KR20220118225A - Composition for preventing or treating cancer by inducing maturation of immature dendritic cells - Google Patents
Composition for preventing or treating cancer by inducing maturation of immature dendritic cells Download PDFInfo
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- KR20220118225A KR20220118225A KR1020210022108A KR20210022108A KR20220118225A KR 20220118225 A KR20220118225 A KR 20220118225A KR 1020210022108 A KR1020210022108 A KR 1020210022108A KR 20210022108 A KR20210022108 A KR 20210022108A KR 20220118225 A KR20220118225 A KR 20220118225A
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Abstract
Description
본 발명은 미성숙 수지상 세포의 성숙화 유도를 이용한 암의 예방 또는 치료용 조성물에 관한 것으로, 구체적으로 신규한 와이셀라 시바리아 LBML2(Weissella cibaria LBML2) 균주를 이용하여 미성숙 수지상 세포를 성숙화 시킴으로써 암 세포에 대한 T 림프구 면역반응을 유도할 수 있는 암의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating cancer using the induction of maturation of immature dendritic cells, and specifically to cancer cells by maturation of immature dendritic cells using a novel Weissella cibaria LBML2 strain. It relates to a composition for preventing or treating cancer capable of inducing a T lymphocyte immune response.
암은 세계적으로 높은 사망률을 보이며, 서구 사회에서는 심혈관 질환 다음으로 가장 일반적인 사망 원인이다. 특히, 식생활이 서구화되어 고지방식의 섭취가 일반화되고, 환경 오염 물질의 급격한 증가, 음주량의 증가 등으로 대장암, 유방암, 전립선암 등이 지속적으로 증가하는 추세에 있으며, 인구의 고령화와 더불어 흡연 인구의 증가 및 대기 오염으로 인해 폐암이 증가하고 있는 실정이다. 이러한 실정에서 암의 조기 예방 및 치료를 가능하게 하여 인간 건강의 증진, 건강한 삶의 질 향상 및 인류 보건 증진에 기여할 수 있는 항암 치료 요법의 개발이 절실히 요구되는 상황이다.Cancer has the highest mortality rate worldwide and is the second most common cause of death in Western societies after cardiovascular disease. In particular, the consumption of high-fat diets has become common due to the westernization of diets, and the incidence of colorectal cancer, breast cancer, and prostate cancer continues to increase due to the rapid increase in environmental pollutants and the increase in alcohol consumption. Lung cancer is increasing due to an increase in the number of cancer cells and air pollution. In this situation, there is an urgent need for the development of an anti-cancer therapy that can contribute to the promotion of human health, the improvement of the quality of healthy life, and the promotion of human health by enabling the early prevention and treatment of cancer.
수지상 세포(dendritic cell, DC)는 1975년 Steinman 등에 의해 T 림프구에 의한 면역반응을 가장 효과적으로 유도할 수 있는 기능을 가진 세포로 알려지면서 항-종양 면역력을 유도할 수 있는 매우 중요한 세포로 밝혀졌다. 수지상 세포는 탐식작용 등을 통해 항원을 획득하고, 세포 내에서 처리하여, 주조직 적합성 복합체(MHC)에 항원 펩티드를 탑재하여 표현하므로써 항원특이 T 세포 수용체를 가진 T 림프구의 활성화를 강력히 유도한다.Dendritic cells (DCs) were known as the cells with the function to induce the most effective immune response by T lymphocytes by Steinman et al. in 1975, and were found to be very important cells capable of inducing anti-tumor immunity. Dendritic cells acquire antigens through phagocytosis, etc., process them within the cells, and express them by loading antigen peptides in the major histocompatibility complex (MHC), thereby strongly inducing activation of T lymphocytes with antigen-specific T cell receptors.
또한 수지상 세포는 활성화되면 IL-12를 발현하여 T 림프구의 자멸사(apoptosis)를 막고 T 림프구의 분화와 CTL 활성을 유도할 뿐 아니라 자연살해세포의 활성을 증가시켜 항-종양 면역력을 높이는 것으로 알려져 있다.In addition, when dendritic cells are activated, they express IL-12 to prevent apoptosis of T lymphocytes, induce T lymphocyte differentiation and CTL activity, and increase the activity of natural killer cells to enhance anti-tumor immunity. .
기존의 수지상 세포를 이용한 암 치료 요법은 수지상 세포에 종양항원을 탑재시키고 이를 다시 인체 내로 주입하여 T 림프구를 활성화시키는 방법에 의한 것이었다. 그러나 이러한 방법은 다른 항암제에 비해 부작용이 적은 장점은 있으나 환자로부터 종양항원을 얻기 힘들고 수지상세포의 활성화가 잘안되는 한계가 존재하였다.The existing cancer treatment regimen using dendritic cells was based on a method of activating T lymphocytes by loading tumor antigens on dendritic cells and injecting them back into the body. However, this method has the advantage of fewer side effects compared to other anticancer drugs, but there are limitations in that it is difficult to obtain tumor antigens from the patient and activation of dendritic cells is poor.
기존에 한국공개특허 제10-2019-0017705호에서는 수지상 세포를 이용한 T 세포의 활성화 방법에 대해 개시하고 있으나, 미생물 균주를 이용하여 활성화된 수지상 세포를 이용하여 암을 치료하는 조성물 등에 대해서는 개시된 바 없다.Previously, Korean Patent Application Laid-Open No. 10-2019-0017705 discloses a method for activating T cells using dendritic cells, but does not disclose a composition for treating cancer using dendritic cells activated using a microbial strain. .
본 발명의 목적은 성숙 수지상 세포를 유효성분으로 포함하는 조성물로서, 상기 성숙 수지상 세포는 미생물 균주를 이용하여 성숙시킨 것을 특징으로 하는 암의 예방, 개선 또는 치료용 조성물을 제공하기 위한 것이다.An object of the present invention is to provide a composition comprising mature dendritic cells as an active ingredient, wherein the mature dendritic cells are matured using a microbial strain to prevent, improve or treat cancer.
또한, 본 발명의 다른 목적은 미생물 균주를 이용한 미성숙 수지상 세포를 성숙시키는 방법을 제공하기 위한 것이다.Another object of the present invention is to provide a method for maturing immature dendritic cells using a microbial strain.
이에, 골수세포로부터 분화시킨 미성숙 수지상 세포를 미생물 균주를 이용하여 성숙한 수지상 세포를 수득하였고, 이를 유효성분으로 포함하는 조성물을 통해 분화된 수지상 세포의 활성화 여부 및 다양한 암종에 대한 예방 또는 치료 효과를 확인하였다.Accordingly, immature dendritic cells differentiated from bone marrow cells were obtained using a microbial strain to obtain mature dendritic cells, and through a composition containing them as an active ingredient, it was confirmed whether the differentiated dendritic cells were activated and the preventive or therapeutic effect on various carcinomas. did.
상기 목적을 달성하기 위하여, 성숙 수지상 세포를 유효성분으로 포함하는 조성물로서, 상기 성숙 수지상 세포는 미생물 균주를 이용하여 성숙시킨 것을 특징으로 하는 암의 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, a composition comprising mature dendritic cells as an active ingredient, wherein the mature dendritic cells are matured using a microbial strain, there is provided a pharmaceutical composition for preventing or treating cancer.
또한, 본 발명의 다른 목적은 성숙 수지상 세포를 유효성분으로 포함하는 조성물로서, 상기 성숙 수지상 세포는 미생물 균주를 이용하여 성숙시킨 것을 특징으로 하는 암의 예방 또는 개선용 식품 조성물 또는 식품 첨가제 조성물을 제공한다.Another object of the present invention is to provide a composition comprising mature dendritic cells as an active ingredient, wherein the mature dendritic cells are matured using a microbial strain to prevent or improve cancer, or a food additive composition do.
또한, 본 발명의 또 다른 목적은 성숙 수지상 세포를 유효성분으로 포함하는 조성물로서, 상기 성숙 수지상 세포는 미생물 균주를 이용하여 성숙시킨 것을 특징으로 하는 암의 예방 또는 개선용 사료 조성물 또는 사료 첨가제 조성물을 제공한다.In addition, another object of the present invention is to provide a composition comprising mature dendritic cells as an active ingredient, wherein the mature dendritic cells are matured using a microbial strain to provide a feed composition for preventing or improving cancer or a feed additive composition to provide.
또한, 본 발명은 미생물 균주를 이용한 미성숙 수지상 세포를 성숙시키는 방법을 제공한다.In addition, the present invention provides a method for maturation of immature dendritic cells using a microbial strain.
본 발명에 따른 미생물을 이용한 성숙 수지상 세포를 유효성분으로 포함하는 조성물은 동물모델에서 우수한 항암 활성을 나타내므로 사람 또는 동물의 암의 치료, 예방 또는 개선 등의 용도를 위한 조성물로서 유용하게 이용될 수 있다.The composition comprising mature dendritic cells using microorganisms according to the present invention as an active ingredient exhibits excellent anticancer activity in an animal model, so it can be usefully used as a composition for the treatment, prevention or improvement of human or animal cancer. have.
도 1은 본 발명의 일 실시예에 따른 미성숙 수지상 세포에 와이셀라 시바리아 LBML2 균주를 처리한 후 DC 활성 마커(CD80)를 측정하여 비교한 그래프를 나타낸 도이다.
도 2는 본 발명의 일 실시예에 따른 미성숙 수지상 세포에 와이셀라 시바리아 LBML2 균주를 처리한 후 DC 활성 마커(CD86)를 측정하여 비교한 그래프를 나타낸 도이다.
도 3은 본 발명의 일 실시예에 따른 미성숙 수지상 세포에 와이셀라 시바리아 LBML2 균주를 처리한 후 DC 활성 마커(CD40)를 측정하여 비교한 그래프를 나타낸 도이다.
도 4는 본 발명의 일 실시예에 따른 미성숙 수지상 와이셀라 시바리아 LBML2 균주를 처리한 후 사이토카인(IL-12 p40)의 발현량을 측정하여 비교한 그래프를 나타낸 도이다.
도 5는 본 발명의 일 실시예에 따른 미성숙 수지상 세포에 와이셀라 시바리아 LBML2 균주를 처리한 후 사이토카인(Tnf-α)의 발현량을 측정하여 비교한 그래프를 나타낸 도이다.
도 6은 본 발명의 일 실시예에 따른 미성숙 수지상 세포에 와이셀라 시바리아 LBML2 균주를 처리한 후 사이토카인(Ifn-γ)의 발현량을 측정하여 비교한 그래프를 나타낸 도이다.
도 7은 본 발명의 일 실시예에 따른 미성숙 수지상 세포에 와이셀라 시바리아 LBML2 균주를 처리한 후 T 세포의 증식(proliferation) 정도를 측정하여 비교한 그래프를 나타낸 도이다.
도 8은 본 발명의 일 실시예에 따른 미성숙 수지상 세포에 와이셀라 시바리아 LBML2 균주를 처리한 후 T 세포의 활성에 따른 세포독성물질(perforin)의 분비량을 측정하여 비교한 그래프를 나타낸 도이다.
도 9는 본 발명의 일 실시예에 따른 미성숙 수지상 세포에 와이셀라 시바리아 LBML2 균주를 처리한 후 T 세포의 활성에 따른 Ifn-γ의 분비량을 측정하여 비교한 그래프를 나타낸 도이다.
도 10은 본 발명의 일 실시예에 따른 와이셀라 시바리아 LBML2 균주를 처리한 후 T 세포의 활성에 따른 granzyme B의 분비량을 측정하여 비교한 그래프를 나타낸 도이다.
도 11은 본 발명의 일 실시예에 따른 조성물을 MC38 세포 이식 마우스에 복강 내 주사한 후 20일 동안 종양 세포의 부피 변화를 측정한 그래프를 나타낸 도이다.1 is a diagram showing a comparison graph by measuring the DC activity marker (CD80) after treating the Weissella cibaria LBML2 strain in immature dendritic cells according to an embodiment of the present invention.
2 is a diagram showing a comparison graph by measuring the DC activity marker (CD86) after treating the Weissella cibaria LBML2 strain in immature dendritic cells according to an embodiment of the present invention.
3 is a diagram showing a comparison graph by measuring the DC activity marker (CD40) after treating the Weissella cibaria LBML2 strain in immature dendritic cells according to an embodiment of the present invention.
4 is a diagram showing a comparison graph by measuring the expression level of cytokine (IL-12 p40) after treating the immature dendritic Weissella civaria LBML2 strain according to an embodiment of the present invention.
5 is a diagram showing a comparison graph by measuring the expression level of cytokine (Tnf-α) after treating the Weissella cibaria LBML2 strain in immature dendritic cells according to an embodiment of the present invention.
6 is a diagram showing a comparison graph by measuring the expression level of cytokines (Ifn-γ) after treating the Weissella cibaria LBML2 strain in immature dendritic cells according to an embodiment of the present invention.
7 is a diagram illustrating a comparison graph by measuring the degree of T cell proliferation after treating the Weissella cibaria LBML2 strain in immature dendritic cells according to an embodiment of the present invention.
8 is a diagram showing a graph comparing immature dendritic cells according to an embodiment of the present invention by measuring and comparing the secretion amount of cytotoxic substances (perforin) according to the activity of T cells after the Weissella cibaria LBML2 strain was treated.
9 is a diagram showing a graph comparing the amount of Ifn-γ secretion according to the activity of T cells after treatment of the Weissella cibaria LBML2 strain in immature dendritic cells according to an embodiment of the present invention.
10 is a diagram showing a comparison graph by measuring the secretion amount of granzyme B according to the activity of T cells after treatment with the Weissella cibaria LBML2 strain according to an embodiment of the present invention.
11 is a diagram illustrating a graph measuring the volume change of tumor cells for 20 days after intraperitoneal injection of a composition according to an embodiment of the present invention into MC38 cell transplanted mice.
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 발명의 성숙 수지상 세포를 유효성분으로 포함하는 조성물은 암의 예방 또는 치료 효과를 가지며, 약제학적 조성물로 이용될 수 있다.The composition comprising mature dendritic cells of the present invention as an active ingredient has a preventive or therapeutic effect on cancer and can be used as a pharmaceutical composition.
상기 성숙 수지상 세포는 미생물 균주를 이용하여 성숙시킨 것을 특징으로 한다. The mature dendritic cells are characterized in that they are matured using a microbial strain.
본 발명의 수지상 세포(dendritic cell, DC)는 내재 면역반응(innate immune response)과 적응 면역반응 (adaptive immune response)을 모두 유도할 수 있는 면역계의 가장 핵심적인 전문 항원제시 세포 (antigen-presenting cell, APC)로서 항원을 접한 적이 없는 naive 및 기억 면역반응을 활성화할 수 있는 특징을 갖는다. 이러한 이유로 "Nature's adjuvant"로 여겨진다. 수지상 세포는 미성숙 상태에서 감시병과 같은 역할을 하여 항원을 찾으러 끊임없이 순찰한다. 일반적으로 항원제시 세포가 항원을 섭취하면, 외인성 항원은 주로 주요 조직 적합성 복합체 클래스 II(major histocompatibility complex class II, MHC class II)를 통해 제시하고(CD4+ T 세포 활성화) 내인성 항원은 MHC class I을 통해 제시한다(CD8+ T 세포 활성화). 그러나, 수지상 세포는 외인성 항원을 MHC class II 뿐만 아니라 MHC class I을 통해 교차 제시(cross presentation)할 수 있는 특별한 능력이 있다. 따라서, 수지상 세포는 보다 효과적으로 CD4+와 CD8+ T 세포를 활성화할 수 있는 기능을 갖는다. 항원을 획득한 후 성숙 과정을 거친 수지상 세포는 림프기관으로 이동하여 naive T 세포에게 항원을 제시한다. T 세포의 활성에는 항원제시 세포의 항원제시 뿐만 아니라 항원제시 세포 표면에 발현된 보조자극 인자(costimulatory molecule; CD80, CD86, CD40 등)와 염증 촉진 사이토카인(cytokine)의 자극도 필요하다. 완전히 성숙한 수지상 세포는 이러한 신호를 통해 CD4+ T 세포가 T helper1(Th1) 세포로 분화되도록 유도하고, CD8+ T 세포(cytolytic T lymphocyte) 또한 활성화한다. 그러나 항원제시 세포의 보조자극 인자 및 염증촉진 사이토카인 자극이 없거나 면역억제 사이토카인 자극을 받으면 CD4+ T 세포는 Th2 세포나 조절 T 세포(regulatory T cell, Treg)로 분화된다.The dendritic cell (DC) of the present invention is the most essential antigen-presenting cell of the immune system capable of inducing both an innate immune response and an adaptive immune response (antigen-presenting cell, APC), which has the ability to activate naive and memory immune responses that have never been exposed to an antigen. For this reason, it is considered "Nature's adjuvant". In their immature state, dendritic cells act as watchmen, constantly patrolling for antigens. In general, when antigen-presenting cells take up antigen, exogenous antigen is mainly presented through major histocompatibility complex class II (MHC class II) (CD4+ T cell activation) and endogenous antigen is expressed through MHC class I present (CD8+ T cell activation). However, dendritic cells have a special ability to cross-present exogenous antigens through MHC class II as well as MHC class I. Therefore, dendritic cells have the ability to more effectively activate CD4+ and CD8+ T cells. After acquiring the antigen, the dendritic cells that have undergone the maturation process move to the lymphatic organ and present the antigen to the naive T cells. T cell activation requires not only antigen presentation by antigen-presenting cells, but also stimulation of costimulatory molecules (CD80, CD86, CD40, etc.) and pro-inflammatory cytokines expressed on the surface of antigen-presenting cells. Through this signal, fully mature dendritic cells induce CD4+ T cells to differentiate into T helper1 (Th1) cells, and also activate CD8+ T cells (cytolytic T lymphocytes). However, CD4+ T cells are differentiated into Th2 cells or regulatory T cells (Tregs) in the absence of stimulation of antigen-presenting cells with co-stimulatory factors and pro-inflammatory cytokines or when stimulated with immunosuppressive cytokines.
상기 미성숙 수지상 세포는 체외 배양에 의해 분화될 수 있다. 바람직하게는 골수세포로부터 수득한 단핵구(monocytes)로부터 단핵구 유도 수지상 세포로 분화될 수 있으나, 이에 제한되지 않는다.The immature dendritic cells may be differentiated by in vitro culture. Preferably, it may be differentiated from monocytes obtained from bone marrow cells into monocyte-derived dendritic cells, but is not limited thereto.
상기 과정을 통하여 분화된 미성숙 수지상 세포는 미생물 균주를 이용하여 성숙한 상태의 수지상 세포로 활성화될 수 있다.Immature dendritic cells differentiated through the above process can be activated into mature dendritic cells using a microbial strain.
상기 미생물 균주는 프로바이오틱스 중 하나일 수 있으며, '프로바이오틱스(probiotics)'는 사람을 포함한 동물의 위장관 내에서 숙주의 장내 미생물 환경을 개선하여 숙주의 건강에 유익한 영향을 주는 살아있는 미생물'이라는 의미로 이해된다. 프로바이오틱스는 프로바이오틱 활성을 갖는 미생물로 단일 또는 복합균주 형태로 사람이나 동물에 건조된 세포 형태나 발효산물 형태로 급여될 경우, 숙주의 장내 균총에 유익한 영향을 미칠 수 있다.The microbial strain may be one of probiotics, and 'probiotics' refers to living microorganisms that beneficially affect the health of the host by improving the intestinal microbial environment of the host in the gastrointestinal tract of animals including humans. . Probiotics are microorganisms with probiotic activity, and when fed to humans or animals in the form of single or multiple strains in the form of dried cells or fermentation products, it can have a beneficial effect on the intestinal flora of the host.
상기 미생물 균주는 락토바실러스(Lactobacillus) 속 균주, 와이셀라(Weissella) 속 균주, 비피도박테리움(Bifidobacterium) 속 균주, 류코노스톡 속(Leuconostoc) 균주 또는 락토코커스 속(Lactococcus) 균주 중 하나일 수 있으며, 바람직하게는 락토바실러스 퍼멘텀 균주(Lactobacillus fermentum), 락토바실러스 사케아이 균주(Lactobacillus sakei), 락토바실러스 가세리 균주(Lactobacillus gasseri), 락토바실러스 플란타룸 균주(Lactobacillus plantarum), 락토바실러스 람노서스 균주(Lactobacillus rhamnosus), 락토바실러스 아시도필루스 균주(Lactobacillus acidophilus), 락토바실러스 카제이 균주(Lactobacillus casei), 락토바실러스 루테리 균주(Lactobacillus reuteri) 와이셀라 시바리아 균주(Weissella cibaria), 와이셀라 헬레니카 균주(Weissella hellenica) 및 류코노스톡 시트래움 균주(Leuconostoc citreum)로 이루어지는 군 중에서 선택되는 1종 이상의 균주일 수 있으나, 이에 제한되지 않는다.The microorganism strain may be one of Lactobacillus sp. strain, Weissella sp. strain, Bifidobacterium sp. strain, Leuconostoc strain or Lactococcus strain. Preferably, Lactobacillus fermentum strain (Lactobacillus fermentum), Lactobacillus sakei strain (Lactobacillus sakei), Lactobacillus gasseri strain (Lactobacillus gasseri), Lactobacillus plantarum strain (Lactobacillus plantarum), Lactobacillus Strain (Lactobacillus rhamnosus), Lactobacillus acidophilus strain (Lactobacillus acidophilus), Lactobacillus casei strain (Lactobacillus casei), Lactobacillus reuteri strain (Lactobacillus reuteri) It may be one or more strains selected from the group consisting of strains (Weissella hellenica) and leuconostoc citreum, but is not limited thereto.
상기 와이셀라 시바리아 균주는 와이셀라 시바리아 LBML2 균주일 수 있으며, 본 발명의 실시예를 통해 미생물의 동정 및 분류를 위한 16S rDNA 염기서열 분석 결과, 서열번호 1의(SEQ ID NO: 1)의 핵산서열을 갖는 것으로 나타났다.The Wasella civaria strain may be a Wasella civaria LBML2 strain, and as a result of 16S rDNA sequencing for identification and classification of microorganisms through an embodiment of the present invention, SEQ ID NO: 1 of (SEQ ID NO: 1) It has been shown to have a nucleic acid sequence.
상기 서열번호 1의 핵산서열을 갖는 본 발명의 미생물을 와이셀라 시바리아 LBML2로 명명하였으며, 한국미생물보존센터에 2021년 02월 03일자로 기탁하였다(기탁번호 KCCM12948P).The microorganism of the present invention having the nucleic acid sequence of SEQ ID NO: 1 was named Weissella civaria LBML2, and was deposited at the Korea Microorganism Conservation Center on February 03, 2021 (Accession No. KCCM12948P).
상기 암은 방광암, 유방암, 흑색종양, 갑상선암, 부갑상선암, 대장암, 직장암, 인후암, 후두암, 식도암, 췌장암, 위암, 설암, 피부암, 뇌종양, 자궁암, 두담낭암, 구강암, 결장암, 항문 부근암, 간암 및 폐암으로 이루어지는 군으로부터 선택되는 어느 하나의 암일 수 있으며, 바람직하게는 대장암일 수 있으나, 이에 한정되지 않는다.The cancer is bladder cancer, breast cancer, melanoma, thyroid cancer, parathyroid cancer, colorectal cancer, rectal cancer, throat cancer, laryngeal cancer, esophageal cancer, pancreatic cancer, stomach cancer, tongue cancer, skin cancer, brain tumor, uterine cancer, double gallbladder cancer, oral cancer, colon cancer, perianal cancer, liver cancer And it may be any one cancer selected from the group consisting of lung cancer, preferably colon cancer, but is not limited thereto.
상기 조성물은 경구 또는 비경구로 투여할 수 있다. 비경구 투여인 경우에는 정맥 내 주입, 피하 주입, 근육 주입, 복강 주입, 내피 투여, 국소 투여, 비내 투여, 폐 내 투여 및 직장 내 투여 등으로 투여할 수 있으며, 바람직하게는 정맥 내 주입방법으로 투여할 수 있으나, 이에 제한되지 않는다.The composition may be administered orally or parenterally. In the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration and rectal administration, etc. may be administered, preferably by intravenous injection. can be administered, but is not limited thereto.
상기 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여시간, 투여경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다.A suitable dosage of the composition may be variously prescribed according to factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity of the patient.
본 발명의 조성물이 약제학적 조성물로 활용될 경우, 본 발명의 약제학적 조성물은 상기 유효성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.When the composition of the present invention is utilized as a pharmaceutical composition, the pharmaceutical composition of the present invention may be prepared using a pharmaceutically suitable and physiologically acceptable adjuvant in addition to the active ingredient, and the adjuvant includes an excipient, bog Release, sweetener, binder, coating agent, swelling agent, lubricant, lubricant or flavoring agent and the like can be used.
상기 약제학적 조성물은 투여를 위해서 상기 기재한 유효성분 이외에 추가로 약제학적으로 허용가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.The pharmaceutical composition may be preferably formulated as a pharmaceutical composition by including one or more pharmaceutically acceptable carriers in addition to the active ingredients described above for administration.
예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해, 유효성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연당, 옥수수감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐아세테이트, 소듐클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸셀룰로스, 아가, 벤토니트, 잔탄검 등을 포함한다. 액상 용액으로 제제화되는 조성물에 있어서 허용가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충식염수, 알부민 주사 용액, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다.For example, for formulation in the form of a tablet or capsule, the active ingredient may be combined with an orally, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. In addition, if desired or required, suitable binders, lubricants, disintegrants and color-developers may also be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate. ate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. In the composition formulated as a liquid solution, acceptable pharmaceutical carriers, which are sterile and biocompatible, include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostats may be added as needed. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to form an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.
나아가 해당 분야의 적절한 방법으로 Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.Furthermore, it can be preferably formulated according to each disease or component using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA by an appropriate method in the field.
본 발명의 성숙 수지상 세포를 유효성분으로 포함하는 조성물은 암의 예방 또는 개선용 식품 조성물 또는 식품 첨가제 조성물로 이용될 수 있다.The composition comprising the mature dendritic cells of the present invention as an active ingredient may be used as a food composition or food additive composition for preventing or improving cancer.
상기 식품 조성물은 건강기능식품의 형태일 수 있다.The food composition may be in the form of a health functional food.
상기 "건강기능식품"은 건강기능식품에 관한 법률에 따라 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미(제3조 제1호)하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것(동조 제2호)을 의미한다.The above "health functional food" means food manufactured and processed using raw materials or ingredients useful for the human body in accordance with the Health Functional Food Act (Article 3, No. 1), and "functionality" means It refers to obtaining useful effects for health purposes such as regulating nutrients or physiological effects on the structure and function of the human body (Article 2).
상기 식품 조성물은 식품 첨가물을 추가로 포함할 수 있으며, "식품첨가물"로서의 적합여부는 다른 규정이 없는 한 식품의약품안전처에 승인된 식품첨가물공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The food composition may additionally contain food additives, and the suitability as a "food additive" is determined according to the general rules and general test methods of the Food Additives Code approved by the Ministry of Food and Drug Safety, unless otherwise specified. and criteria.
상기 "식품첨가물공전"에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀롤로오스, 구아검 등의 천연첨가물, L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합 제제류 들을 들 수 있다.As items listed in the "Food Additives Codex", for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as depigmentation, licorice extract, crystalline cellulose, and guar gum, L- Mixed preparations such as sodium glutamate preparation, noodle-added alkali preparation, preservative preparation, and tar color preparation can be mentioned.
본 발명의 유효성분이 포함된 식품으로는 빵, 떡류, 건과류, 캔디류, 초콜릿류, 츄잉껌, 쨈류와 같은 과자류 아이스크림류, 빙과류, 아이스크림 분말류와 같은 아이스크림 제품류 우유류, 저지방 우유류, 유당분해 우유, 가공유류, 산양유, 발효유류, 버터유류, 농축유류, 유크림류, 버터유, 자연치즈, 가공치즈, 분유류, 유청류와 같은 유가공품류 식육가공품, 알가공품, 햄버거와 같은 식육제품류 어묵, 햄, 소세지, 베이컨 등의 어육가공품과 같은 어육제품류 라면류, 건면류, 생면류, 유탕면류, 호화건먼류, 개량숙면류, 냉동면류, 파스타류와 같은 면류 과실음료, 채소류음료, 탄산음료, 두유류, 요구르트 등의 유산균음료, 혼합음료와 같은 음료 간장, 된장, 고추장, 춘장, 청국장, 혼합장, 식초, 소스류, 토마토케첩, 카레, 드레싱과 같은 조미식품 마가린, 쇼트닝 및 피자를 들 수 있으나, 이에 제한되는 것은 아니다.Foods containing the active ingredient of the present invention include bread, rice cakes, dried fruits, candies, chocolates, chewing gum, confectionery products such as jams, ice cream products, ice cream products, ice cream products such as ice cream powder milk, low-fat milk, lactose-decomposed milk, Processed milk, goat milk, fermented milk, buttermilk, concentrated milk, milk cream, butter oil, natural cheese, processed cheese, milk powder, milk products such as whey Processed meat products, processed eggs, meat products such as hamburgers Fish cakes, ham, Fish and meat products such as sausage and bacon processed fish and meat products Ramen, dried noodles, raw noodles, fried noodles, luxurious dried noodles, improved soft noodles, frozen noodles, pasta, etc. Fruit drinks, vegetable drinks, carbonated drinks, soy milk, Beverages such as lactic acid bacteria drinks such as yogurt, mixed drinks, soy sauce, soybean paste, red pepper paste, chunjang, cheonggukjang, mixed soy sauce, vinegar, sauces, tomato ketchup, curry and seasoning foods such as dressings, margarine, shortening and pizza, but limited thereto it's not going to be
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 포함할 수 있다. 그밖에 본 발명의 조성물은 천연 과일주스, 과일주스 음료 및 야채 음료의 제조를 위한 과육을 포함할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. In addition to the above, the composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, It may include a carbonation agent used in carbonated beverages, and the like. In addition, the composition of the present invention may include fruit for the production of natural fruit juice, fruit juice beverage, and vegetable beverage. These components may be used independently or in combination.
본 발명의 유효성분을 포함한 음료 조성물은 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가성분으로 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, (예를 들어, 포도당, 과당 등); 디사카라이드, (예를 들어 말토스, 슈크로스 등); 및 폴리사카라이드, (예를 들어 덱스트린, 시클로덱스트린 등)과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등)) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.The beverage composition including the active ingredient of the present invention is not particularly limited in other ingredients, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. Examples of the aforementioned natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.); disaccharides, (eg maltose, sucrose, etc.); and conventional sugars such as polysaccharides (eg, dextrin, cyclodextrin, etc.), and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (eg rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have.
또한, 본 발명의 성숙 수지상 세포를 유효성분으로 포함하는 조성물은 가축의 암 예방 또는 개선용 사료 조성물 또는 사료 첨가제 조성물로 이용될 수 있다.In addition, the composition comprising mature dendritic cells of the present invention as an active ingredient can be used as a feed composition for preventing or improving cancer in livestock or as a feed additive composition.
상기 조성물이 사료 첨가제로서 제조될 경우, 상기 조성물은 20 내지 90% 고농축액이거나 분말 또는 과립 형태로 제조될 수 있다. 상기 사료 첨가제는 구연산, 후말산, 아디픽산, 젖산, 사과산등의 유기산이나 인산 나트륨, 인산 칼륨, 산성 피로인산염, 폴리인산염(중합인산염) 등의 인산염이나, 폴리페놀, 카테킨, 알파-토코페롤, 로즈마리 추출물, 비타민 C, 녹차 추출물, 감초 추출물, 키토산, 탄닌산, 피틴산 등의 천연 항산화제 중 어느 하나 또는 하나 이상을 추가로 포함할 수 있다. 사료로서 제조될 경우, 상기 조성물은 통상의 사료 형태로 제제화될 수 있으며, 통상의 사료 성분을 함께 포함할 수 있다.When the composition is prepared as a feed additive, the composition may be 20 to 90% highly concentrated or may be prepared in powder or granular form. The feed additives include organic acids such as citric acid, humic acid, adipic acid, lactic acid, and malic acid, or phosphates such as sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate (polyphosphate), polyphenol, catechin, alpha-tocopherol, rosemary Extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, any one or more of natural antioxidants such as phytic acid may be further included. When prepared as a feed, the composition may be formulated in the form of a conventional feed, and may include common feed ingredients together.
상기 사료 및 사료 첨가제는 곡물, 예를 들면 분쇄 또는 파쇄된 밀, 귀리, 보리, 옥수수 및 쌀; 식물성 단백질 사료, 예를 들면 평지, 콩, 및 해바라기를 주성분으로 하는 사료; 동물성 단백질 사료, 예를 들면 혈분, 육분, 골분 및 생선분; 당분 및 유제품, 예를 들면 각종 분유 및 유장 분말로 이루어지는 건조성분 등을 더 포함할 수 있으며, 이외에도 영양보충제, 소화 및 흡수향상제, 성장촉진제 등을 더 포함할 수 있다.The feed and feed additives include grains such as milled or crushed wheat, oats, barley, corn and rice; plant protein feeds, such as feeds based on rape, soybean, and sunflower; animal protein feeds such as blood meal, meat meal, bone meal and fish meal; Sugar and dairy products, for example, may further include dry ingredients made of various powdered milk and whey powder, and may further include nutritional supplements, digestion and absorption enhancers, growth promoters, and the like.
상기 사료 첨가제는 동물에게 단독으로 투여하거나 식용 담체 중에서 다른 사료 첨가제와 조합하여 투여할 수도 있다. 또한, 상기 사료 첨가제는 탑드레싱으로서 또는 이들을 동물사료에 직접 혼합하거나 또는 사료와 별도의 경구제형으로 용이하게 동물에게 투여할 수 있다. 상기 사료 첨가제를 동물사료와 별도로 투여할 경우, 당해 기술분야에 잘 알려진 바와 같이 약제학적으로 허용 가능한 식용 담체와 조합하여, 즉시 방출 또는 서방성 제형으로 제조할 수 있다. 이러한 식용 담체는 고체 또는 액체, 예를 들어 옥수수전분, 락토오스, 수크로오스, 콩플레이크, 땅콩유, 올리브유, 참깨유 및 프로필렌글리콜일 수 있다. 고체 담체가 사용될 경우, 사료 첨가제는 정제, 캡슐제, 산제, 트로키제 또는 함당정제 또는 미분산성 형태의 탑 드레싱일 수 있다. 액체 담체가 사용될 경우, 사료 첨가제는 젤라틴 연질 캡슐제, 또는 시럽제나 현탁액, 에멀젼제, 또는 용액제의 제형일 수 있다.The feed additive may be administered to the animal alone or in combination with other feed additives in an edible carrier. In addition, the feed additive can be easily administered to the animal as a top dressing, directly mixing them with animal feed, or in an oral formulation separate from the feed. When the feed additive is administered separately from animal feed, it can be combined with a pharmaceutically acceptable edible carrier as well known in the art to prepare an immediate release or sustained release formulation. Such edible carriers may be solid or liquid, for example cornstarch, lactose, sucrose, soybean flakes, peanut oil, olive oil, sesame oil and propylene glycol. When a solid carrier is used, the feed additive may be a tablet, capsule, powder, troche or sugar-containing tablet or top dressing in microdispersed form. When a liquid carrier is used, the feed additive may be in the form of a gelatin soft capsule, or a syrup or suspension, emulsion, or solution.
또한, 상기 사료 및 사료 첨가제는 보조제, 예를 들어 보존제, 안정화제, 습윤제 또는 유화제, 용액 촉진제 등을 함유할 수 있다. 상기 사료 첨가제는 침주, 분무 또는 혼합하여 동물의 사료에 첨가하여 이용될 수 있다.In addition, the feed and feed additives may contain adjuvants, for example, preservatives, stabilizers, wetting or emulsifying agents, solution accelerators, and the like. The feed additive may be used by being added to animal feed by immersion, spraying, or mixing.
본 발명의 사료 또는 사료 첨가제는 포유류, 가금 및 어류를 포함하는 다수의 동물 식이에 적용할 수 있다.The feed or feed additive of the present invention can be applied to a number of animal diets including mammals, poultry and fish.
상기 포유류로서 돼지, 소, 말, 양, 토끼, 염소, 설치동물 및 실험용 설치동물인 쥐, 햄스터, 기니피그뿐만 아니라, 애완동물(예: 개, 고양이) 등에게 사용할 수 있으며, 상기 가금류로서 닭, 칠면조, 오리, 거위, 꿩, 및 메추라기 등에도 사용할 수 있고, 상기 어류로서 잉어, 붕어 및 송어 등에 이용될 수 있으나, 이에 제한되는 것은 아니다.Pigs, cows, horses, sheep, rabbits, goats, rodents and experimental rodents as the mammals, as well as rats, hamsters, and guinea pigs, can be used for pets (eg, dogs, cats), etc., and chickens as the poultry, It can also be used for turkey, duck, geese, pheasant, and quail, and can be used as the fish, such as carp, crucian carp and trout, but is not limited thereto.
실시예 1. 균주의 분리 및 동정Example 1. Isolation and identification of strains
여러 종류의 김치 시료를 파쇄한 후, 김치액을 PBS(phosphate buffered saline)로 연속 희석(serial dilution, 103~108)하여 젖산균 선택 배지인 MRS에 도말한 후 30℃ 또는 37℃에서 각각 24시간 배양한다. 배양 후, 형성된 단일 콜로니를 수거하여 MRS 액체배지에 넣고 배양하였다. 24시간 배양한 배양액으로부터 genomic DNA를 추출하였다. 16S rDNA 염기서열을 확인하기 위해, 얻어진 genomic DNA 산물을 마크로젠에 분석 의뢰하였다. 확인한 염기서열을 National Center for Biotechnology information (NCBI, www.ncbi.nlm.nih.gov)의 Basic Local Alignment Search Tool (BLAST)을 이용하여 유사도 분석하였고, 이 결과를 통해 최종적으로 와이셀라 시바리아 LBML2 (Weissella cibaria LBML2)균주로 명명하고, 한국미생물보존센터에 2021년 2월 3일자로 기탁하였다.After crushing various types of kimchi samples, serial dilution (10 3 ~ 10 8 ) of the kimchi solution with PBS (phosphate buffered saline) is applied to MRS, a lactic acid bacteria selection medium, and then 24 at 30°C or 37°C, respectively. time to incubate. After culturing, the formed single colonies were collected and cultured in MRS broth. Genomic DNA was extracted from the culture medium cultured for 24 hours. In order to confirm the 16S rDNA base sequence, the obtained genomic DNA product was requested for analysis by Macrogen. The confirmed nucleotide sequence was analyzed for similarity using the Basic Local Alignment Search Tool (BLAST) of the National Center for Biotechnology information (NCBI, www.ncbi.nlm.nih.gov), and through this result, Weissella civaria LBML2 ( It was named Weissella cibaria LBML2) strain and was deposited at the Korea Microorganism Conservation Center on February 3, 2021.
이 결과를 통해 최종적으로 와이셀라 시바리아 LBML2(Weissella cibaria LBML2) 균주로 명명하고, 한국미생물 보존센터에 2021년 2월 3일자로 기탁하였다.Through this result, it was finally named Weissella cibaria LBML2 (Weissella cibaria LBML2) strain, and was deposited at the Korea Microorganism Conservation Center on February 3, 2021.
실시예 2. 미생물 균주의 배양Example 2. Cultivation of microbial strains
상기 와이셀라 시바리아 LBML2(Weissella cibaria LBML2) 균주를 MRS 액체배지 30ml에 0.1% 접종하여 37℃에서 18시간 동안 배양하였다. 배양 후, 3500 rpm에서 10분 동안 원심분리하고, 균체는 PBS 용액으로 3회 세척한 후 남아 있는 배지 성분을 제거하여 수득하였다.The Weissella cibaria LBML2 (Weissella cibaria LBML2) strain was inoculated with 0.1% in 30ml of MRS broth and cultured at 37°C for 18 hours. After incubation, centrifugation was performed at 3500 rpm for 10 minutes, and the cells were washed three times with PBS solution and then the remaining medium components were removed.
실시예 3. 미성숙 수지상 세포의 분화 방법Example 3. Method of Differentiation of Immature Dendritic Cells
마우스의 대퇴골(femur)과 경골(tibia)로의 골수세포(bone marrow cells)로부터 단핵구(monocytes)를 Ficoll gradient 방법을 이용하여 원심분리를 통해 분리하였다. 상기 분리된 단핵구는 2 x 106/well의 농도로 6 well 플레이트에 준비하였으며, 태아 소 혈청(Fetal Bovine Serum, FBS)이 포함된 배양액(RPMI)에 GM-CSF 20 ng/ml, IL-4 10 ng/ml를 함께 처리하였다. 그 후 6일 동안 배양하였으며 3일이 경과하였을 때, 신선한 배지와 사이토카인으로 교체해주어 분화된 미성숙 수지상 세포를 수득하였다.Monocytes were isolated from the bone marrow cells of the mouse femur and tibia by centrifugation using the Ficoll gradient method. The isolated monocytes were prepared in a 6-well plate at a concentration of 2 x 10 6 /well, GM-
실시예 4. 성숙 수지상 세포의 분화 방법Example 4. Differentiation method of mature dendritic cells
상기 실시예 3에서 수득한 미성숙 수지상 세포(Immature DC)를 성숙 수지상 세포(mature DC)로의 분화를 위해 2차 자극원인 미생물 균주와 공동배양하였다.The immature dendritic cells (Immature DC) obtained in Example 3 were co-cultured with a microbial strain as a secondary stimulus for differentiation into mature dendritic cells (mature DC).
먼저 상기 실시예 2에서 준비된 미생물 균주인 와이셀라 시바리아 LBML2 균주를 각각 미성숙 수지상 세포에 하기 실시예 4-1 내지 4-3의 조건으로 처리하였다. First, the Weissella civaria LBML2 strain prepared in Example 2 was treated with the conditions of Examples 4-1 to 4-3 below to immature dendritic cells, respectively.
4-1. 미성숙 수지상 세포에 다양한 종양의 항원 (tumor cell lysate)을 24시간 탑재(대조군)4-1. Immature dendritic cells loaded with various tumor antigens (tumor cell lysate) for 24 hours (control)
4-2. 상기 준비된 미생물 균주를 미성숙 수지상 세포에 각각 1 MOI 로 24시간 동안 처리4-2. The prepared microbial strains were treated with 1 MOI for each immature dendritic cell for 24 hours.
4-3. 미성숙 수지상 세포에 각각 종양 항원과 준비된 미생물 균주를 각각 1 MOI로 처리한 후 24시간 동안 배양4-3. Immature dendritic cells were treated with a tumor antigen and a prepared microbial strain, respectively, at an MOI of 1, and cultured for 24 hours.
실시예 5. 성숙 수지상 세포의 특성화(characterization) 확인Example 5. Confirmation of characterization of mature dendritic cells
5-1. 바이오 5-1. Bio 마커를marker 통한 확인 confirmation through
상기 실시예 4에서 기재된 방법으로 분화된 수지상 세포의 활성화를 확인하기 위하여 하기 표 1에 기재된 바이오 마커들을 flow cytometry, realtime PCR를 통해 확인하였다. In order to confirm the activation of dendritic cells differentiated by the method described in Example 4, the biomarkers listed in Table 1 below were confirmed through flow cytometry and realtime PCR.
도 1 내지 도 3에 나타난 바와 같이, 와이셀라 시바리아 LBML2 균주를 골수유래 수지상 세포에 처리하였을 경우 보조활성 마커(CD80, CD86, CD40) 발현에는 큰 차이를 보이지 않았으나, 종양 항원과 와이셀라 시바리아 LBML2 균주를 공동자극 시켰을 때 종양항원만 자극시켰을 때 보다 보조활성 마커가 더 증가됨을 확인하였다.As shown in FIGS. 1 to 3, when the Weissella civaria LBML2 strain was treated with bone marrow-derived dendritic cells, there was no significant difference in the expression of the auxiliary activity markers (CD80, CD86, CD40), but the tumor antigen and the Wasella civaria strain When the LBML2 strain was co-stimulated, it was confirmed that the co-activity marker was increased more than when only the tumor antigen was stimulated.
또한, 도 4 내지 도 6에 나타난 바와 같이, 와이셀라 시바리아 LBML2 균주를 단독 처리한 경우 대조군 또는 균주와 종양항원을 공동자극 처리한 경우보다 골수유래 수지상 세포의 사이토카인(IL-12 p40, TNF-a 또는 IFN-γ) 발현을 크게 증가시킴을 확인하였다. 이는 와이셀라 시바리아 LBML2 균주의 처리가 수지상 세포의 활성을 유도할 수 있다는 것을 의미한다.In addition, as shown in FIGS. 4 to 6 , when the Weissella civaria LBML2 strain was treated alone, the cytokines of bone marrow-derived dendritic cells (IL-12 p40, TNF -a or IFN-γ) was confirmed to significantly increase expression. This means that the treatment of the Weissella civaria LBML2 strain can induce the activity of dendritic cells.
5-2. In vitro T 세포 활성화 분석(T cell activation assay)5-2. In vitro T cell activation assay
상기 실시예에서 준비된 각 균주에 의해 분화된 성숙 수지상 세포가 T 세포의 활성을 얼마나 유도하는지 확인하기 위해 in vitro 상에서 T 세포의 활성을 측정하였다.In order to determine how much the mature dendritic cells differentiated by each strain prepared in the above Example induces the activity of T cells, T cell activity was measured in vitro.
먼저 마우스의 비장을 단일 세포화 후, MACS에 의해 CD3+ T 세포를 분리하였다. 상기 분리된 CD3+ T 세포는 96 well round bottom plate에 1x106/well 개씩 분주하고 성숙 수지상 세포와 3일 동안 공동배양하였다. 공동배양후 T 세포는 활성 및 증식의 정도를 각각 flow cytometry와 CCK8 assay를 이용하여 측정하였다.First, the mouse spleen was single-celled, and then CD3+ T cells were isolated by MACS. The isolated CD3+ T cells were seeded 1x10 6 /well each in a 96 well round bottom plate and co-cultured with mature dendritic cells for 3 days. After co-culture, the degree of activation and proliferation of T cells was measured using flow cytometry and CCK8 assay, respectively.
도 7에서 나타난 바와 같이 상기 균주에 의해 분화된 성숙 수지상 세포가 대조군 또는 종양항원이 탑재된 수지상 세포에 비해 T 세포의 증식(proliferation)이 보다 높게 나타남을 확인할 수 있었으며, 도 8 내지 도 10에서 나타난 바와 같이, 상기 활성화된 T 세포에 의해 Perforin, IFN-γ, granzyme B의 분비량이 증가함을 확인할 수 있었다.As shown in FIG. 7 , it was confirmed that the mature dendritic cells differentiated by the strain showed higher T cell proliferation than the control or tumor antigen-loaded dendritic cells, as shown in FIGS. 8 to 10 . As can be seen, it was confirmed that the secretion of Perforin, IFN-γ, and granzyme B was increased by the activated T cells.
실시예 6. 성숙 수지상 세포 조성물의 항암효과 확인Example 6. Confirmation of anticancer effect of mature dendritic cell composition
상기 실시예에서 준비된 각 균주에 의해 분화된 성숙 수지상 세포가 종양을 보다 효과적으로 억제할 수 있는지 확인하기 위해 in vivo 상에서 실험을 진행하였다.In order to confirm that the mature dendritic cells differentiated by each strain prepared in the above Example can more effectively suppress the tumor, an experiment was conducted in vivo.
먼저 마우스에 MC38 대장암 세포주 1x105 개를 마우스의 피하 내로 주입 이식한 후, 종양세포의 크기가 70-100mm3에 도달하였을 때, PBS(대조군), 상기 각 균주에 의해 성숙화된 수지상 세포 및 항원이 탑재된 수지상 세포를 각각 복강내 주사로 1주에 1회씩 총 2회 투여하였다. 투여한 후 20일이 경과된 때에 종양의 크기 및 부피를 측정하여 확인한 결과를 도 11에 나타내었다.First, 1x10 5 MC38 colorectal cancer cell lines were injected into mice subcutaneously and transplanted, and then, when the tumor cells reached 70-100 mm 3 in size, PBS (control), dendritic cells matured by each strain and antigen The mounted dendritic cells were administered by intraperitoneal injection, once a week, for a total of two times. The results confirmed by measuring the size and volume of the tumor when 20 days have elapsed after administration are shown in FIG. 11 .
도 11에 나타난 바와 같이, 와이셀라 시바리아 LBML2 균주에 의해 성숙화된 수지상 세포를 처리한 경우에 대조군 또는 종양항원이 처리된 경우에 비해 종양의 크기 및 부피가 크게 감소함을 확인하였으며, 대조군 대비 약 30% 감소함을 확인하였다.As shown in FIG. 11 , it was confirmed that the size and volume of the tumor was greatly reduced when the dendritic cells matured by the Weissella civaria LBML2 strain were treated compared to the control group or the case where the tumor antigen was treated. A 30% reduction was confirmed.
상기 결과에 비추어 볼 때, 미생물 균주를 처리하여 수지상 세포를 성숙화시킨 조성물을 투여한 경우에 항암 효과가 우수하여 암의 예방, 개선 및 치료용 조성물로써 이용가능함을 확인할 수 있었다.In light of the above results, it was confirmed that when the composition obtained by treating microbial strains and maturing dendritic cells was administered, the anticancer effect was excellent, so that it could be used as a composition for the prevention, improvement and treatment of cancer.
<110> LISCURE BIOSCIENCES CO., LTD. <120> Composition for preventing or treating cancer by inducing maturation of immature dendritic cells <130> KP21-0018-LB <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 1517 <212> DNA <213> Weissella cibaria <400> 1 agacttcacc ctaatcatcg tcccacctta gacggctggc tcccgaaggt taccccaccg 60 gctttgggtg ttacaaactc tcatggtgtg acgggcggtg tgtacaagac ccgggaacgt 120 attcaccgcg gcgtgctgat ccgcgattac tagcgattcc gacttcatgt aggcgagttg 180 cagcctacaa tccgaactga gacgtacttt aagagattag ctcaccctcg cgggttggca 240 actcgttgta tacgccattg tagcacgtgt gtagcccagg tcataagggg catgatgatt 300 tgacgtcatc cccaccttcc tccggtttgt caccggcagt ctcactagag tgcccaactr 360 aatgctggca actagtaata agggttgcgc tcgttgcggg acttaaccca acatctcacg 420 acacgagctg acgacaacca tgcaccacct gtcaccttgt ccccgaaggg aacgctccat 480 ctctggagtt gtcaagggat gtcaagacct ggtaaggttc ttcgcgttgc ttcgaattaa 540 accacatgct ccaccgcttg tgcgggtccc cgtcaattcc tttgagtttc aaccttgcgg 600 tcgtactccc caggcggagt gcttaatgcg ttagctgcgg cacttaaggg cggaaaccct 660 caaacaccta gcactcatcg tttacggtgt ggactaccag ggtatctaat cctgtttgct 720 acccacactt tcgagcctca acgtcagtta cagtccagaa agccgccttc gccactggtg 780 ttcttccata tatctacgca tttcaccgct acacatggag ttccactttc ctctactgca 840 ctcaagtcat ccagtttcca aagcaattcc tcagttgagc tgagggcttt cacttcagac 900 ttaaataacc gtctgcgctc gctttacgcc caataaatcc ggataacgct tggaacatac 960 gtattaccgc ggctgctggc acgtatttag ccgttccttt ctggtaagat accgtcacac 1020 attgaacagt tactctcaat gtcattcttc tcttacaaca gtgttttacg agccgaaacc 1080 cttcatcaca cacgcggcgt tgctccatca ggctttcgcc cattgtggaa gattccctac 1140 tgctgcctcc cgtaggagta tgggccgtgt ctcagtccca ttgtggccga tcagtctctc 1200 aactcggcta tgcatcatcg tcttggtgag ccattacctc accaactaac taatgcaccg 1260 cgggaccatc tcttagtgat agcagaacca tcttttaagt agcaaccatg cggttgctat 1320 tgttatacgg tattagcatc tgtttccaaa tgttatcccc tgctaagagg taggtttccc 1380 acgtgttact cacccgttcg ccactctttg caatgtccat cgtcatatct gagcaagctc 1440 ttcaaatcag ttgaaccaca aagcgttcga cttgcatgta ttaggcacgc cgccagcgtc 1500 atcctacgag aaaaaca 1517 <110> LISCURE BIOSCIENCES CO., LTD. <120> Composition for preventing or treating cancer by inducing maturation of immature dendritic cells <130> KP21-0018-LB <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 1517 <212> DNA <213> Weissella cibaria <400> 1 agacttcacc ctaatcatcg tcccacctta gacggctggc tcccgaaggt taccccaccg 60 gctttgggtg ttacaaactc tcatggtgtg acgggcggtg tgtacaagac ccgggaacgt 120 attcaccgcg gcgtgctgat ccgcgattac tagcgattcc gacttcatgt aggcgagttg 180 cagcctacaa tccgaactga gacgtacttt aagagattag ctcaccctcg cgggttggca 240 actcgttgta tacgccattg tagcacgtgt gtagcccagg tcataagggg catgatgatt 300 tgacgtcatc cccaccttcc tccggtttgt caccggcagt ctcactagag tgcccaactr 360 aatgctggca actagtaata agggttgcgc tcgttgcggg acttaaccca acatctcacg 420 acacgagctg acgacaacca tgcaccacct gtcaccttgt ccccgaaggg aacgctccat 480 ctctggagtt gtcaagggat gtcaagacct ggtaaggttc ttcgcgttgc ttcgaattaa 540 accacatgct ccaccgcttg tgcgggtccc cgtcaattcc tttgagtttc aaccttgcgg 600 tcgtactccc caggcggagt gcttaatgcg ttagctgcgg cacttaaggg cggaaaccct 660 caaacaccta gcactcatcg tttacggtgt ggactaccag ggtatctaat cctgtttgct 720 acccacactt tcgagcctca acgtcagtta cagtccagaa agccgccttc gccactggtg 780 ttcttccata tatctacgca tttcaccgct acacatggag ttccactttc ctctactgca 840 ctcaagtcat ccagtttcca aagcaattcc tcagttgagc tgagggcttt cacttcagac 900 ttaaataacc gtctgcgctc gctttacgcc caataaatcc ggataacgct tggaacatac 960 gtattaccgc ggctgctggc acgtatttag ccgttccttt ctggtaagat accgtcacac 1020 attgaacagt tactctcaat gtcattcttc tcttacaaca gtgttttacg agccgaaacc 1080 cttcatcaca cacgcggcgt tgctccatca ggctttcgcc cattgtggaa gattccctac 1140 tgctgcctcc cgtaggagta tgggccgtgt ctcagtccca ttgtggccga tcagtctctc 1200 aactcggcta tgcatcatcg tcttggtgag ccattacctc accaactaac taatgcaccg 1260 cgggaccatc tcttagtgat agcagaacca tcttttaagt agcaaccatg cggttgctat 1320 tgttatacgg tattagcatc tgtttccaaa tgttatcccc tgctaagagg taggtttccc 1380 acgtgttact cacccgttcg ccactctttg caatgtccat cgtcatatct gagcaagctc 1440 ttcaaatcag ttgaaccaca aagcgttcga cttgcatgta ttaggcacgc cgccagcgtc 1500 atcctacgag aaaaaca 1517
Claims (12)
상기 성숙 수지상 세포는 와이셀라 시바리아(Weissella cibaria) 균주를 이용하여 성숙시킨 것을 특징으로 하는 암의 예방 또는 치료용 약학적 조성물.A composition comprising mature dendritic cells as an active ingredient, comprising:
The mature dendritic cells are a pharmaceutical composition for the prevention or treatment of cancer, characterized in that it is matured using a strain of Weissella cibaria.
상기 와이셀라 시바리아 균주는 와이셀라 시바리아 LBML2(Weissella cibaria LBML2, 기탁번호 KCCM12948P) 균주인, 암의 예방 또는 치료용 약학 조성물.According to claim 1,
The Weissella cibaria strain is a Weissella cibaria LBML2 (Weissella cibaria LBML2, accession number KCCM12948P) strain, a pharmaceutical composition for preventing or treating cancer.
상기 암은 방광암, 유방암, 흑색종양, 갑상선암, 부갑상선암, 대장암, 직장암, 인후암, 후두암, 식도암, 췌장암, 위암, 설암, 피부암, 뇌종양, 자궁암, 두담낭암, 구강암, 결장암, 항문 부근암, 간암 또는 폐암인 것을 특징으로 하는 암의 예방 또는 치료용 약학 조성물.According to claim 1,
The cancer is bladder cancer, breast cancer, melanoma, thyroid cancer, parathyroid cancer, colorectal cancer, rectal cancer, throat cancer, laryngeal cancer, esophageal cancer, pancreatic cancer, stomach cancer, tongue cancer, skin cancer, brain tumor, uterine cancer, double gallbladder cancer, oral cancer, colon cancer, perianal cancer, liver cancer Or a pharmaceutical composition for the prevention or treatment of cancer, characterized in that lung cancer.
상기 조성물은 경구 투여 또는 비경구 투여의 방법으로 투여 가능한 것을 특징으로 하는 조성물.According to claim 1,
The composition is a composition, characterized in that it can be administered by the method of oral administration or parenteral administration.
상기 비경구 투여의 방법은 정맥 내 주입, 피하 주입, 근육 주입, 복강 주입, 내피 투여, 국소 투여, 비 내 투여, 폐 내 투여 또는 직장 내 투여인 것인, 암의 예방 또는 치료용 약학 조성물.5. The method of claim 4,
The method of parenteral administration is intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration or rectal administration, the pharmaceutical composition for the prevention or treatment of cancer.
상기 성숙 수지상 세포는 와이셀라 시바리아 (Weissella cibaria) 균주를 이용하여 성숙시킨 것을 특징으로 하는 암의 예방 또는 개선용 식품 조성물.A composition comprising mature dendritic cells as an active ingredient, comprising:
The mature dendritic cell is a food composition for preventing or improving cancer, characterized in that it is matured using a Weissella cibaria strain.
상기 식품은 건강기능식품인, 암의 예방 또는 개선용 식품 조성물.7. The method of claim 6,
The food is a health functional food, a food composition for the prevention or improvement of cancer.
상기 식품은 빵, 떡, 캔디, 초콜릿, 껌, 아이스크림, 우유, 치즈, 식육가공품, 어육가공품, 김치, 간장, 된장, 고추장, 춘장, 청국장, 식초, 케첩, 카레, 드레싱, 음료 및 발효유로 이루어지는 군으로부터 선택되는 어느 하나의 식품인 것을 특징으로 하는 암의 예방 또는 개선용 식품 조성물.7. The method of claim 6,
The food is bread, rice cake, candy, chocolate, gum, ice cream, milk, cheese, processed meat products, processed fish meat products, kimchi, soy sauce, soybean paste, red pepper paste, chunjang, cheonggukjang, vinegar, ketchup, curry, dressing, beverage and fermented milk consisting of Food composition for the prevention or improvement of cancer, characterized in that any one food selected from the group.
상기 성숙 수지상 세포는 와이셀라 시바리아(Weissella cibaria) 균주를 이용하여 성숙시킨 것을 특징으로 하는 암의 예방 또는 개선용 식품 첨가제 조성물.A composition comprising mature dendritic cells as an active ingredient, comprising:
The mature dendritic cells are a food additive composition for the prevention or improvement of cancer, characterized in that it is matured using a strain of Weissella cibaria.
상기 성숙 수지상 세포는 와이셀라 시바리아(Weissella cibaria) 균주를 이용하여 성숙시킨 것을 특징으로 하는 암의 예방 또는 개선용 사료 조성물.A composition comprising mature dendritic cells as an active ingredient, comprising:
The mature dendritic cell is a feed composition for preventing or improving cancer, characterized in that it is matured using a Weissella cibaria strain.
상기 가축은 돼지, 소, 말, 양, 토끼, 염소, 쥐, 햄스터, 기니피그, 개, 고양이, 닭, 칠면조, 오리, 거위, 꿩, 메추라기, 잉어, 붕어 및 송어로 이루어지는 군으로부터 선택되는 어느 하나인 것인, 가축의 암 예방 또는 개선용 사료 조성물.11. The method of claim 10,
The livestock is any one selected from the group consisting of pig, cow, horse, sheep, rabbit, goat, rat, hamster, guinea pig, dog, cat, chicken, turkey, duck, goose, pheasant, quail, carp, crucian carp and trout A feed composition for preventing or improving cancer in livestock.
상기 성숙 수지상 세포는 와이셀라 시바리아(Weissella cibaria) 균주를 이용하여 성숙시킨 것을 특징으로 하는 암의 예방 또는 개선용 사료 첨가제 조성물.
A composition comprising mature dendritic cells as an active ingredient, comprising:
The mature dendritic cells are a feed additive composition for the prevention or improvement of cancer, characterized in that it is matured using a strain of Weissella cibaria.
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