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[PMID]: 29327244 [Au] Autor: Menssen HD; Harnack U; Erben U; Neri D; Hirsch B; Dürkop H [Ad] Endereço: Division of Hematology and Oncology, Campus Benjamin Franklin, Department of Medicine, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany. hans_dietrich.menssen@charite.de. [Ti] Título: Antibody-based delivery of tumor necrosis factor (L19-TNFα) and interleukin-2 (L19-IL2) to tumor-associated blood vessels has potent immunological and anticancer activity in the syngeneic J558L BALB/c myeloma model. [So] Source: J Cancer Res Clin Oncol;144(3):499-507, 2018 Mar. [Is] ISSN: 1432-1335 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: PURPOSE: To analyze the impact of TNFα or IL2 on human lymphocytes in vitro and the anti-tumor and immune-modifying effects of L19-IL2 and L19-TNFα on subcutaneously growing J558L myeloma in immunocompetent mice. METHODS: PBMCs from three healthy volunteers were incubated with IL2, TNFα, or with IL2 plus addition of TNFα (final 20 h). BALB/c J558L mice with subcutaneous tumors were treated with intravenous L19-TNFα plus L19-IL2, or controls. Tumor growth and intra- and peri-tumoral tissues were analyzed for micro-vessel density, necrosis, immune cell composition, and PD1 or PD-L1 expressing cells. RESULTS: Exposure of PBMC in vitro to IL2, TNFα, or to IL2 over 3 and 5 days plus TNFα for the final 20 h resulted in an approximately 50 and 75% reduction of the CD25low effector cell/CD25high Treg cell ratio, respectively, compared to medium control. IL2 or TNFα increased the proportion of CD4- CD25low effector lymphocytes while reducing the proportion of CD4+ CD25low Teff cells. In the J558L myeloma model, tumor eradication was observed in 58, 42, 25, and 0% of mice treated with L19-TNFα plus L19-IL2, L19-TNFα, L19-IL2, and PBS, respectively. L19-TNFα/L19-IL2 combination caused tumor necrosis, capillary density doubling, peri-tumoral T cell and PD1+ T cell reduction (- 50%), and an increase in PD-L1+ myeloma cells. CONCLUSION: IL2, TNFα, or IL2 plus TNFα (final 20 h) increased the proportion of CD4- CD25low effector lymphocytes possibly indicating immune activation. L19-TNFα/L19-IL2 combination therapy eradicated tumors in J558L myeloma BALB/c mice likely via TNFα-induced tumor necrosis and L19-TNFα/L19-IL2-mediated local cellular immune reactions. [Mh] Termos MeSH primário: Inibidores da Angiogênese/uso terapêutico Anticorpos Monoclonais/uso terapêutico Imunoterapia/métodos Interleucina-2/uso terapêutico Mieloma Múltiplo/terapia Neovascularização Patológica/tratamento farmacológico Fator de Necrose Tumoral alfa/uso terapêutico [Mh] Termos MeSH secundário: Animais Vacinas Anticâncer/uso terapêutico Linhagem Celular Tumoral Sistemas de Liberação de Medicamentos Feminino Imunotoxinas/uso terapêutico Camundongos Camundongos Endogâmicos BALB C Mieloma Múltiplo/imunologia Mieloma Múltiplo/patologia Linfócitos T Reguladores/efeitos dos fármacos Linfócitos T Reguladores/imunologia Transplante Isogênico [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Angiogenesis Inhibitors); 0 (Antibodies, Monoclonal); 0 (Cancer Vaccines); 0 (Immunotoxins); 0 (Interleukin-2); 0 (Tumor Necrosis Factor-alpha) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180113 [St] Status: MEDLINE [do] DOI: 10.1007/s00432-017-2564-6

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[PMID]: 28457141 [Au] Autor: Liu X; Zhang P; Rödl W; Maier K; Lächelt U; Wagner E [Ad] Endereço: Pharmaceutical Biotechnology, Center for System-based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München , Butenandtstrasse 5-13, D-81377 Munich, Germany. [Ti] Título: Toward Artificial Immunotoxins: Traceless Reversible Conjugation of RNase A with Receptor Targeting and Endosomal Escape Domains. [So] Source: Mol Pharm;14(5):1439-1449, 2017 May 01. [Is] ISSN: 1543-8392 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The specific transport of bioactive proteins into designated target cells is an interesting and challenging perspective for the generation of innovative biopharmaceuticals. Natural protein cytotoxins perform this task with outstanding efficacy. They enter cells with receptor-targeted specificity, respond to changing intracellular microenvironments, and by various mechanisms translocate their cytotoxic protein subunit into the cytosol. Here we imitate this toxin-based delivery strategy in an artificial setting, by bioreversible conjugation of a cytotoxic cargo protein (RNase A) with receptor-targeting PEG-folate and the pH-specific endosomolytic peptide INF7 as synthetic delivery domains. Covalent modification of the cargo protein was achieved using the pH-labile AzMMMan linker and copper-free click chemistry with DBCO-modified delivery modules. This linkage is supposed to enable traceless intracellular release of the RNase A after exposure to the endosomal weakly acidic environment. Delivery of RNase A via this polycation-free delivery strategy resulted in high cytotoxicity against receptor-positive KB tumor cells only when both PEG-folate and INF7 were attached. [Mh] Termos MeSH primário: Química Click/métodos Endossomos/metabolismo Imunotoxinas/química Ribonuclease Pancreático/química [Mh] Termos MeSH secundário: Linhagem Celular Tumoral Eletroforese em Gel de Poliacrilamida Ácido Fólico/análogos & derivados Ácido Fólico/química Seres Humanos Concentração de Íons de Hidrogênio Imunotoxinas/metabolismo Modelos Biológicos Peptídeos/química Polietilenoglicóis/química Ribonuclease Pancreático/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (INF7 peptide); 0 (Immunotoxins); 0 (Peptides); 0 (poly(ethylene glycol)-folate); 30IQX730WE (Polyethylene Glycols); 935E97BOY8 (Folic Acid); EC 3.1.27.5 (Ribonuclease, Pancreatic) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180220 [Lr] Data última revisão: 180220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170502 [St] Status: MEDLINE [do] DOI: 10.1021/acs.molpharmaceut.6b00701

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[PMID]: 29277757 [Au] Autor: Michalska M; Schultze-Seemann S; Kuckuck I; Wolf P [Ad] Endereço: Department of Urology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [Ti] Título: Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer. [So] Source: Anticancer Res;38(1):61-69, 2018 01. [Is] ISSN: 1791-7530 [Cp] País de publicação: Greece [La] Idioma: eng [Ab] Resumo: BACKGROUND: We generated humanized/de-immunized immunotoxins targeting the prostate-specific membrane antigen (PSMA) and tested their cytotoxic activity against prostate cancer cells in vitro. MATERIALS AND METHODS: The humanized/de-immunized version of our murine anti-PSMA single-chain antibody fragment (scFv) D7, termed hD7-1(VL-VH), was ligated to the 40-kDa toxin domain of Pseudomonas aeruginosa exotoxin A (PE40), and to the deimmunized 24-kDa toxin domains PE24 or PE24mut. The immunotoxins designated as hD7-1(VL-VH)-PE40, hD7-1(VL-VH)-PE24 and hD7-1(VL-VH)-PE24mut were bacterially expressed and purified by affinity chromatography. Binding and cytotoxicity were examined by flow cytometry and viability assay, respectively. RESULTS: All immunotoxins revealed strong binding to prostate cancer cells expressing PSMA and specific cytotoxicity, with half-maximal inhibitory concentration values in the picomolar range. CONCLUSION: We successfully created powerful anti-PSMA immunotoxins with reduced immunogenicity for further clinical development and application against advanced prostate cancer. [Mh] Termos MeSH primário: Antígenos de Superfície/imunologia Glutamato Carboxipeptidase II/imunologia Imunotoxinas/farmacologia Neoplasias da Próstata/imunologia [Mh] Termos MeSH secundário: ADP Ribose Transferases/genética ADP Ribose Transferases/imunologia Animais Toxinas Bacterianas/genética Toxinas Bacterianas/imunologia Linhagem Celular Tumoral Escherichia coli/genética Exotoxinas/genética Exotoxinas/imunologia Seres Humanos Masculino Camundongos Neoplasias da Próstata/tratamento farmacológico Fatores de Virulência/genética Fatores de Virulência/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, Surface); 0 (Bacterial Toxins); 0 (Exotoxins); 0 (Immunotoxins); 0 (Virulence Factors); EC 2.4.2.- (ADP Ribose Transferases); EC 2.4.2.31 (toxA protein, Pseudomonas aeruginosa); EC 3.4.17.21 (Glutamate Carboxypeptidase II); EC 3.4.17.21 (glutamate carboxypeptidase II, human) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180104 [Lr] Data última revisão: 180104 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171227 [St] Status: MEDLINE

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[PMID]: 29028806 [Au] Autor: Fukuhara T; Kim J; Hokaiwado S; Nawa M; Okamoto H; Kogiso T; Watabe T; Hattori N [Ad] Endereço: Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. [Ti] Título: A novel immunotoxin reveals a new role for CD321 in endothelial cells. [So] Source: PLoS One;12(10):e0181502, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: There are currently several antibody therapies that directly target tumors, and antibody-drug conjugates represent a novel moiety as next generation therapeutics. Here, we used a unique screening probe, DT3C, to identify functional antibodies that recognized surface molecules and functional epitopes, and which provided toxin delivery capability. Accordingly, we generated the 90G4 antibody, which induced DT3C-dependent cytotoxicity in endothelial cells. Molecular analysis revealed that 90G4 recognized CD321, a protein localized at tight junctions. Although CD321 plays a pivotal role in inflammation and lymphocyte trans-endothelial migration, little is known about its mechanism of action in endothelial cells. Targeting of CD321 by the 90G4 immunotoxin induced cell death. Moreover, 90G4 immunotoxin caused cytotoxicity primarily in migratory endothelial cells, but not in those forming sheets, suggesting a critical role for CD321 in tumor angiogenesis. We also found that hypoxia triggered redistribution of CD321 to a punctate localization on the basal side of cells, resulting in functional impairment of tight junctions and increased motility. Thus, our findings raise the intriguing possibility that endothelial CD321 presented cellular localization in tight junction as well as multifunctional dynamics in several conditions, leading to illuminate the importance of widely-expressed CD321 as a potential target for antitumor therapy. [Mh] Termos MeSH primário: Células Endoteliais/efeitos dos fármacos Células Endoteliais/metabolismo Imunotoxinas/toxicidade Molécula A de Adesão Juncional/metabolismo [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Morte Celular/efeitos dos fármacos Linhagem Celular Movimento Celular/efeitos dos fármacos Células Endoteliais/citologia Seres Humanos Imunotoxinas/imunologia Molécula A de Adesão Juncional/química Molécula A de Adesão Juncional/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Immunotoxins); 0 (Junctional Adhesion Molecule A) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171031 [Lr] Data última revisão: 171031 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171014 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0181502

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[PMID]: 28983018 [Au] Autor: Wayne AS; Shah NN; Bhojwani D; Silverman LB; Whitlock JA; Stetler-Stevenson M; Sun W; Liang M; Yang J; Kreitman RJ; Lanasa MC; Pastan I [Ad] Endereço: Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA. [Ti] Título: Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia. [So] Source: Blood;130(14):1620-1627, 2017 Oct 05. [Is] ISSN: 1528-0020 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Novel therapies are needed to overcome chemotherapy resistance for children with relapsed/refractory acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is a recombinant anti-CD22 immunotoxin. A multicenter phase 1 study was conducted to determine the maximum-tolerated cumulative dose (MTCD) and evaluate safety, activity, pharmacokinetics, and immunogenicity of moxetumomab pasudotox in children, adolescents, and young adults with ALL (N = 55). Moxetumomab pasudotox was administered as a 30-minute IV infusion at doses of 5 to 50 µg/kg every other day for 6 (cohorts A and B) or 10 (cohort C) doses in 21-day cycles. Cohorts B and C received dexamethasone prophylaxis against capillary leak syndrome (CLS). The most common treatment-related adverse events were reversible weight gain, hepatic transaminase elevation, and hypoalbuminemia. Dose-limiting CLS occurred in 2 of 4 patients receiving 30 µg/kg of moxetumomab pasudotox every other day for 6 doses. Incorporation of dexamethasone prevented further dose-limiting CLS. Six of 14 patients receiving 50 µg/kg of moxetumomab pasudotox for 10 doses developed hemolytic uremic syndrome (HUS), thrombotic microangiopathy (TMA), or HUS-like events, exceeding the MTCD. Treatment expansion at 40 µg/kg for 10 doses (n = 11) exceeded the MTCD because of 2 HUS/TMA/HUS-like events. Dose level 6B (ie, 50 µg/kg × 6 doses) was the MTCD, selected as the recommended phase 2 dose. Among 47 evaluable patients, an objective response rate of 32% was observed, including 11 (23%) composite complete responses, 5 of which were minimal residual disease negative by flow cytometry. Moxetumomab pasudotox showed a manageable safety profile and evidence of activity in relapsed or refractory childhood ALL. This trial was registered at www.clinicaltrials.gov as #NCT00659425. [Mh] Termos MeSH primário: Toxinas Bacterianas/uso terapêutico Exotoxinas/uso terapêutico Imunotoxinas/uso terapêutico Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia [Mh] Termos MeSH secundário: Adolescente Adulto Toxinas Bacterianas/efeitos adversos Toxinas Bacterianas/imunologia Toxinas Bacterianas/farmacocinética Síndrome de Vazamento Capilar/prevenção & controle Criança Pré-Escolar Dexametasona/uso terapêutico Exotoxinas/efeitos adversos Exotoxinas/imunologia Exotoxinas/farmacocinética Feminino Glucocorticoides/uso terapêutico Síndrome Hemolítico-Urêmica/induzido quimicamente Seres Humanos Hipoalbuminemia/induzido quimicamente Imunotoxinas/efeitos adversos Imunotoxinas/imunologia Imunotoxinas/farmacocinética Lactente Masculino Dose Máxima Tolerável Recidiva Local de Neoplasia/tratamento farmacológico Recidiva Local de Neoplasia/imunologia Recidiva Local de Neoplasia/patologia Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia Microangiopatias Trombóticas/induzido quimicamente Ganho de Peso/efeitos dos fármacos Adulto Jovem [Pt] Tipo de publicação: CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; MULTICENTER STUDY [Nm] Nome de substância: 0 (Bacterial Toxins); 0 (Exotoxins); 0 (Glucocorticoids); 0 (Immunotoxins); 0 (Sialic Acid Binding Ig-like Lectin 2); 2NDX4B6N8F (immunotoxin HA22); 7S5I7G3JQL (Dexamethasone) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 171007 [St] Status: MEDLINE [do] DOI: 10.1182/blood-2017-02-749101

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[PMID]: 28923397 [Au] Autor: Wang S; Zhou R; Sun F; Li R; Wang M; Wu M [Ad] Endereço: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. [Ti] Título: The two novel DLL4-targeting antibody-drug conjugates MvM03 and MGD03 show potent anti-tumour activity in breast cancer xenograft models. [So] Source: Cancer Lett;409:125-136, 2017 Nov 28. [Is] ISSN: 1872-7980 [Cp] País de publicação: Ireland [La] Idioma: eng [Ab] Resumo: The anti-human Delta-like 4 (DLL4) monoclonal antibody MMGZ01 has a high affinity to hrDLL4 and arrests the DLL4-mediated human umbilical vein endothelial cell (HUVEC) phenotype, promotes immature vessels, and effectively reduces breast cancer cell growth in vivo. To develop a much more effective therapy, we conjugated MMGZ01 with two small-molecule cytotoxic agents, i.e., monomethyl auristatin E (MMAE) and doxorubicin (DOX), with different linkers to generate antibody-drug conjugates (ADCs), i.e., MMGZ01-vc-MMAE (named MvM03) and MMGZ01-GMBS-DOX (named MGD03), that are more potent therapeutic agents than naked antibody therapeutic agents. The produced anti-DLL4 ADCs can be effectively directed against DLL4 and internalized. Then, the release of MMAE or DOX into the cytosol can induce G2/M or G0/G1 phase growth arrest and cell death through the induction of apoptosis. In vitro, MvM03 was highly potent and selective against DLL4 cell lines. The anti-DLL4 ADCs, particularly MvM03, showed more potent anti-tumour activity than Docetaxel, which is an inhibitor of the depolymerisation of microtubules, in two xenograft breast cancer tumour models. Our findings indicate that anti-DLL4 ADCs have promising potential as an effective therapy for breast cancer. [Mh] Termos MeSH primário: Neoplasias da Mama/tratamento farmacológico Doxorrubicina/farmacologia Imunotoxinas/farmacologia Peptídeos e Proteínas de Sinalização Intercelular/imunologia Oligopeptídeos/farmacologia [Mh] Termos MeSH secundário: Animais Anticorpos Monoclonais/imunologia Apoptose/efeitos dos fármacos Neoplasias da Mama/genética Neoplasias da Mama/imunologia Neoplasias da Mama/patologia Linhagem Celular Tumoral Doxorrubicina/administração & dosagem Feminino Seres Humanos Camundongos Camundongos Endogâmicos BALB C Camundongos Nus Terapia de Alvo Molecular Oligopeptídeos/administração & dosagem Distribuição Aleatória Ensaios Antitumorais Modelo de Xenoenxerto [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antibodies, Monoclonal); 0 (DLL4 protein, human); 0 (Immunotoxins); 0 (Intercellular Signaling Peptides and Proteins); 0 (Oligopeptides); 80168379AG (Doxorubicin); V7I58RC5EJ (monomethyl auristatin E) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170920 [St] Status: MEDLINE

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[PMID]: 28704435 [Au] Autor: Klose D; Woitok M; Niesen J; Beerli RR; Grawunder U; Fischer R; Barth S; Fendel R; Nachreiner T [Ad] Endereço: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany. [Ti] Título: Generation of an artificial human B cell line test system using Transpo-mAbTM technology to evaluate the therapeutic efficacy of novel antigen-specific fusion proteins. [So] Source: PLoS One;12(7):e0180305, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The antigen-specific targeting of autoreactive B cells via their unique B cell receptors (BCRs) is a novel and promising alternative to the systemic suppression of humoral immunity. We generated and characterized cytolytic fusion proteins based on an existing immunotoxin comprising tetanus toxoid fragment C (TTC) as the targeting component and the modified Pseudomonas aeruginosa exotoxin A (ETA') as the cytotoxic component. The immunotoxin was reconfigured to replace ETA' with either the granzyme B mutant R201K or MAPTau as human effector domains. The novel cytolytic fusion proteins were characterized with a recombinant human lymphocytic cell line developed using Transpo-mAb™ technology. Genes encoding a chimeric TTC-reactive immunoglobulin G were successfully integrated into the genome of the precursor B cell line REH so that the cells could present TTC-reactive BCRs on their surface. These cells were used to investigate the specific cytotoxicity of GrB(R201K)-TTC and TTC-MAPTau, revealing that the serpin proteinase inhibitor 9-resistant granzyme B R201K mutant induced apoptosis specifically in the lymphocytic cell line. Our data confirm that antigen-based fusion proteins containing granzyme B (R201K) are suitable candidates for the depletion of autoreactive B cells. [Mh] Termos MeSH primário: Linfócitos B/citologia Engenharia Celular/métodos Granzimas/genética Toxoide Tetânico/imunologia [Mh] Termos MeSH secundário: Linfócitos B/metabolismo Linhagem Celular Tumoral Granzimas/metabolismo Seres Humanos Imunotoxinas/metabolismo Receptores de Antígenos de Linfócitos B/imunologia Proteínas Recombinantes de Fusão/imunologia Proteínas Recombinantes de Fusão/metabolismo Anticorpos de Cadeia Única/metabolismo Toxoide Tetânico/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Immunotoxins); 0 (Receptors, Antigen, B-Cell); 0 (Recombinant Fusion Proteins); 0 (Single-Chain Antibodies); 0 (Tetanus Toxoid); EC 3.4.21.- (GZMB protein, human); EC 3.4.21.- (Granzymes) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170921 [Lr] Data última revisão: 170921 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170714 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0180305

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[PMID]: 28683958 [Au] Autor: Jacquin-Porretaz C; Nardin C; Puzenat E; Roche-Kubler B; Aubin F; Comité de suivi des effets secondaires des immunothérapies anti-cancéreuses(CSESIAC) [Ad] Endereço: CHU de Besançon, service de dermatologie, 25030 Besançon France. [Ti] Título: [Adverse effects of immune checkpoint inhibitors used to treat melanoma and other cancer]. [Ti] Título: Effets secondaires des inhibiteurs de checkpoint utilisés dans le traitement des mélanomes et d'autres cancers.. [So] Source: Presse Med;46(9):808-817, 2017 Sep. [Is] ISSN: 2213-0276 [Cp] País de publicação: France [La] Idioma: fre [Ab] Resumo: Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers and metastatic renal cancer. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events that may be life threatening if not anticipated and managed appropriately. This new family of dysimmune toxicities remains largely unknown to the broad oncology community. We propose here some practical guidelines for the oncologist to help in the clinical care of patients under immune checkpoint molecules. [Mh] Termos MeSH primário: Anticorpos Monoclonais/efeitos adversos Anticorpos Monoclonais/uso terapêutico Antígeno CTLA-4/antagonistas & inibidores Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico Carcinoma Pulmonar de Células não Pequenas/genética Carcinoma de Células Renais/tratamento farmacológico Carcinoma de Células Renais/genética Genes cdc/efeitos dos fármacos Imunotoxinas/efeitos adversos Imunotoxinas/uso terapêutico Neoplasias Renais/tratamento farmacológico Neoplasias Renais/genética Neoplasias Pulmonares/tratamento farmacológico Neoplasias Pulmonares/genética Melanoma/tratamento farmacológico Melanoma/genética Receptor de Morte Celular Programada 1/antagonistas & inibidores Neoplasias Cutâneas/tratamento farmacológico Neoplasias Cutâneas/genética [Mh] Termos MeSH secundário: Antígeno CTLA-4/genética Carcinoma Pulmonar de Células não Pequenas/patologia Carcinoma de Células Renais/patologia Fidelidade a Diretrizes Neoplasias Renais/patologia Neoplasias Pulmonares/patologia Metástase Neoplásica Receptor de Morte Celular Programada 1/genética Neoplasias Cutâneas/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antibodies, Monoclonal); 0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 0 (Immunotoxins); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171013 [Lr] Data última revisão: 171013 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170708 [St] Status: MEDLINE

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[PMID]: 28677577 [Au] Autor: Gill MR; Falzone N; Du Y; Vallis KA [Ad] Endereço: CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK. [Ti] Título: Targeted radionuclide therapy in combined-modality regimens. [So] Source: Lancet Oncol;18(7):e414-e423, 2017 Jul. [Is] ISSN: 1474-5488 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Targeted radionuclide therapy (TRT) is a branch of cancer medicine concerned with the use of radioisotopes, radiolabelled molecules, nanoparticles, or microparticles that either naturally accumulate in or are designed to target tumours. TRT combines the specificity of molecular and sometimes physical targeting with the potent cytotoxicity of ionising radiation. Targeting vectors for TRT include antibodies, antibody fragments, proteins, peptides, and small molecules. The diversity of available carrier molecules, together with the large panel of suitable radioisotopes with unique physicochemical properties, allows vector-radionuclide pairings to be matched to the molecular, pathological, and physical characteristics of a tumour. Some pairings are designed for dual therapeutic and diagnostic applications. Use of TRT is increasing with the adoption into practice of radium-223 dichloride for the treatment of bone metastases and with the ongoing clinical development of, among others, Lu-dodecanetetraacetic acid tyrosine-3-octreotate (DOTATATE) for the treatment of neuroendocrine tumours and Y-microspheres for the treatment of hepatic tumours. The increasing use of TRT raises the question of how best to integrate TRT into multimodality protocols. Achievements in this area and the future prospects of TRT are evaluated in this Review. [Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico Imunotoxinas/uso terapêutico Neoplasias/terapia Radioisótopos/uso terapêutico Radioterapia/métodos [Mh] Termos MeSH secundário: 3-Iodobenzilguanidina/uso terapêutico Anticorpos Monoclonais/uso terapêutico Quimiorradioterapia/métodos Reparo do DNA/efeitos dos fármacos Seres Humanos Microesferas Terapia de Alvo Molecular Octreotida/análogos & derivados Octreotida/uso terapêutico Compostos Organometálicos/uso terapêutico Rádio (Elemento)/uso terapêutico [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 ((177lutetium-DOTA(O)Tyr3)octreotate); 0 (90Y-octreotate, DOTA(0)-Tyr(3)-Thr(8)-); 0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents); 0 (Immunotoxins); 0 (Organometallic Compounds); 0 (Radioisotopes); 0 (radium Ra 223 dichloride); 35MRW7B4AD (3-Iodobenzylguanidine); 4Q52C550XK (ibritumomab tiuxetan); RWM8CCW8GP (Octreotide); W90AYD6R3Q (Radium) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170911 [Lr] Data última revisão: 170911 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170706 [St] Status: MEDLINE

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MEDLINE

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[PMID]: 28669053 [Au] Autor: Grieger E; Gresch G; Niesen J; Woitok M; Barth S; Fischer R; Fendel R; Stein C [Ad] Endereço: Department of Immunotherapy, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Forckenbeckstr. 6, 52074, Aachen, Germany. elena.grieger@ime.fraunhofer.de. [Ti] Título: Efficient targeting of CD13 on cancer cells by the immunotoxin scFv13-ETA' and the bispecific scFv [13xds16]. [So] Source: J Cancer Res Clin Oncol;143(11):2159-2170, 2017 Nov. [Is] ISSN: 1432-1335 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: PURPOSE: Treatment of cancer using standard chemotherapy still offers a poor prognosis combined with severe side effects. Novel antibody-based therapies have been shown to overcome low efficiency and lack of selectivity by targeting cancer-associated antigens, such as aminopeptidase CD13. METHODS: We isolated a high-affinity CD13-specific single-chain fragment variable (scFv13) from a phage display library of V-genes from mice immunized with soluble antigen. An immunotoxin comprising the scFv13 and a truncated version of the exotoxin A of Pseudomonas aeruginosa (ETA', scFv13-ETA') and a bispecific scFv targeting CD13 and CD16 simultaneously (bsscFv[13xds16]) was generated and investigated for their therapeutic potential. RESULTS: Both fusion proteins bound specifically to target cells with high affinity. Furthermore, scFv13-ETA' inhibited the proliferation of human cancer cell lines efficiently at low concentrations (IC values of 408 pM-7 nM) and induced apoptosis (40-85% of target cells). The bsscFv triggered dose-dependent antibody-dependent cell-mediated cytotoxicity, resulting in the lysis of up to 23.9% A2058 cells, 18.0% MDA-MB-468 cells and 19.1% HL-60 cells. CONCLUSION: The provided data demonstrate potent therapeutic activity of the scFv13-ETA' and the bsscFv[13xds16]. The CD13-specific scFv is therefore suitable for the direct and specific delivery of both cytotoxic agents and effector cells to cancer-derived cells, making it ideal for further therapeutic evaluation. [Mh] Termos MeSH primário: ADP Ribose Transferases/imunologia Anticorpos Biespecíficos/farmacologia Apoptose/efeitos dos fármacos Toxinas Bacterianas/imunologia Antígenos CD13/antagonistas & inibidores Proliferação Celular/efeitos dos fármacos Exotoxinas/imunologia Imunotoxinas/farmacologia Neoplasias/tratamento farmacológico Anticorpos de Cadeia Única/imunologia Fatores de Virulência/imunologia [Mh] Termos MeSH secundário: Antígenos CD13/imunologia Seres Humanos Neoplasias/imunologia Neoplasias/patologia Proteínas Recombinantes/farmacologia Células Tumorais Cultivadas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antibodies, Bispecific); 0 (Bacterial Toxins); 0 (Exotoxins); 0 (Immunotoxins); 0 (Recombinant Proteins); 0 (Single-Chain Antibodies); 0 (Virulence Factors); EC 2.4.2.- (ADP Ribose Transferases); EC 2.4.2.31 (toxA protein, Pseudomonas aeruginosa); EC 3.4.11.2 (CD13 Antigens) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170703 [St] Status: MEDLINE [do] DOI: 10.1007/s00432-017-2468-5

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