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- 주제어 : Immunotoxin (검색결과 26 건)
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Woo, Byung Ho,Lee, Jung Tae,Park, Myung Ok,Lee, Kang Ro,Han, Jeung Whan,Park, Eun-Seok,Yoo, Sun Dong,Lee, Kang Choon 성균관대학교 약학연구소 1999 成均藥硏論文集 Vol.11 No.-
The effects of the hindered and non-hindered water soluble long-chain disulfide bonds on the stability and cytotoxicity of the ricin A chain (RTA) immunotoxin were examined. The RTA immunotoxins were prepared with the Fab fragments of anti-common acute lymphoblastic leukemia antigen (CALLA) monoclonal antibody (Fab-RTA) using sulfosuccinimidyl-6-[(-methyl-(-(2-pyridyldithio)toluamido]hexanoate (S-LC-SMPT) and sulfosuccinimidyl-6-[3-(2-pyridyldithio)-propionamido]hexanoate (S-LC-SPDP). The prepared Fab-RTA immunotoxin were evaluated for their conjugation yield, immunoreactivity, thermal and disulfide bond stability and cytotoxicity. The conjugation yield of the Fab-RTA immunotoxin from the water soluble long chain crosslinking agents, S-LC-SMPT and S-LC-SPDP, were comparable. Both Fab-RTA immunotoxins exhibited a similar immunoreactivity and thermal stability in aqueous solution. However, S-LC-SMPT -mediated Fab-RTA, sterically hindered, showed an enhanced disulfide bond stability in vitro over S-LC-SPDP mediated one. In the cytotoxicity against antigenic cell Daudi, the S-LC-SMPT -mediated RTA immunotoxin maintained a comparable cytotoxicity, compared with S-LC-SPDP mediated Fab-RTA immunotoxin.
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Woo, Byung-Ho,Lee, Jung-Tae,Park, Myung-Ok,Lee, Kang-Ro,Han, Jeung-Whan,Park, Eun-Seok,Yoo, Sun-Dong,Lee, Kang-Choon The Pharmaceutical Society of Korea 1999 Archives of Pharmacal Research Vol.22 No.5
The effects of the hindered and non-hindered water soluble long-chain disulfide bonds on the stability and cytotoxicity of the ricin A chain (RTA) immunotoxin were examined. The RTA immunotoxins were prepared with the Fab fragments of anti-common acute lymphoblastic leukemia antigen (CALLA) monoclonal antibody (Fab-RTA) using sulfosuccinimidyl-6-[(-methyl-(-2-pyridyldithio)toluamido]toluamido]hexanoate (S-LC-SMPT) and sulfosuccinimidyl-6-[3-(2-pyridyldithio-propionamido]hexanoate (S-LC-SPDP). The prepared Fab-RTA immunotoxins were evaluated for their conjugation yield, immunoreactivity, thermal and disulfide bond stability and cytotoxicity. The conjugation yield of the Fab-RTA immunotoxin from the water soluble long chain crosslinking agents, S-LC-SMPT and S-LC-SPDP, were comparable. Both Fab-RTA immunotoxins exhibited a similar immunoreactivity and thermal stability in aqueous solution. However, S-LC-SMPT -mediated Fab-RTA, sterically hindered, showed an enhanced disulfide bond stability in vitro over S-LC-SPDP mediated one. In the cytotoxicity against antigenic cell Daudi, the S-LC-SMPT -mediated RTA immunotoxin maintained a comparable cytotoxicity, compared with S-LC-SPDP mediated Fab-RTA immunotoxin.
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A Divalent Immunotoxin Formed by the Disulfide Bond between Hinge Regions of Fab Domain
최성혁,김지은,이용찬,장영주,최무현,Choe, Seong Hyeok,Kim, Ji Eun,Lee, Yong Chan,Jang, Yeong Ju,Choe, Mu Hyeon Korean Chemical Society 2001 Bulletin of the Korean Chemical Society Vol.22 No.12
Recombinant immunotoxins are hybrid cytotoxic proteins designed to selectively kill cancer cells. A divalent immunotoxins, [B3(FabH1)-PE38]2, was constructed by recombining Fab domain of B3 antibody as a cell-targeting domain and Pseudo monas exotoxin A (PE) as a cytotoxic domain. Monoclonal antibody, B3, is the murine antibody (IgG1k) directed against Lewis Y-related carbohydrate antigens, which are abundant on the surface of many carcinomas. Fab fragment of this antibody was used in this study with the modified hinge sequence where last two cysteines out of three were mutated to serine. PE is a 66 kDa bacterial toxin that kills eukaryotic cells by inhibiting protein synthesis with ADP ribosylation of ribosomal elongation factor 2 (EF2). Fc region of B3 antibody was substituted with the truncated form of PE (38 kDa, PE38) on DNA level. [B3(FabH1)-PE38]2 was formed by disulfide bond between cysteines in the modified hinge region of B3(FabH1)-PE38. Each polypeptide for recombinant immunotoxins was overexpressed in Escherichia coli and collected as inclusion bodies. Each inclusion body was solubilized and refolded, and cytotoxic effects were measured. Divalent immunotoxins, [B3(FabH1)-PE38]2, had ID50 values of about 10 ng/mL on A431 cell lines and about 4 ng/mL on CRL1739 cell lines. Control immunotoxins, B3(scFv)-PE40, had ID50 values of about 28 ng/mL on A431 cell lines and about 41 ng/mL on CRL1739 cell lines. Divalent immunotoxins, [B3(FabH1)-PE38]2, had higher cytotoxic effects than B3(scFv)-PE40 control immunotoxins.
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김은애,박영상 대한화학회 2016 Bulletin of the Korean Chemical Society Vol.37 No.12
Most tumor cells express specific antigen molecules, and these antigen molecules are shed from the cell surface. In targeted delivery of anti-cancer agents in tumor tissues, immunotoxins or antibody drug conjugates are designed to kill the target cancer cells. Previously, shed antigens were presumed to be a factor preventing the delivery of immunotoxins to solid tumors, since shed antigens act as a decoy to hinder the effective delivery of toxin molecules in solid tumors. However, a recent mathematical model study showed that antigen shedding could be beneficial for the delivery of immunotoxins. In this work, using this mathematical model, the possible condition in which large antigen shedding positively or negatively affects the efficacy of the delivered immunotoxin was thoroughly investigated in terms of three biological variables: number of surface antigen molecules, endocytosis rate constant, and immunotoxin dose. The present study showed that the positive or negative effect of antigen shedding on the delivery efficiency could be modulated by these three key parameters.
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이병성,이유미,이상우,박지수,정보석,조미경,정상택,유태현 한국공업화학회 2019 한국공업화학회 연구논문 초록집 Vol.2019 No.1
Immunotoxins consisting of a toxin from bacteria or plants, and a targeting module have been developed as potent anti-cancer therapeutics. The majority of them, especially those in preclinical or clinical testing stages, are based on antibody fragments, even though the advantage of using full-length antibodies has been well documented. Here, we generated an immunotoxin via site-specific conjugation using a cysteine (Cys) residue introduced to IgG and a bio-orthogonally reactive unnatural amino acid. A Her2-targeting IgG, trastuzumab, was engineered to have an unpaired Cys at position 425 in the heavy chain, and an unnatural amino acid having the azido group (azidophenylalanine) was incorporated into an engineered Pseudomonas exotoxin A (PE24). The two protein molecules were conjugated site-specifically using a bifunctional linker having dibenzocyclooctyne and maleimide groups. The resulting trastuzumab-PE24 conjugate was cytotoxic to Her2-overexpressing cell lines.
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CDH17 nanobodies facilitate rapid imaging of gastric cancer and efficient delivery of immunotoxin
Jingbo Ma,Xiaolong Xu,Chunjin Fu,Peng Xia,Ming Tian,Liuhai Zheng,Kun Chen,Xiaolian Liu,Yilei Li,Le Yu,Qinchang Zhu,Yangyang Yu,Rongrong Fan,Haibo Jiang,Zhifen Li,Chuanbin Yang,Chengchao Xu,Ying Long,J 한국생체재료학회 2022 생체재료학회지 Vol.26 No.4
Background: It is highly desirable to develop new therapeutic strategies for gastric cancer given the low survival rate despite improvement in the past decades. Cadherin 17 (CDH17) is a membrane protein highly expressed in cancers of digestive system. Nanobody represents a novel antibody format for cancer targeted imaging and drug delivery. Nanobody targeting CHD17 as an imaging probe and a delivery vehicle of toxin remains to be explored for its theragnostic potential in gastric cancer. Methods: Naïve nanobody phage library was screened against CDH17 Domain 1-3 and identified nanobodies were extensively characterized with various assays. Nanobodies labeled with imaging probe were tested in vitro and in vivo for gastric cancer detection. A CDH17 Nanobody fused with toxin PE38 was evaluated for gastric cancer inhibition in vitro and in vivo. Results: Two nanobodies (A1 and E8) against human CDH17 with high affinity and high specificity were successfully obtained. These nanobodies could specifically bind to CDH17 protein and CDH17-positive gastric cancer cells. E8 nanobody as a lead was extensively determined for tumor imaging and drug delivery. It could efficiently co-localize with CDH17-positive gastric cancer cells in zebrafish embryos and rapidly visualize the tumor mass in mice within 3 h when conjugated with imaging dyes. E8 nanobody fused with toxin PE38 showed excellent anti-tumor effect and remarkably improved the mice survival in cell-derived (CDX) and patient-derived xenograft (PDX) models. The immunotoxin also enhanced the anti-tumor effect of clinical drug 5-Fluorouracil. Conclusions: The study presents a novel imaging and drug delivery strategy by targeting CDH17. CDH17 nanobodybased immunotoxin is potentially a promising therapeutic modality for clinical translation against gastric cancer.
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Han Choe,Minh Quan Nguyen,Do Hyung Kim,Hye Ji Shim,Huynh Kim Khanh Ta,Thi Luong Vu,Thi Kieu Oanh Nguyen,Jung Chae Lim 한국분자세포생물학회 2023 Molecules and cells Vol.46 No.12
Recombinant immunotoxins (RITs) are fusion proteins consisting of a targeting domain linked to a toxin, offering a highly specific therapeutic strategy for cancer treatment. In this study, we engineered and characterized RITs aimed at mesothelin, a cell surface glycoprotein overexpressed in various malignancies. Through an extensive screening of a large nanobody library, four mesothelin-specific nanobodies were selected and genetically fused to a truncated Pseudomonas exotoxin (PE24B). Various optimizations, including the incorporation of furin cleavage sites, maltose-binding protein tags, and tobacco etch virus protease cleavage sites, were implemented to improve protein expression, solubility, and purification. The RITs were successfully overexpressed in Escherichia coli, achieving high solubility and purity post-purification. In vitro cytotoxicity assays on gastric carcinoma cell lines NCI-N87 and AGS revealed that Meso(Nb2)-PE24B demonstrated the highest cytotoxic efficacy, warranting further characterization. This RIT also displayed selective binding to human and monkey mesothelins but not to mouse mesothelin. The competitive binding assays between different RIT constructs revealed significant alterations in IC50 values, emphasizing the importance of nanobody specificity. Finally, a modification in the endoplasmic reticulum retention signal at the C-terminus further augmented its cytotoxic activity. Our findings offer valuable insights into the design and optimization of RITs, showcasing the potential of Meso(Nb2)-PE24B as a promising therapeutic candidate for targeted cancer treatment.
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Ricinus Communis로부터 분리된 ricin과 RCA의 독성 비교연구
김재호,장혜영 한국독성학회 1995 Toxicological Research Vol.11 No.2
Antibody-toxin conjugates, termed immunotoxins, are currently being evaluated as potential new anticancer agents and one of the most extensively studied toxins for construction of immunotoxin is ricin which exists in the seeds of castor bean, Ricinus communis. Another toxic lectin from castor bean is RCA (Ricinus communis agglutinin). Both toxins are very homologous. We reported the puriffcation procedure and biological properties of ricin from the Korean castor bean in another place and here we report those of RCA. The purified RCA shows three bands on denatured SDS PAGE while ricin shows two bands. On cultured $K_{562}$ cells ricin and RCA both inhibit the multiplication of cells extensively. $30{\mu}g/ml$ of ricin shows 73% of inhibition rate at day 4 compared to 68% in same condition of RCA. The inhibition of multiplication of cells are directly proportional to the concentration of toxins and the incubation period. In every case ricin was more toxic than RCA. The $LD_{50}$ dose of ricin on ICR mice was 60 ng at day 3 but that of RCA was $10{\mu}g$.
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