recognize PD-L1 as an antigen and have a characteristic of strongly binding thereto.
본 발명에서, "키메릭 항원 수용체 발현 전문적 항원표출세포 (chimeric antigen receptor professional antigen presenting cell, 이하 간략하게 'CAR-pAPC 세포’라 약칭함)" 란 정상의 전문적 항원표출세포를 형질도입 등의 방법으로 본래의 전문적 항원표출세포 표면 수용체가 아닌 암세포에 특이적으로 반응하는 키메라 항원 수용체를 발현하는 전문적 항원표출세포를 의미한다. 이 수용체를 갖는 전문적 항원표출세포는 타겟 세포의 세포자살을 유도하여 세포독성을 나타낸다.In the present invention, "chimeric antigen receptor professional antigen presenting cell (hereinafter abbreviated as 'CAR-pAPC cell')" is a method such as transduction of normal professional antigen presenting cells It refers to a specialized antigen-presenting cell expressing a chimeric antigen receptor that specifically responds to cancer cells rather than the original specialized antigen-expressing cell surface receptor. Professional antigen-expressing cells with this receptor induce apoptosis of target cells and exhibit cytotoxicity.
본 발명에 있어, 특히 CAR-pAPC 세포는 전문적 항원표출세포에 본 발명의 키메릭 항원 수용체가 도입된 세포일 수 있다. 상기 세포는 CAR-T 치료제의 기존 장점인 항암 특이적 표적 치료의 장점을 가지며, 특히, 본 발명의 키메라 항원 수용체를 장착시킨 전문적 항원표출세포는 PD-L1을 발현하는 암세포를 인지하여 효과적으로 파괴할 수 있다.In the present invention, in particular, the CAR-pAPC cell may be a cell in which the chimeric antigen receptor of the present invention is introduced into a professional antigen-expressing cell. The cells have the advantage of anticancer-specific targeted therapy, which is the existing advantage of CAR-T therapeutics. In particular, the specialized antigen-expressing cells equipped with the chimeric antigen receptor of the present invention recognize and effectively destroy PD-L1-expressing cancer cells. can
따라서 본 발명의 다른 하나의 양태는 상기 세포를 포함하는 세포치료제; 이를 유효성분으로 포함하는 PD-L1을 발현하는 암의 치료용 약학적 조성물; 및 상기 세포를 개체에 투여하는 단계를 포함하는 암을 치료하는 방법이다. Therefore, another aspect of the present invention is a cell therapy agent comprising the cell; A pharmaceutical composition for the treatment of cancer expressing PD-L1 comprising it as an active ingredient; and administering the cells to a subject.
본 발명에 있어 상기 세포는, 상기 세포는 세포독성 T 세포(cytotoxic T cell)와 NK 세포, 종양 침윤 림프구, B 세포, NK 세포, 또는 NK-T 세포일 수 있으며, 바람직하게는, 전문적 항원표출세포인 대식세포, 수지상세포, 미감작 B 세포(naive B cell) 일 수 있다. 또는 전구 세포(progenitor cell), 예를 들어, 조혈 줄기세포, 중간엽 간질 세포, 줄기세포, 전분화능 줄기세포, 및 배아 줄기세포일 수 있으며, 이들은 항암치료 등의 세포 요법에 사용될 수 있다. 세포는 공여자로부터 올 수 있거나, 환자로부터 얻어진 세포가 될 수 있다. 세포는 예를 들어, 병에 걸린 세포의 기능을 대체하는 재생에 사용될 수 있다. 세포는 또한 이종 유전자를 발현하도록 변형되어 생물학 제제가, 예를 들어, 병에 걸린 골수 또는 전이성 침착물과 같은 특정 미세 환경으로 전달될 수 있다.In the present invention, the cell, the cell may be a cytotoxic T cell (cytotoxic T cell) and NK cells, tumor infiltrating lymphocytes, B cells, NK cells, or NK-T cells, preferably, specialized antigen expression The cells may be macrophages, dendritic cells, or naive B cells. Or progenitor cells, for example, hematopoietic stem cells, mesenchymal stromal cells, stem cells, pluripotent stem cells, and may be embryonic stem cells, which may be used in cell therapy such as anticancer therapy. The cells may come from a donor, or they may be cells obtained from a patient. Cells can be used, for example, in regeneration, replacing the function of diseased cells. Cells can also be modified to express heterologous genes so that biological agents can be delivered to specific microenvironments, such as, for example, diseased bone marrow or metastatic deposits.
본 발명에서, "세포 치료제"는 개체로부터 분리, 배양 및 특수한 조작을 통해 제조된 세포 및 조직으로 치료, 진단 및 예방의 목적으로 사용되는 의약품(미국 FDA 규정)으로서, 세포 혹은 조직의 기능을 복원시키기 위하여 살아있는 자가, 동종, 또는 이종 세포를 체외에서 증식 선별하거나 다른 방법으로 세포의 생물학적 특성을 변화시키는 등의 일련의 행위를 통하여 치료, 진단 및 예방의 목적으로 사용되는 의약품을 의미한다.In the present invention, "cell therapeutic" refers to cells and tissues manufactured through isolation, culture, and special manipulation from an individual, and is a drug (US FDA regulations) used for the purpose of treatment, diagnosis, and prevention, restoring the function of cells or tissues. It refers to a drug used for the purpose of treatment, diagnosis, and prevention through a series of actions such as proliferating and selecting living autologous, allogeneic, or xenogeneic cells in vitro or changing the biological properties of cells in other ways.
본 발명의 용어 "예방"은 상기 조성물의 투여에 의해 PD-L1을 발현하는 암을 억제시키거나 발생을 지연시키는 모든 행위를 의미한다.As used herein, the term “prevention” refers to any action of inhibiting or delaying the development of a cancer expressing PD-L1 by administration of the composition.
본 발명의 용어, "치료"는 상기 조성물의 투여에 의해 PD-L1을 발현하는 암에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term “treatment” refers to any action in which symptoms caused by cancer expressing PD-L1 are improved or beneficially changed by administration of the composition.
상기 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다.The composition may include a pharmaceutically acceptable carrier.
상기 "약학적으로 허용 가능한 담체"란 생물체를 자극하지 않으면서, 주입되는 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 의미할 수 있다. 본 발명에 사용 가능한 상기 담체의 종류는 특별히 제한되지 아니하며 당해 기술 분야에서 통상적으로 사용되고 약학적으로 허용되는 담체라면 어느 것이든 사용할 수 있다. 상기 담체의 비제한적인 예로는, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사 용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 등을 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.The "pharmaceutically acceptable carrier" may mean a carrier or diluent that does not inhibit the biological activity and properties of the injected compound without irritating the organism. The type of carrier usable in the present invention is not particularly limited, and any carrier commonly used in the art and pharmaceutically acceptable may be used. Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like. These may be used alone or in combination of two or more.
약학적으로 허용 가능한 담체를 포함하는 상기 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다.The composition comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used.
상세하게는, 경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 오일, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient to the compound, for example, starch, calcium carbonate, sucrose, lactose. , gelatin, etc. may be mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, Witepsol, Macrogol, Tween 61, cacao butter, laurin fat, glycerogelatin, etc. may be used.
상기 조성물은 약학적으로 유효한 양으로 투여할 수 있다.The composition may be administered in a pharmaceutically effective amount.
상기 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 감염된 바이러스 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.The "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is dependent on the subject's type and severity, age, sex, infected virus type, and drug. Activity, sensitivity to drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant drugs and other factors well known in the medical field.
상기 투여는 어떠한 적절한 방법으로 환자에게 본 발명의 조성물을 도입하는 것을 의미하며, 상기 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강 내 투여, 정맥내 투여, 근육 내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비 내 투여될 수 있으나, 이에 제한되지는 않는다.The administration means introducing the composition of the present invention to the patient by any suitable method, and the administration route of the composition may be administered through any general route as long as it can reach the target tissue. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, may be administered intranasally, but is not limited thereto.
본 발명의 조성물을 매일 투여 또는 간헐적으로 투여해도 좋고, 1일당 투여 횟수는 1회 또는 2~3회로 나누어 투여하는 것이 가능하다. 두 유효성분이 각각 단제인 경우의 투여횟수는 같은 횟수여도 좋고, 다른 횟수로 해도 된다. 또한, 본 발명의 조성물은 혈액암의 예방 또는 치료를 위하여 단독으로, 또는 다른 약물 치료와 병용하여 사용할 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The composition of the present invention may be administered daily or intermittently, and the number of administrations per day may be administered once or divided into two to three times. When the two active ingredients are single drugs, the number of administrations may be the same or different. In addition, the composition of the present invention may be used alone or in combination with other drug treatments for the prevention or treatment of hematologic cancer. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art.
상기 개체란, PD-L1을 발현하는 암이 발병하였거나 발병할 수 있는 인간과, 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미한다. 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 질환을 효과적으로 예방 또는 치료할 수 있다면 개체의 종류는 제한 없이 포함된다.The subject means a human, monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig that has or can develop cancer expressing PD-L1. all animals, including If the disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the subject, the type of subject is included without limitation.
본 발명에 있어 치료 대상이 되는 PD-L1을 발현하는 암의 종류로는 암종은 흑색종(melanoma), 폐암(lung cancer), 육종(Sarcoma), 신장암(renal-cell carcinoma), 림프종(lymphoma), 직장암(colorectal cancer), 위암(gastric cancer), 식도암(esophageal cancer), 진행된 고형암(advanced solid tumor), 유방암(breast cancer), 두경부암(head and neck cancer), 난소암(ovarian cancer), 전립선암(prostate cancer) 일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, as the type of PD-L1-expressing cancer to be treated, carcinoma is melanoma, lung cancer, sarcoma, renal-cell carcinoma, and lymphoma. ), colorectal cancer, gastric cancer, esophageal cancer, advanced solid tumor, breast cancer, head and neck cancer, ovarian cancer, It may be prostate cancer, but is not limited thereto.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. These Examples are for illustrating the present invention in more detail, and the scope of the present invention is not limited to these Examples.
실시예Example 1. 유전자 합성 방법에 의한 유전자의 1. Gene by gene synthesis method 클로닝cloning
본 발명의 키메릭 항원 수용체를 제조하기 위해서 PD-1의 세포외 도메인과 TLR-2의 막관통 도메인의 서열을 가지며, 서로 다른 세포 내 신호 전달 도메인을 암호화하는 서열을 가진 4종류의 키메릭 항원 수용체 단백질 암호화 서열을 합성하였다. 키메릭 항원 수용체는 PD-1의 세포외 도메인 한쌍을 각각 인간 이뮤노글로불린 G1 중쇄 불변 영역(IgG1 heavy chain constant region)에 연결시킨 항원 인식 부위, TLR-2의 막관통 도메인, TLR-4 신호 펩타이드를 공통적으로 포함하며. 신호전달 도메인을 각각 다른 4가지 구성으로 하여 제작하였다. 하기 표 1에 상기 4종류의 신호전달 도메인의 구성을 기재하였다.In order to prepare the chimeric antigen receptor of the present invention, four types of chimeric antigens having sequences of the extracellular domain of PD-1 and the transmembrane domain of TLR-2, and sequences encoding different intracellular signal transduction domains The receptor protein coding sequence was synthesized. The chimeric antigen receptor is an antigen recognition site linking a pair of extracellular domains of PD- 1 to human immunoglobulin G 1 heavy chain constant region, respectively, a transmembrane domain of TLR-2, TLR-4 It commonly contains a signal peptide. Each of the signaling domains was constructed in four different configurations. Table 1 below describes the configuration of the four types of signaling domains.
상기 제작한 키메릭 항원 수용체를 발현시키는 각 도메인의 cDNA 모식도를 도 1 내지 도 4에 나타내었다. 각 도메인 부분의 단백질 암호화 서열은 유전자 데이터베이스(database)에서 확인하였으며, 유전자 합성의 정확도는 단백질 발현 플라스미드를 제작한 후 시퀀싱을 통해 확인하였다.Schematic diagrams of cDNAs of each domain expressing the chimeric antigen receptor constructed above are shown in FIGS. 1 to 4 . The protein coding sequence of each domain part was confirmed in a gene database, and the accuracy of gene synthesis was confirmed through sequencing after a protein expression plasmid was prepared.
실시예Example 2. 단백질 발현 플라스미드 제조 2. Preparation of protein expression plasmids
상기 실시예 1에서 제작한 4종의 키메릭 항원 수용체의 PD-1의 세포외 도메인과 대식 세포 신호전달 단백질을 융합시킨 재조합 단백질(도5 ~ 도8)을 대식 세포에서 발현시키기 위해, 해당 유전자를 렌티바이러스 유래 발현벡터인 pCDH-CMV-MCS-EF1-copGFP(System Biosciences)에 제한효소 XbaI과 NotI의 절단 부위를 이용하여 클로닝 하였다. In order to express in macrophages the recombinant protein ( FIGS. 5 to 8 ) in which the extracellular domain of PD-1 of the four chimeric antigen receptors prepared in Example 1 and a macrophage signaling protein are fused, the corresponding gene was cloned into a lentivirus-derived expression vector, pCDH-CMV-MCS-EF1-copGFP (System Biosciences), using restriction enzymes Xba I and Not I cleavage sites.
그 결과 도 9 내지 도 12의 구조로 된 PD-1의 세포외 도메인과 신규 신호 전달 단백질이 융합된 단백질 4종을 발현하는 재조합 벡터를 완성하였다(도 5 내지 도 8 참조).As a result, a recombinant vector expressing four proteins in which the extracellular domain of PD-1 having the structure of FIGS. 9 to 12 and a novel signal transduction protein was fused was completed (see FIGS. 5 to 8 ).
실시예Example 3. PD-L1을 발현하는 사람 세포주 screening 3. Screening of human cell lines expressing PD-L1
PD-L1을 세포 표면에 발현하는 사람 세포주를 screening하기 위해서, B 세포 림프종(B cell lymphoma)유래 세포주인 Raji (ATCC) 세포주에서 PD-L1의 발현을 확인하였다. 발현 확인을 위해 형광단백질이 부착된 PD-L1과 결합이 가능한 항체(biolegend)를 세포주에 처리한 후, 유세포 분석(fluorescence-activated cell sorting)을 이용하였다. 분석결과, Raji 세포주에서 PD-L1을 발현하는 것을 확인하였다(도 13참조). 상기 결과를 근거로 PD-L1을 발현하는 Raji 세포주를 표적세포(target cell)로 사용하였다.In order to screen a human cell line expressing PD-L1 on the cell surface, the expression of PD-L1 was confirmed in the Raji (ATCC) cell line, which is a B cell lymphoma-derived cell line. In order to confirm the expression, the cell line was treated with an antibody (biolegend) capable of binding to PD-L1 to which the fluorescent protein was attached, and then flow cytometry (fluorescence-activated cell sorting) was used. As a result of the analysis, it was confirmed that PD-L1 was expressed in the Raji cell line (see FIG. 13 ). Based on the above results, a Raji cell line expressing PD-L1 was used as a target cell.
실시예Example 4. 4. 키메릭chimeric 항원 수용체 발현 전문적 항원표출세포 제작 Antigen receptor expression specialized antigen-expressing cell production
상기 실시예 2를 통해 제작한 재조합 키메릭 항원 수용체 발현 벡터 4종을 전문적 항원표출세포의 일종인 THP-1 세포(사람 대식 세포주)에 도입하기 위하여 293FT 세포(Thermo Fisher Scientific社)를 사용한 렌티바이러스 시스템을 이용하였다. Lentivirus using 293FT cells (Thermo Fisher Scientific) to introduce the four recombinant chimeric antigen receptor expression vectors prepared in Example 2 into THP-1 cells (human macrophage cell line), a type of specialized antigen-expressing cells. system was used.
먼저, 293FT 세포를 100π 세포 배양 접시에 2.5Х106 세포가 되도록 접종한 후, 10% 송아지 혈청을 함유한 DMEM 배지에서 배양하였다. 배양 24시간 후, 세포가 접시의 60~70% 정도를 덮을 정도로 자라면, 상기 실시예 2의 4종의 벡터 DNA 각각을 20μg으로 분주하여, 10μg의 psPAX2(Addgene)와 3μg의 pMD2.G(Addgene) 벡터와 함께 Calcium phosphate를 Calcium phosphate 및 Hepes-buffered solution을 이용하여 결정화시킨 후 293FT 세포에 도입하였다. 그 후, 상기 발현 벡터가 도입된 293FT 세포를 48시간 후 24시간 간격으로 바이러스(렌티바이러스)를 포함하는 배양 상층액을 모았다. 모은 상층액을 초고속 원심분리기를 21,000rpm으로 2시간 동안 원심분리하여 바이러스를 농축시켰다. 농축된 바이러스를 polybrene 4μg/ml과 혼합하여 대식 세포주인 THP-1 세포의 배양액에 추가하여 형질도입을 진행하였다. 24시간 간격으로 2회 농축된 바이러스를 넣어준 배양액으로 THP-1 세포의 배양액을 변경하여 형질도입의 효율을 증가시켰다. 마지막 배양액 교체 후, 24시간이 지난 다음, 형질도입한 THP-1 세포의 일부를 형질도입 효율 측정에 사용하였다. 형질도입 효율은 세포 내부의 GFP 발현량을 유세포 분석을 이용해 측정했으며, 4종의 재조합 키메릭 항원 수용체 발현 벡터가 각각 형질도입된 THP-1 세포를, empty vetor (Mock)를 형질도입한 THP-1 세포의 형질도입 비율과 비교한 결과를 도 14에 나타내었다.First, 293FT cells were inoculated to become 2.5Х10 6 cells in a 100π cell culture dish, and then cultured in DMEM medium containing 10% calf serum. After 24 hours of incubation, when the cells have grown to cover about 60-70% of the dish, 20 µg of each of the four vector DNAs of Example 2 is aliquoted, 10 µg of psPAX2 (Addgene) and 3 µg of pMD2.G ( Addgene) vector and calcium phosphate were crystallized using calcium phosphate and Hepes-buffered solution, and then introduced into 293FT cells. Then, the culture supernatant containing the virus (lentivirus) was collected at intervals of 24 hours after 48 hours of the 293FT cells introduced with the expression vector. The collected supernatant was centrifuged at 21,000 rpm in an ultra-high speed centrifuge for 2 hours to concentrate the virus. The concentrated virus was mixed with 4 μg/ml of polybrene and added to the culture medium of THP-1 cells, a macrophage cell line, for transduction. The efficiency of transduction was increased by changing the culture medium of THP-1 cells to the culture medium in which the concentrated virus was added twice at 24 hour intervals. 24 hours after the last culture medium change, a portion of the transduced THP-1 cells was used to measure the transduction efficiency. Transduction efficiency was measured using flow cytometry for the expression level of GFP inside the cells, and THP-1 cells transduced with each of the four recombinant chimeric antigen receptor expression vectors, and THP- cells transduced with an empty vector (Mock) The results compared with the transduction ratio of one cell are shown in FIG. 14 .
실시예Example 5. 5. 키메릭chimeric 항원 수용체와 PD-L1을 발현하는 사람 세포주의 친화도 측정 Affinity determination of antigen receptors and human cell lines expressing PD-L1
상기 실시예 4에서 제작한 4종의 재조합 키메릭 항원 수용체가 PD-L1을 발현하는 사람 세포주와 친화도가 있는지 확인하기 위하여, 4종의 키메릭 항원 수용체 발현 전문적 항원표출세포들에 수용성 재조합 human PD-L1 IgG (R&D system)를 처리하여 유세포 분석을 통하여 확인하였다. 그 결과, 수용성 재조합 human PD-L1 IgG는 Mock CAR-pAPC와 결합하지 않았지만, 4종의 PD-1 키메릭 항원 수용체 발현 전문적 항원표출세포들에 결합하였다(도 15 참조). 상기 결과를 근거로 제작한 키메릭 항원 수용체를 발현하는 4종의 PD-1 키메릭 항원 수용체 발현 전문적 항원표출세포들을 작동 세포(effector cell)로 PD-L1을 발현하는 Raji 세포주를 표적세포로, PD-1 CAR-pAPC의 PD-L1 특이적 세포독성을 검증하였다. In order to confirm whether the four recombinant chimeric antigen receptors prepared in Example 4 have affinity with the PD-L1 expressing human cell line, the soluble recombinant human It was confirmed through flow cytometry by treating PD-L1 IgG (R&D system). As a result, the water-soluble recombinant human PD-L1 IgG did not bind to Mock CAR-pAPC, but bound to 4 types of PD-1 chimeric antigen receptor-expressing specialized antigen-expressing cells (see FIG. 15). Based on the above results, four types of PD-1 chimeric antigen receptor-expressing PD-1 chimeric antigen receptor-expressing specialized antigen-expressing cells prepared based on the above results were used as effector cells, and the Raji cell line expressing PD-L1 was used as target cells, PD-L1-specific cytotoxicity of PD-1 CAR-pAPC was verified.
실시예Example 6. PD-L1을 발현하는 세포(PD-L1 positive cell)와의 6. With cells expressing PD-L1 (PD-L1 positive cells) 공배양을co-culture 통한 PD-L1 특이적 세포독성 검증 PD-L1-specific cytotoxicity verification through
상기 제작한 키메릭 항원 수용체 발현 THP-1 세포 4종이 PD-L1을 발현하는 세포(PD-L1 positive cell, PD-L1+ cell)를 선택적으로 인지하여 독성을 나타내는지 확인하기 위해 실시예 3에서 선정한 타겟 세포인 Raji 세포를 키메릭 항원 수용체 발현 THP-1 세포 4종 혹은 공벡터를 도입한 THP-1 세포(Mock)와 공배양하였다. 공배양 후, 24시간 혹은 48시간 뒤에 7-Aminoactinomycin D (7-AAD)를 처리하여 7-AAD의 형광 발현량을 유세포 분석으로 비교하여 각 키메릭 항원 수용체 발현 THP-1 세포의 세포독성을 측정하였다. 7-Aminoactinomycin D (7-AAD)는 세포자살(apoptosis)이 유도된 세포의 DNA와 결합하여 형광을 띠게 된다(Zembruski et al., 2012).In Example 3, in Example 3, in order to confirm that the four prepared chimeric antigen receptor-expressing THP-1 cells selectively recognize cells expressing PD-L1 (PD-L1 positive cells, PD-L1 + cells) and show toxicity. The selected target cells, Raji cells, were co-cultured with 4 types of chimeric antigen receptor-expressing THP-1 cells or THP-1 cells (Mock) introduced with an empty vector. After co-culture, treatment with 7-Aminoactinomycin D (7-AAD) was performed 24 or 48 hours later, and the cytotoxicity of each chimeric antigen receptor-expressing THP-1 cell was measured by comparing the fluorescence expression level of 7-AAD by flow cytometry. did. 7-Aminoactinomycin D (7-AAD) binds to the DNA of the cell in which apoptosis is induced and becomes fluorescent (Zembruski et al., 2012).
먼저, 24 well 세포 배양 접시의 well에 키메릭 항원 수용체 발현 THP-1 세포 4종 각각을 5Х105로 분주하고, 표적 세포인 PD-L1+ cell (Raji cell)을 1Х105씩 분주하여 effector: target ratio가 5:1로 공배양 진행하였다. 공배양의 well당 부피는 1 ml가 되도록 진행하였고, 원심분리기를 이용해 250g에서 4분 동안 원심분리하여 세포 간 간격을 가깝게 만들었다. 그 후, 24시간 또는 48시간 공배양 진행 후 각 well의 세포를 원심분리기를 이용하여 300g, 3분 원심분리하여 상층액을 제거한 뒤, 7-AAD (Biolegend)로 세포를 염색하였다. 그 후 유세포 분석을 이용하여 7-AAD에 의해 형광을 나타내는 세포의 비율을 측정하여 제작한 키메릭 항원 수용체 발현 THP-1 세포 4종의 세포독성을 정도를 정량화하였다.First, each of the 4 types of chimeric antigen receptor-expressing THP-1 cells was dispensed at 5Х10 5 into the wells of a 24-well cell culture dish, and PD-L1 + cells (Raji cells), the target cells, were dispensed by 1Х10 5 each to effector: target. Co-culture was carried out at a ratio of 5:1. The volume per well of the co-culture was proceeded to be 1 ml, and centrifuged at 250 g for 4 minutes using a centrifuge to make the intercellular space close. Then, after co-culture for 24 hours or 48 hours, the cells in each well were centrifuged at 300 g for 3 minutes using a centrifuge to remove the supernatant, and then the cells were stained with 7-AAD (Biolegend). Thereafter, the cytotoxicity of the four chimeric antigen receptor-expressing THP-1 cells prepared by measuring the proportion of cells exhibiting fluorescence by 7-AAD using flow cytometry was quantified.
그 결과 도 16에서 나타낸 바와 같이, 제작한 키메릭 항원 수용체 발현 THP-1 세포를 PD-L1+ cell (Raji cell)과 공배양 후, 24시간이 지났을 때, 키메릭 항원 수용체를 발현하지 않는 THP-1 세포(Mock)는 15.5% 정도의 세포독성을 보인 반면, 4종의 키메릭 항원 수용체 발현 THP-1 세포인 3-4-3 THP-1 세포(TLR-3+TLR-4+FcεRIγ ITAM trimer), 3-4-2A THP-1 세포(TLR-3+TLR4+FcγR2Aα ITAM trimer), 3-4-1B THP-1 세포(TLR-3+TLR4+FcεRIβ ITAM trimer), 3-4-ABC THP-1 세포(TLR-3+TLR4+FcγR2A ITAM monomer+FcεRIβ ITAM monomer+FcγR2Aα ITAM monomer)에서는 각각 27.7%, 25.2%, 25.6%, 27.8%의 매우 높은 세포독성을 보임을 확인할 수 있었다. As a result, as shown in FIG. 16 , when the prepared chimeric antigen receptor-expressing THP-1 cells were co-cultured with PD-L1 + cells (Raji cells), 24 hours passed, THP not expressing the chimeric antigen receptor -1 cells (Mock) showed about 15.5% cytotoxicity, whereas 3-4-3 THP-1 cells (TLR-3+TLR-4+FcεRIγ ITAM), which are THP-1 cells expressing 4 types of chimeric antigen receptors trimer), 3-4-2A THP-1 cells (TLR-3+TLR4+FcγR2Aα ITAM trimer), 3-4-1B THP-1 cells (TLR-3+TLR4+FcεRIβ ITAM trimer), 3-4-ABC THP-1 cells (TLR-3+TLR4+FcγR2A ITAM monomer+FcεRIβ ITAM monomer+FcγR2Aα ITAM monomer) showed very high cytotoxicity of 27.7%, 25.2%, 25.6%, and 27.8%, respectively.
또한, 도 17에서 나타낸 바와 같이, 공배양 후, 48시간이 지난 다음 공배양한 Raji cell의 세포독성을 확인해 보았을 때, Mock의 경우 35% 정도의 세포독성을 보인 반면, 4종의 키메릭 항원 수용체 발현 THP-1 세포인 3-4-3 THP-1 세포(TLR-3+TLR-4+FcεRIγ ITAM trimer), 3-4-2A THP-1 세포(TLR-3+TLR4+FcγR2Aα ITAM trimer), 3-4-1B THP-1 세포(TLR-3+TLR4+FcεRIβ ITAM trimer), 3-4-ABC THP-1 세포(TLR-3+TLR4+FcγR2A ITAM monomer+FcεRIβ ITAM monomer+FcγR2Aα ITAM monomer)에서는 각각 63.3%, 54.1%, 53.9%, 50.4%의 매우 높은 세포독성을 보임을 확인할 수 있었다. 이를 통해 제작한 키메릭 항원 인지 수용체 발현 THP-1 세포가 PD-L1 단백질에 특이적인 세포독성을 보임을 확인할 수 있었다.In addition, as shown in FIG. 17 , when the cytotoxicity of the co-cultured Raji cells was confirmed 48 hours after the co-culture, the Mock showed about 35% cytotoxicity, while the 4 types of chimeric antigens Receptor expressing THP-1 cells, 3-4-3 THP-1 cells (TLR-3+TLR-4+FcεRIγ ITAM trimer), 3-4-2A THP-1 cells (TLR-3+TLR4+FcγR2Aα ITAM trimer) , 3-4-1B THP-1 cells (TLR-3+TLR4+FcεRIβ ITAM trimer), 3-4-ABC THP-1 cells (TLR-3+TLR4+FcγR2A ITAM monomer+FcεRIβ ITAM monomer+FcγR2Aα ITAM monomer) showed very high cytotoxicity of 63.3%, 54.1%, 53.9%, and 50.4%, respectively. Through this, it was confirmed that the prepared chimeric antigen recognition receptor-expressing THP-1 cells showed specific cytotoxicity to PD-L1 protein.
상기 결과를 통해 본 발명에 따른 키메릭 항원 수용체를 포함한 형질전환된 THP-1 세포가 PD-L1 단백질에 특이적인 세포독성을 보임으로써, 상기 형질전환된 항원 특이적 전문적 항원표출세포를 이용하여 관련된 암 세포 치료가 가능함을 확인할 수 있었다.Through the above results, the transformed THP-1 cells containing the chimeric antigen receptor according to the present invention were PD-L1 By showing the protein-specific cytotoxicity, it was confirmed that the treatment of related cancer cells was possible using the transformed antigen-specific specialized antigen-expressing cells.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
<110> IMMUNOLOGICAL DESIGNINGLAB CO., LTD <120> PD1.CAR-MAC <130> KP21-0030-ILDL <160> 20 <170> KoPatentIn 3.0 <210> 1 <211> 144 <212> PRT <213> Artificial Sequence <220> <223> PD-1 extracellular domain <400> 1 Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu 1 5 10 15 Val Val Thr Glu Gly Asp Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn 20 25 30 Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn 35 40 45 Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly 50 55 60 Gln Asp Cys Arg Phe Arg Val Thr Gln Leu Pro Asn Gly Arg Asp Phe 65 70 75 80 His Met Ser Val Val Arg Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu 85 90 95 Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu 100 105 110 Arg Ala Glu Leu Arg Val Thr Glu Arg Arg Ala Glu Val Pro Thr Ala 115 120 125 His Pro Ser Pro Ser Pro Arg Ser Ala Gly Gln Phe Gln Thr Leu Val 130 135 140 <210> 2 <211> 234 <212> PRT <213> Artificial Sequence <220> <223> IgG1 heavy chain constant region <400> 2 Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 1 5 10 15 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 20 25 30 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 35 40 45 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 50 55 60 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 65 70 75 80 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 85 90 95 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 100 105 110 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 115 120 125 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 130 135 140 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 145 150 155 160 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 165 170 175 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 180 185 190 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 195 200 205 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 210 215 220 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 225 230 <210> 3 <211> 143 <212> PRT <213> Artificial Sequence <220> <223> hTLR-3 TIR domain <400> 3 Phe Glu Tyr Ala Ala Tyr Ile Ile His Ala Tyr Lys Asp Lys Asp Trp 1 5 10 15 Val Trp Glu His Phe Ser Ser Met Glu Lys Glu Asp Gln Ser Leu Lys 20 25 30 Phe Cys Leu Glu Glu Arg Asp Phe Glu Ala Gly Val Phe Glu Leu Glu 35 40 45 Ala Ile Val Asn Ser Ile Lys Arg Ser Arg Lys Ile Ile Phe Val Ile 50 55 60 Thr His His Leu Leu Lys Asp Pro Leu Cys Lys Arg Phe Lys Val His 65 70 75 80 His Ala Val Gln Gln Ala Ile Glu Gln Asn Leu Asp Ser Ile Ile Leu 85 90 95 Val Phe Leu Glu Glu Ile Pro Asp Tyr Lys Leu Asn His Ala Leu Cys 100 105 110 Leu Arg Arg Gly Met Phe Lys Ser His Cys Ile Leu Asn Trp Pro Val 115 120 125 Gln Lys Glu Arg Ile Gly Ala Phe Arg His Lys Leu Gln Val Ala 130 135 140 <210> 4 <211> 147 <212> PRT <213> Artificial Sequence <220> <223> hTLR-4 TIR domain <400> 4 Asn Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp 1 5 10 15 Val Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe 20 25 30 Gln Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala 35 40 45 Ala Asn Ile Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val 50 55 60 Val Val Ser Gln His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr 65 70 75 80 Glu Ile Ala Gln Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile 85 90 95 Phe Ile Val Leu Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val 100 105 110 Glu Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp 115 120 125 Ser Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu 130 135 140 Leu Asp Gly 145 <210> 5 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> ITAM of IgE receptor gamma chain <400> 5 Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser 1 5 10 15 Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu 20 25 <210> 6 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> ITAM of IgG receptor 2A alpha chain <400> 6 Asp Gly Gly Tyr Met Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp 1 5 10 15 Lys Asn Ile Tyr Leu Thr Leu 20 <210> 7 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> ITAM of IgE receptor beta chain <400> 7 Lys Val Pro Glu Asp Arg Val Tyr Glu Glu Leu Asn Ile Tyr Ser Ala 1 5 10 15 Thr Tyr Ser Glu Leu Glu Asp Pro Gly Glu Met Ser Pro 20 25 <210> 8 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Flexible linker <400> 8 Gly Gly Gly Gly Ser 1 5 <210> 9 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> hTLR-2 transmembrane domain <400> 9 Ala Leu Val Ser Gly Met Cys Cys Ala Leu Phe Leu Leu Ile Leu Leu 1 5 10 15 Thr Gly Val Leu Cys 20 <210> 10 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> hTLR-4 Signal peptide <400> 10 Met Met Ser Ala Ser Arg Leu Ala Gly Thr Leu Ile Pro Ala Met Ala 1 5 10 15 Phe Leu Ser Cys Val Arg Pro 20 <210> 11 <211> 432 <212> DNA <213> Artificial Sequence <220> <223> PD-1 extracellular domain <400> 11 tccccagaca ggccctggaa cccccccacc ttctccccag ccctgctcgt ggtgaccgaa 60 ggggacaacg ccaccttcac ctgcagcttc tccaacacat cggagagctt cgtgctaaac 120 tggtaccgca tgagccccag caaccagacg gacaagctgg ccgccttccc cgaggaccgc 180 agccagcccg gccaggactg ccgcttccgt gtcacacaac tgcccaacgg gcgtgacttc 240 cacatgagcg tggtcagggc ccggcgcaat gacagcggca cctacctctg tggggccatc 300 tccctggccc ccaaggcgca gatcaaagag agcctgcggg cagagctcag ggtgacagag 360 agaagggcag aagtgcccac agcccacccc agcccctcac ccaggtcagc cggccagttc 420 caaaccctgg tg 432 <210> 12 <211> 702 <212> DNA <213> Artificial Sequence <220> <223> IgG1 heavy chain constant region <400> 12 ggatccgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 60 ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 120 tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 180 aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 240 gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 300 ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 360 aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 420 tcacgagatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 480 cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 540 acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 600 aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 660 aaccactaca cgcagaagag cctctccctg tctccgggta aa 702 <210> 13 <211> 429 <212> DNA <213> Artificial Sequence <220> <223> hTLR-3 TIR domain <400> 13 tttgaatatg cagcatatat aattcatgcc tataaagata aggattgggt ctgggaacat 60 ttctcttcaa tggaaaagga agaccaatct ctcaaatttt gtctggaaga aagggacttt 120 gaggcgggtg tttttgaact agaagcaatt gttaacagca tcaaaagaag cagaaaaatt 180 atttttgtta taacacacca tctattaaaa gacccattat gcaaaagatt caaggtacat 240 catgcagttc aacaagctat tgaacaaaat ctggattcca ttatattggt tttccttgag 300 gagattccag attataaact gaaccatgca ctctgtttgc gaagaggaat gtttaaatct 360 cactgcatct tgaactggcc agttcagaaa gaacggatag gtgcctttcg tcataaattg 420 caagtagca 429 <210> 14 <211> 441 <212> DNA <213> Artificial Sequence <220> <223> hTLR-4 TIR domain <400> 14 aacatctatg atgcctttgt tatctactca agccaggatg aggactgggt aaggaatgag 60 ctagtaaaga atttagaaga aggggtgcct ccatttcagc tctgccttca ctacagagac 120 tttattcccg gtgtggccat tgctgccaac atcatccatg aaggtttcca taaaagccga 180 aaggtgattg ttgtggtgtc ccagcacttc atccagagcc gctggtgtat ctttgaatat 240 gagattgctc agacctggca gtttctgagc agtcgtgctg gtatcatctt cattgtcctg 300 cagaaggtgg agaagaccct gctcaggcag caggtggagc tgtaccgcct tctcagcagg 360 aacacttacc tggagtggga ggacagtgtc ctggggcggc acatcttctg gagacgactc 420 agaaaagccc tgctggatgg t 441 <210> 15 <211> 87 <212> DNA <213> Artificial Sequence <220> <223> ITAM of IgE receptor gamma chain <400> 15 gctataacca gctatgagaa atcagatggt gtttacacgg gcctgagcac caggaaccag 60 gagacttacg agactctgaa gcatgag 87 <210> 16 <211> 69 <212> DNA <213> Artificial Sequence <220> <223> ITAM of IgG receptor 2A alpha chain <400> 16 gacggcggct acatgactct gaaccccagg gcacctactg acgatgataa aaacatctac 60 ctgactctt 69 <210> 17 <211> 87 <212> DNA <213> Artificial Sequence <220> <223> ITAM of IgE receptor beta chain <400> 17 aaggttccag aggatcgtgt ttatgaagaa ttaaacatat attcagctac ttacagtgag 60 ttggaagacc caggggaaat gtctcct 87 <210> 18 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Flexible linker <400> 18 ggtggcggtg gctcg 15 <210> 19 <211> 63 <212> DNA <213> Artificial Sequence <220> <223> hTLR-2 transmembrane domain <400> 19 gcactggtgt ctggcatgtg ctgtgctctg ttcctgctga tcctgctcac cggtgtcctg 60 tgc 63 <210> 20 <211> 69 <212> DNA <213> Artificial Sequence <220> <223> hTLR-4 Signal peptide <400> 20 atgatgtctg cctcgcgcct ggctgggact ctgatcccag ccatggcctt cctctcctgc 60 gtgagacca 69 <110> IMMUNOLOGICAL DESIGNINGLAB CO., LTD <120> PD1.CAR-MAC <130> KP21-0030-ILDL <160> 20 <170> KoPatentIn 3.0 <210> 1 <211> 144 <212> PRT <213> Artificial Sequence <220> <223> PD-1 extracellular domain <400> 1 Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu 1 5 10 15 Val Val Thr Glu Gly Asp Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn 20 25 30 Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn 35 40 45 Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly 50 55 60 Gln Asp Cys Arg Phe Arg Val Thr Gln Leu Pro Asn Gly Arg Asp Phe 65 70 75 80 His Met Ser Val Val Arg Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu 85 90 95 Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu 100 105 110 Arg Ala Glu Leu Arg Val Thr Glu Arg Arg Ala Glu Val Pro Thr Ala 115 120 125 His Pro Ser Pro Ser Pro Arg Ser Ala Gly Gln Phe Gln Thr Leu Val 130 135 140 <210> 2 <211> 234 <212> PRT <213> Artificial Sequence <220> <223> IgG1 heavy chain constant region <400> 2 Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 1 5 10 15 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 20 25 30 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 35 40 45 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 50 55 60 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 65 70 75 80 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 85 90 95 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 100 105 110 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 115 120 125 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 130 135 140 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 145 150 155 160 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 165 170 175 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 180 185 190 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 195 200 205 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 210 215 220 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 225 230 <210> 3 <211> 143 <212> PRT <213> Artificial Sequence <220> <223> hTLR-3 TIR domain <400> 3 Phe Glu Tyr Ala Ala Tyr Ile Ile His Ala Tyr Lys Asp Lys Asp Trp 1 5 10 15 Val Trp Glu His Phe Ser Ser Met Glu Lys Glu Asp Gln Ser Leu Lys 20 25 30 Phe Cys Leu Glu Glu Arg Asp Phe Glu Ala Gly Val Phe Glu Leu Glu 35 40 45 Ala Ile Val Asn Ser Ile Lys Arg Ser Arg Lys Ile Ile Phe Val Ile 50 55 60 Thr His His Leu Leu Lys Asp Pro Leu Cys Lys Arg Phe Lys Val His 65 70 75 80 His Ala Val Gln Gln Ala Ile Glu Gln Asn Leu Asp Ser Ile Ile Leu 85 90 95 Val Phe Leu Glu Glu Ile Pro Asp Tyr Lys Leu Asn His Ala Leu Cys 100 105 110 Leu Arg Arg Gly Met Phe Lys Ser His Cys Ile Leu Asn Trp Pro Val 115 120 125 Gln Lys Glu Arg Ile Gly Ala Phe Arg His Lys Leu Gln Val Ala 130 135 140 <210> 4 <211> 147 <212> PRT <213> Artificial Sequence <220> <223> hTLR-4 TIR domain <400> 4 Asn Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp 1 5 10 15 Val Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe 20 25 30 Gln Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala 35 40 45 Ala Asn Ile Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val 50 55 60 Val Val Ser Gln His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr 65 70 75 80 Glu Ile Ala Gln Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile 85 90 95 Phe Ile Val Leu Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val 100 105 110 Glu Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp 115 120 125 Ser Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu 130 135 140 Leu Asp Gly 145 <210> 5 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> ITAM of IgE receptor gamma chain <400> 5 Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser 1 5 10 15 Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu 20 25 <210> 6 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> ITAM of IgG receptor 2A alpha chain <400> 6 Asp Gly Gly Tyr Met Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp 1 5 10 15 Lys Asn Ile Tyr Leu Thr Leu 20 <210> 7 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> ITAM of IgE receptor beta chain <400> 7 Lys Val Pro Glu Asp Arg Val Tyr Glu Glu Leu Asn Ile Tyr Ser Ala 1 5 10 15 Thr Tyr Ser Glu Leu Glu Asp Pro Gly Glu Met Ser Pro 20 25 <210> 8 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Flexible linker <400> 8 Gly Gly Gly Gly Ser 1 5 <210> 9 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> hTLR-2 transmembrane domain <400> 9 Ala Leu Val Ser Gly Met Cys Cys Ala Leu Phe Leu Leu Ile Leu Leu 1 5 10 15 Thr Gly Val Leu Cys 20 <210> 10 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> hTLR-4 Signal peptide <400> 10 Met Met Ser Ala Ser Arg Leu Ala Gly Thr Leu Ile Pro Ala Met Ala 1 5 10 15 Phe Leu Ser Cys Val Arg Pro 20 <210> 11 <211> 432 <212> DNA <213> Artificial Sequence <220> <223> PD-1 extracellular domain <400> 11 tccccagaca ggccctggaa cccccccacc ttctccccag ccctgctcgt ggtgaccgaa 60 ggggacaacg ccaccttcac ctgcagcttc tccaacacat cggagagctt cgtgctaaac 120 tggtaccgca tgagccccag caaccagacg gacaagctgg ccgccttccc cgaggaccgc 180 agccagcccg gccaggactg ccgcttccgt gtcacacaac tgcccaacgg gcgtgacttc 240 cacatgagcg tggtcagggc ccggcgcaat gacagcggca cctacctctg tggggccatc 300 tccctggccc ccaaggcgca gatcaaagag agcctgcggg cagagctcag ggtgacagag 360 agaagggcag aagtgcccac agcccacccc agcccctcac ccaggtcagc cggccagttc 420 caaaccctgg tg 432 <210> 12 <211> 702 <212> DNA <213> Artificial Sequence <220> <223> IgG1 heavy chain constant region <400> 12 ggatccgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 60 ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 120 tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 180 aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 240 gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 300 ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 360 aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 420 tcacgagatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 480 cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 540 acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 600 aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 660 aaccactaca cgcagaagag cctctccctg tctccgggta aa 702 <210> 13 <211> 429 <212> DNA <213> Artificial Sequence <220> <223> hTLR-3 TIR domain <400> 13 tttgaatatg cagcatatat aattcatgcc tataaagata aggattgggt ctgggaacat 60 ttctcttcaa tggaaaagga agaccaatct ctcaaatttt gtctggaaga aagggacttt 120 gaggcgggtg tttttgaact agaagcaatt gttaacagca tcaaaagaag cagaaaaatt 180 atttttgtta taacacacca tctattaaaa gacccattat gcaaaagatt caaggtacat 240 catgcagttc aacaagctat tgaacaaaat ctggattcca ttatattggt tttccttgag 300 gagatccag attataaact gaaccatgca ctctgtttgc gaagaggaat gtttaaatct 360 cactgcatct tgaactggcc agttcagaaa gaacggatag gtgcctttcg tcataaattg 420 caagtagca 429 <210> 14 <211> 441 <212> DNA <213> Artificial Sequence <220> <223> hTLR-4 TIR domain <400> 14 aacatctatg atgcctttgt tatctactca agccaggatg aggactgggt aaggaatgag 60 ctagtaaaga atttagaaga aggggtgcct ccatttcagc tctgccttca ctacagagac 120 tttattcccg gtgtggccat tgctgccaac atcatccatg aaggtttcca taaaagccga 180 aaggtgattg ttgtggtgtc ccagcacttc atccagagcc gctggtgtat ctttgaatat 240 gagatgctc agacctggca gtttctgagc agtcgtgctg gtatcatctt cattgtcctg 300 cagaaggtgg agaagaccct gctcaggcag caggtggagc tgtaccgcct tctcagcagg 360 aacacttacc tggagtggga ggacagtgtc ctggggcggc acatcttctg gagacgactc 420 agaaaagccc tgctggatgg t 441 <210> 15 <211> 87 <212> DNA <213> Artificial Sequence <220> <223> ITAM of IgE receptor gamma chain <400> 15 gctataacca gctatgagaa atcagatggt gtttacacgg gcctgagcac caggaaccag 60 gagacttacg agactctgaa gcatgag 87 <210> 16 <211> 69 <212> DNA <213> Artificial Sequence <220> <223> ITAM of IgG receptor 2A alpha chain <400> 16 gacggcggct acatgactct gaaccccagg gcacctactg acgatgataa aaacatctac 60 ctgactctt 69 <210> 17 <211> 87 <212> DNA <213> Artificial Sequence <220> <223> ITAM of IgE receptor beta chain <400> 17 aaggttccag aggatcgtgt ttatgaagaa ttaaacatat attcagctac ttacagtgag 60 ttggaagacc caggggaaat gtctcct 87 <210> 18 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Flexible linker <400> 18 ggtggcggtg gctcg 15 <210> 19 <211> 63 <212> DNA <213> Artificial Sequence <220> <223> hTLR-2 transmembrane domain <400> 19 gcactggtgt ctggcatgtg ctgtgctctg ttcctgctga tcctgctcac cggtgtcctg 60 tgc 63 <210> 20 <211> 69 <212> DNA <213> Artificial Sequence <220> <223> hTLR-4 Signal peptide <400> 20 atgatgtctg cctcgcgcct ggctgggact ctgatcccag ccatggcctt cctctcctgc 60 gtgagacca 69
Claims (16)
상기 키메릭 항원 수용체는 PD-L1(programmed death-ligand 1)에 특이적으로 결합하는 항원 결합 도메인, 막관통 도메인 및 세포 내 신호전달 도메인을 포함하며, 상기 세포는 표적화된 효과기 활성을 갖는 항원 특이적 전문적 항원표출세포로서 대식세포, 수지상세포 또는 미감작 B 세포(naive B cell)를 포함하는, 형질전환된 세포.A transformed cell comprising a chimeric antigen receptor (CAR), comprising:
The chimeric antigen receptor comprises an antigen binding domain that specifically binds to a programmed death-ligand 1 (PD-L1), a transmembrane domain and an intracellular signaling domain, wherein the cell has an antigen-specific activity having a targeted effector activity. Transformed cells, including macrophages, dendritic cells or naive B cells, as specialized antigen-expressing cells.
상기 항원 결합 도메인은 PD-L1에 특이적으로 결합하는 PD1(Programmed cell death protein 1)의 세포외 도메인인 것인, 형질전환된 세포.According to claim 1,
The antigen-binding domain is an extracellular domain of PD1 (Programmed cell death protein 1) that specifically binds to PD-L1, the transformed cell.
상기 PD1의 세포외 도메인은 서열번호 1로 표시되는 아미노산 서열을 포함하는 것인, 형질전환된 세포.3. The method of claim 2,
The extracellular domain of the PD1 will include the amino acid sequence represented by SEQ ID NO: 1, the transformed cell.
상기 항원 결합 도메인은 PD1의 세포외 도메인 한 쌍이 이합체(dimer)의 형태로 각각 인간 이뮤노글로불린 G1 중쇄 불변 영역(IgG1 heavy chain constant region)에 연결된 것을 특징으로 하는 형질전환된 세포.3. The method of claim 2,
The antigen binding domain is a pair of extracellular domains of PD1 in the form of dimers, respectively, human immunoglobulin G 1 heavy chain constant region (IgG 1 heavy chain constant region), characterized in that connected to the transformed cell.
인간 이뮤노글로불린 G1 중쇄 불변 영역(IgG1 heavy chain constant region)은 서열번호 2로 표시되는 아미노산 서열을 포함하는 것인, 형질전환된 세포.5. The method of claim 4,
Human immunoglobulin G 1 heavy chain constant region (IgG 1 heavy chain constant region) is a transformed cell comprising the amino acid sequence represented by SEQ ID NO: 2.
상기 세포 내 신호전달 도메인은 TLR-3-TLR-4의 구성에, 면역수용체 타이로신 기반 활성화 모티프(immunoreceptortyrosine-based activation motif, ITAM)를 소단위(subunit)로 하여 링커(linker)로 연결시킨 것인, 형질전환된 세포.According to claim 1,
The intracellular signaling domain is linked to the structure of TLR-3-TLR-4 with an immunoreceptor tyrosine-based activation motif (ITAM) as a subunit and linked by a linker. transformed cells.
상기 ITAM은 IgE 수용체 gamma chain (Fcε receptor I gamma chain, FcεRIγ), IgG 수용체 2A alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα) 또는 IgE 수용체 beta chain (Fcε receptor I beta chain, FcεRIβ)의 면역수용체 타이로신 기반 활성화 모티프인 것인, 형질전환된 세포.7. The method of claim 6,
The ITAM is based on immunoreceptor tyrosine of IgE receptor gamma chain (Fcε receptor I gamma chain, FcεRIγ), IgG receptor 2A alpha chain (Fcγ receptor 2A alpha chain, FcγR2Aα) or IgE receptor beta chain (Fcε receptor I beta chain, FcεRIβ) An activation motif, the transformed cell.
상기 ITAM은 링커로 3개를 연결시킨 것인, 형질전환된 세포.7. The method of claim 6,
The ITAM is a transformed cell that connects three with a linker.
상기 TLR-3는 서열번호 3; 및 TLR-4는 서열번호 4로 표시되는 아미노산 서열을 포함하는 것인, 형질전환된 세포.7. The method of claim 6,
The TLR-3 is SEQ ID NO: 3; And TLR-4 is a transformed cell comprising the amino acid sequence shown in SEQ ID NO: 4.
상기 ITAM은 서열번호 5; 서열번호 6; 또는 서열번호 7로 표시되는 아미노산 서열을 포함하는 것인, 형질전환된 세포.7. The method of claim 6,
The ITAM is SEQ ID NO: 5; SEQ ID NO: 6; Or comprising the amino acid sequence represented by SEQ ID NO: 7, the transformed cell.
상기 링커는 서열번호 8로 표시되는 아미노산 서열을 포함하는 것인, 형질전환된 세포.7. The method of claim 6,
Wherein the linker comprises the amino acid sequence represented by SEQ ID NO: 8, the transformed cell.
상기 막관통 도메인은 TLR-2이며, 서열번호 9로 표시되는 아미노산 서열을 포함하는 것인, 형질전환된 세포.According to claim 1,
The transmembrane domain is TLR-2, and the transformed cell comprising the amino acid sequence shown in SEQ ID NO: 9.
상기 키메릭 항원 수용체는 신호 펩타이드를 포함하며, 서열번호 10으로 표시되는 아미노산 서열을 포함하는 것인, 형질전환된 세포.According to claim 1,
The chimeric antigen receptor comprises a signal peptide and will comprise the amino acid sequence shown in SEQ ID NO: 10, the transformed cell.
상기 암은 흑색종(melanoma), 폐암(lung cancer), 육종(Sarcoma), 신장암(renal-cell carcinoma), 림프종(lymphoma), 직장암(colorectal cancer), 위암(gastric cancer), 식도암(esophageal cancer), 진행된 고형암(advanced solid tumor), 유방암(breast cancer), 두경부암(head and neck cancer), 난소암(ovarian cancer) 및 전립선암(prostate cancer)으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 조성물.15. The method of claim 14,
The cancer is melanoma, lung cancer, sarcoma, renal-cell carcinoma, lymphoma, colorectal cancer, gastric cancer, esophageal cancer ), advanced solid tumor, breast cancer, head and neck cancer, ovarian cancer (ovarian cancer) and prostate cancer (prostate cancer), characterized in that selected from the group consisting of a composition.
A cell therapeutic agent comprising the cell of any one of claims 1 to 13 as an active ingredient.
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