• Biomolecules & Therapeutics
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• 제23권6호
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• pp.493-509
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• 2015

Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris$^{(R)}$(anti-CD30-drug conjugate) and Kadcyla$^{(R)}$(anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed.

• Preventive Nutrition and Food Science
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• 제21권4호
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• pp.384-388
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• 2016

Reactive oxygen species are tumorigenic by their ability to increase cell proliferation, survival, and cellular migration. The purpose of the present study was to compare the antioxidant activity and cytotoxic effects of 3 berry extracts (strawberry, Korean raspberry, and mulberry) in A2780 human ovarian carcinoma cells. Except for raspberry, the ethyl acetate or methylene chloride fractions of berries containing phenolic compounds exerted dose dependent free radical scavenging activities. In the raspberry fractions, the hexane fraction also exhibited potent antioxidant activity. The cytotoxic effects of berries extracts in A2780 human ovarian carcinoma cells were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Surprisingly, co-treatment with n-butanol (BuOH) fractions of berries showed stronger cytotoxic effects compared to the other fractions. These findings suggest that potent anticancer molecules are found in the BuOH fractions of berries that have stronger cytotoxic activity than antioxidants.

• Molecules and Cells
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• 제19권1호
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• pp.143-148
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• 2005

Heptaplatin, cis-malonato [(4R,5R)-4,5-bis (amino-methyl)-2-isopropyl-1,3-dioxolane] platinum(II) (SKI-2053R, Sunpla) is a new platinum derivative with antitumor activity comparable to cisplatin on various cancer cell lines. Preclinical studies suggest that it is less nephrotoxic than cisplatin. This study was undertaken to examine the combined effect of heptaplatin and ionizing radiation on two established human squamous carcinoma cell lines (NCI-H520, SQ20B). The cytotoxic activity of heptaplatin was concentration-dependent in both cell lines. When low dose heptaplatin was combined with high dose ionizing radiation, there was an additive cytotoxic effect on NCI-H520 cells (P < 0.05), while a moderate dose of heptaplatin and a low dose of ionizing radiation had an additive cytotoxic effect on the growth of SQ20B cells (P < 0.05). FACS analysis and DAPI staining showed that their additive cytotoxic effects were correlated with the induction of apoptosis. Further studies are warranted using heptaplatin and ionizing radiation in squamous cell carcinoma as a substitute for cisplatin.

• Molecules and Cells
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• 제45권8호
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• pp.513-521
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• 2022

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an immune checkpoint molecule that is mainly expressed on activated T cells and regulatory T (Treg) cells that inhibits T-cell activation and regulates immune homeostasis. Due to the crucial functions of CTLA-4 in T-cell biology, CTLA-4-targeted immunotherapies have been developed for autoimmune disease as well as cancers. CTLA-4 is known to compete with CD28 to interact with B7, but some studies have revealed that its downstream signaling is independent of its ligand interaction. As a signaling domain of CTLA-4, the tyrosine motif plays a role in inhibiting T-cell activation. Recently, the lysine motif has been shown to be required for the function of Treg cells, emphasizing the importance of CTLA-4 signaling. In this review, we summarize the current understanding of CTLA-4 biology and molecular signaling events and discuss strategies to target CTLA-4 signaling for immune modulation and disease therapy.

• 대한의생명과학회지
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• 제18권1호
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• pp.16-21
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• 2012

Although there are many potential cytotoxic molecules released from bacteria, the role of these molecules on the apoptosis of various cancer cells is not well understood. Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative, aerobic and rod-shaped bacterium, and has a number of virulence factors. To understand the cytotoxic effect of bacterial extracts on the colorectal cancer cell line, HCT 116 cells, we examined alteration of the cell viability, proliferation, cell cycle and apoptosis of HCT 116 cells after treatment with extract of P. aeruginosa (PaE). These cytotoxicity of PaE occurred in a time- and a dose-dependent manners. In addition, PaE arrested the cell cycle of HCT 116 cell in a time-dependent manner. PaE inhibited the protein levels of Bcl-2 and induced the release of cytochrome c from mitochondria of HCT 116 cells. The decrease of procaspase-3 was induced by the treatment of PaE. These results indicate that PaE has a cytotoxicity in HCT 116 cells via the induction of apoptosis associated with mitochondrial pathway. Therefore, PaE may used as the potential target for the treatment of colorectal cancer.

• BMB Reports
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• 제44권6호
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• pp.369-374
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• 2011

MHC-I molecules play a critical role in immune surveillance against viruses by presenting peptides to cytotoxic T lymphocytes. Although the mechanisms by which MHC-I molecules assemble and acquire peptides in the ER are well characterized, how MHC-I molecules traffic to the cell surface remains poorly understood. To identify novel proteins that regulate the intracellular transport of MHC-I molecules, MHC-I-interacting proteins were isolated by affinity purification, and their identity was determined by mass spectrometry. Among the identified MHC-I-associated proteins was Tmp21, the human ortholog of yeast Emp24p, which mediates the ER-Golgi trafficking of a subset of proteins. Here, we show that Tmp21 binds to human classical and non-classical MHC-I molecules. The Tmp21-MHC-I complex lacks ${\beta}_2$-microglobulin, and the number of the complexes is increased when free MHC-I heavy chains are more abundant. Taken together, these results suggest that Tmp21 is a novel protein that preferentially binds to ${\beta}_2$-microglobulin-free MHC-I heavy chains.

• Biomolecules & Therapeutics
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• 제12권3호
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• pp.189-193
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• 2004

Over the past several years, research efforts have been directed both at economically producing valuable substances from the wood biomass and at producing lignolytic enzymes at a lower cost. In the present study, we found that Phellinus igniarius, the basidiomycetes, secreted lignin peroxidase as a main lignolytic enzyme, which was detected maximum activity at 16th day of culture and showed 37 kDa of molecular mass in identification by activity assay and purification by anion-exchange chromatography. The Phellinus igniarius-derived lignin peroxidase hydrolyzed steam-exploded wood (Quercus mongolica) powder into small molecules showing cytotoxicity against cancer cel1s (HepG2 hepatoma, SK-N-SH neuroblastoma, B16 melanoma, MBT-2 bladder cancer). In addition, the enzyme hydrlysates of lignins (ELg) that were extracted from the steam-exploded oak showed more potent cytotoxic effects on the cancer cells than the enzyme hydrolysates of wood biomass (EWp), indicating that the cytotoxic effect of EWp may be due to the enzyme-degraded products of lignin among the lignocellulosics. Furthermore, the cytotoxic effect of ELg on Chang, normal liver cells, was much less potent than that of ELg on HepG2 and B16 cancer cells, indicating that the cytotoxic effect of ELg may be specific for cancer cells. The present results suggest that Phellinus igniarius may be a useful resource for the large-scale production of lignin peroxidase and that the lignin peroxidase may be applied for the generation of valuable biodegradation products from wood lignocellulosics for medical use.

• 대한의생명과학회지
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• 제27권3호
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• pp.121-133
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• 2021

Antibody-drug conjugates (ADCs) are drawing much interest due to its great potential to be one of the important options in cancer treatments. ADCs are acting like a magic bullet which delivers cytotoxic drugs specifically to cancerous cells throughout the body, thus attacks these cells, while not harming healthy cells. ADCs are complex molecules that are composed of an antibody having targeting capability and linked-payload or cytotoxic drug killing cancerous cells. The key factors of the success in the development of ADC are selection of appropriate antibody, cytotoxic payload and linker for conjugation. Recently there was considerable progress in ADCs development, and a large number of ADCs gained US FDA approval. About 80 new ADCs are under active clinical studies. In this review we present a brief introduction of the US-FDA approved ADCs and global situation in the clinical studies of ADC pipelines. We address an overview on each component of an ADC design such as target antigens, payloads, linkers, conjugation methods, drug antibody ratio. In addition, we discuss on the trend of ADC market where global big pharmas and domestic biopharmaceutical companies are competing to develop safer and more effective ADCs.

• 융합정보논문지
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• 제10권6호
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• pp.164-176
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• 2020

인체 적응 면역 반응을 일으키는데 중요한 항원 특이적 T 세포를 활용한 면역 세포 치료에서 T 세포를 체외에서 배양하고 클론 확장시키는 과정은 매우 섬세하고 복잡하여 조절하기가 쉽지 않아 T 세포의 활성화와 클론 확장을 유도하면서도 조절 및 취급이 용이한 인공 항원제시세포 개발의 필요성이 대두되고 있다. 인공 항원제시세포는 인체의 항원제시세포의 세포 표면 분자와 작용을 모방하게 되는데, 기본적인 신호 분자인 MHC-항원 복합체, 공동 자극 분자, 그리고 용해성 면역 조절 분자를 필수적으로 발현하여야 한다. 또한 T 세포가 항원과 접촉할 때, 이들 분자들이 잘 조직화되어 작용하는 것이 효과적인 T 세포 활성화에 중요하다. 본 논문에서는 여러 인공 항원제시세포 제작 방법과 세포 표면 분자들의 결합 방법과 물리적인 특성이 T 세포와의 상호작용에 중요함을 고찰하였으며, 효과적인 T 세포 활성화를 유도하며 면역세포치료에 적용 가능한 인공항원제세세포의 제작 방법을 살펴보았다.

• 대한한의학회지
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• 제27권4호
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• pp.84-95
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• 2006

Costunolide is an active sesquiterpene lactone isolated from the root of Saussurea lappa Clarke and is known to exhibit a variety of biological activities, including anti-carcinogenic and anti-inflammatory effects. Nevertheless, the pharmacological pathways of costunolide have not yet been fully elucidated. In this study, its cytotoxic effects were examined using AGS gastric cancer cells. Its treatment resulted in apoptosis in a dose- and time-dependent manner. The effects were attributed to the regulation of pro-apoptotic molecules and suppression of anti-apoptotic molecules. These results suggest that costunolide may be a candidate to deal with gastric cancers by chemopreventive agents.