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1.
Cancer Immunol Immunother ; 68(9): 1493-1500, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31501955

RESUMO

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.


Assuntos
Imunoterapia/métodos , Melanoma/metabolismo , Ligante OX40/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Ligante OX40/genética , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Sobrevida , Resultado do Tratamento
2.
Cancer Immunol Immunother ; 68(9): 1467-1477, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31451841

RESUMO

BACKGROUND: The lethal effects of multiple antigen-specific cellular therapy (MASCT) may be enhanced by blocking PD-1 in vitro and vascular endothelial growth factor receptor 2 inhibitor (apatinib). We analyzed the pooled data from our phase I/II trials to determine the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in advanced solid tumors. METHODS: Patients with advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The safety profile was the primary end point. The secondary end points were antitumor response, progression-free survival (PFS), and overall survival (OS). The circulating T cells were quantified before and after aMASCT infusion. RESULTS: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate (34.2% and 18.8%) and PFS (median 6.0 and 4.5 months, P = 0.002) were improved in the aMASCT plus apatinib group compared with the aMASCT group; however, the OS was not improved (median 10.0 and 8.2 months, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent and favorable prognostic factor of PFS and OS. The circulating T cells increased and Tregs decreased in both groups after one cycle of aMASCT treatment. CONCLUSIONS: Treatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Piridinas/uso terapêutico , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Células Dendríticas/transplante , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Prospectivos , Piridinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Análise de Sobrevida
3.
Anticancer Res ; 39(8): 4117-4128, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366496

RESUMO

BACKGROUND/AIM: Carbonic anhydrase 12 (CA12) is a membrane-associated enzyme that is highly expressed on many human cancers. It is a poor prognostic marker and hence an attractive target for cancer therapy. This study aimed to develop a humanized CA12-antibody with anti-cancer activity. MATERIALS AND METHODS: Antibody libraries were constructed and screened by the Retrocyte display®. Antibody binding and blocking properties were determined by ELISA, flow cytometry and enzymatic activity assays. Spheroid viability was determined by Cell-Titer-Fluor assay. RESULTS: We developed a novel humanized CA12-specific antibody, 4AG4, which recognized CA12 as an antigen and blocked CA12 enzymatic activity. Our humanized CA12-antibody significantly inhibited spheroid growth of lung adenocarcinoma A549-cells in vitro by blocking CA12 enzymatic activity. Similar anti-tumor effects were recapitulated with CA12-gene knockout of A549-cells. CONCLUSION: Our newly identified humanized CA12-antibody with anti-cancer activity, represents a new tool for the treatment of CA12-positive tumors.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anidrases Carbônicas/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Anticorpos Monoclonais Humanizados/imunologia , Anidrases Carbônicas/imunologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Esferoides Celulares/efeitos dos fármacos
4.
Medicine (Baltimore) ; 98(32): e16682, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393368

RESUMO

Some patients have poor response to adult-onset Still disease (AOSD) traditional treatment, which easily recurs during the reduction of prednisone. We observed the efficacy and safety of tocilizumab combined with methotrexate (MTX) in the treatment of refractory AOSD, and to explore the possibility of reducing the dosage of tocilizumab after disease control.A total of 28 refractory AOSD cases who had an inadequate response to corticosteroids combined with at least 1 traditional immunosuppressive agent, and even large-dose prednisone could not relieve their conditions after recurrence, were selected in this study. They were treated with tocilizumab (intravenous 8 mg/kg) combined with MTX (oral 12.5 mg once a week). In detail, tocilizumab was firstly given every 4 weeks and after 6-month remission, it was then given every 8 weeks. Some items including body temperature, skin rash, joint swelling and pain, hepatosplenomegaly, blood routine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum ferritin, and dosage of prednisone were observed before treatment as well as 2, 4, 8, 12, 24, 36, and 48 weeks after treatment. The adverse reactions occurring during the treatment were recorded.The body temperature was normal, the skin rash as well as joint swelling and pain disappeared, and laboratory indexes including CRP, ESR, white blood cell, neutrophilic granulocyte, platelet, hemoglobin, and ferritin were significantly improved after 8-week treatment (all P < .05). The clinical symptoms and laboratory indexes above mentioned were continuously improved 12, 24, 36, and 48 weeks after treatment. The mean dosage of prednisone was reduced from 71.4 ±â€Š20.7 mg/day to 55.0 ±â€Š11.1 mg/day after 2-week treatment, and to 3.3 ±â€Š2.1 mg/day after 48-week treatment (all P < .05). Prednisone was discontinued in 5 cases after 36-week treatment and in 7 cases after 48-week treatment. No serious adverse reactions occurred during the treatment.Tocilizumab can rapidly and markedly improve the clinical symptoms and laboratory indexes and contribute to reduction and discontinuation of prednisone in refractory AOSD. The patients' conditions are stable after reduction or discontinuation of prednisone and the tocilizumab possesses good safety.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Metotrexato/administração & dosagem , Doença de Still de Início Tardio/tratamento farmacológico , Administração Intravenosa , Administração Oral , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Antirreumáticos/farmacologia , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Masculino , Metotrexato/farmacologia , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Resultado do Tratamento
5.
Expert Opin Drug Saf ; 18(9): 769-776, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31303060

RESUMO

Introduction: Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas of skin-homing T-cells that initially or mainly manifest cutaneously. Treatment of CTCL is challenging given the disease states' varying presentation and prognosis. Systemic treatment options often lack comparative evidence and have relatively low response rates and short duration of response. The recent Food and Drug Administration (FDA) approval of mogamulizumab in adult patients with relapsed or refractory (R/R) CTCL after at least one prior line of therapy provided a new treatment option to patients with advanced disease. Areas covered: The authors discuss basic information about CTCL and mogamulizumab's mechanism of action. Then, the authors discuss the agent's efficacy. Finally, the authors evaluate the safety of mogamulizumab in comparison to other agents available in CTCL. Expert opinion: Mogamulizumab has been shown to be an effective and well tolerated therapy for patients with relapsed and refractory MF/SS with excellent activity in the circulating component of the disease.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Animais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Humanos , Linfoma Cutâneo de Células T/patologia , Prognóstico , Neoplasias Cutâneas/patologia
6.
Medicine (Baltimore) ; 98(27): e16164, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277120

RESUMO

Thrombosis are severe complications of paroxysmal nocturnal hemoglobinuria (PNH), effectively reduced by eculizumab. Extracellular vesicles (EVs) may play a central role. The objective of this study was to assess the procoagulant activity of plasma isolated from PNH patients (treated or not by eculizumab) and to quantify their circulating EVs.We iteratively collected the platelet-free-plasma of 17 PNH patients and 16 matched healthy volunteers, quantified their circulating EVs by flow cytometry and evaluated their procoagulant activity by thrombin generation and STA-Procoag-procoagulant phospholipid (PPL) assays.A significant decrease of EVs from platelets (P = .024) and an increase of the STA-Procoag-PPL clotting time (P = .049) was observed after initiation of eculizumab and up to 11 weeks after. This reduction of prothrombotic biomarkers was not observed with the thrombin generation test due to a lack of sensitivity of this assay. Active hemolysis was observed in 90% of patients and elevated D-dimers in 41% of them. However, no significant difference was observed between patients and control subjects regarding the procoagulant activity, the EVs quantity, or the cellular origin. Lactate dehydrogenase (LDH) levels were lower in eculizumab-treated patients compared to nontreated patients (441 vs 2448 IU/L). D-dimers and LDH decreased after administration of eculizumab (mean decrease of 1307 ng/mL and 4159 IU/L, respectively).These observations suggest a decrease of the phospholipid-dependent procoagulant potential of EVs after eculizumab therapy in PNH patients. TRIAL REGISTRATION:: NUB: B039201214365.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Hemoglobinúria Paroxística/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Estudos de Casos e Controles , Citometria de Fluxo , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/complicações , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Trombose/etiologia
7.
Hosp Pract (1995) ; 47(3): 113-122, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317796

RESUMO

Direct oral anticoagulants (DOACs) include dabigatran etexilate, a direct thrombin inhibitor, and specific inhibitors of activated coagulation factor X (FXa; e.g. apixaban, betrixaban, edoxaban, rivaroxaban). DOACs are associated with lower rates of major and fatal bleeding events compared with warfarin. Clinicians may need to achieve rapid reversal of anticoagulation effects of the DOACs in an emergency setting. Idarucizumab and andexanet alfa, which reverse the anticoagulant effects of dabigatran and FXa inhibitors, respectively, are DOAC reversal agents available in the US. Other reversal agents (e.g. ciraparantag for heparins, DOACs) are in development. Alternative nonspecific agents (e.g. fresh frozen plasma, prothrombin complex concentrate) are available. Nonspecific prohemostatic agents can counteract the anticoagulant action of DOACs in emergency situations, when specific reversal agents are unavailable. However, specific reversal agents are efficacious and safe and should be preferred when available. In this review, we discuss practical issues in the initiation of DOAC therapy, situations where reversal may be needed, coagulation assays, reversal agents, and post-reversal complications in the context of published evidence and guidelines.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticoagulantes/administração & dosagem , Antitrombinas/uso terapêutico , Dabigatrana/antagonistas & inibidores , Fator X/antagonistas & inibidores , Fator Xa/farmacologia , Pacientes Internados , Proteínas Recombinantes/farmacologia , Administração Oral , Coagulação Sanguínea/efeitos dos fármacos , Serviços Médicos de Emergência , Fator Xa/agonistas , Inibidores do Fator Xa/uso terapêutico , Hemorragia/tratamento farmacológico , Humanos , Corpo Clínico Hospitalar
8.
Expert Opin Investig Drugs ; 28(7): 617-627, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31230485

RESUMO

INTRODUCTION: Despite improvements in the management of HER2+ breast cancer, metastatic disease is still fatal. Usually, these patients receive several lines of chemotherapy associated with HER2 targeted treatments. Most of the trials using innovative approaches are positioning themselves in disease that is resistant to pertuzumab and trastuzumab emtansine (TDM1). AREAS COVERED: We describe the recent advances in clinical development of anti-HER2 treatments. To this aim, we used literature search via Pubmed and made an inventory of abstracts published during the last two years in major oncology conferences. EXPERT OPINION: Further changes will probably occur during the next decade in the management of metastatic HER2-positive breast cancer. This is mainly driven by the fact that the two mainstay drugs (pertuzumab and TDM-1) that confer prolonged survival (56 months) to these patients are currently being used in the treatment of early-stage disease in a subset of patients. Thus, there is an urgent need to develop new, innovative approaches in those patients whose disease has become resistant to these highly potent drugs. Several new antibody-drug conjugates, bispecific antibodies or new generation tyrosine kinase inhibitor (TKIs) hold promise and should be assessed and compared with drugs currently used.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/administração & dosagem , Neoplasias da Mama/patologia , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacologia , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/farmacologia , Maitansina/administração & dosagem , Maitansina/análogos & derivados , Maitansina/farmacologia , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Trastuzumab/administração & dosagem , Trastuzumab/farmacologia
10.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096713

RESUMO

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and "educate" (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.


Assuntos
Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/imunologia , Imunossupressores/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Imunossupressores/uso terapêutico , Células Matadoras Naturais , Maraviroc/farmacologia , Nivolumabe/farmacologia , Prognóstico , Receptores CCR5/efeitos dos fármacos , Células de Reed-Sternberg/efeitos dos fármacos , Células de Reed-Sternberg/imunologia , Linfócitos T , Trabectedina/farmacologia , Triptofano/análogos & derivados , Triptofano/farmacologia , Evasão Tumoral/efeitos dos fármacos , Ácido Zoledrônico/farmacologia
11.
Pharm Res ; 36(7): 103, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101998

RESUMO

PURPOSE: A rapid and broadly applicable method to assess relevant oxidative damage in biopharmaceuticals is important for lifecycle management of product quality. Multiple methods are currently employed as stress tests to induce oxidative damage for assessment of stability, safety, and efficacy. We compared two common methods for inducing oxidative damage to assess differences in impact on bioactivity and structure of the biopharmaceuticals. METHODS: Biopharmaceuticals were treated with either metal-catalyzed oxidation (MCO) conditions or the reactive-oxygen species (ROS) inducer 2,2'-Azobis(2-amidinopropane) dihydrochloride (AAPH), then analyzed for changes in structure and bioactivity. RESULTS: We demonstrate that commonly used chemical methods for assessing oxidation yield distinct oxidation profiles for each of the biotechnology products analyzed, including monoclonal antibodies. We further report oxidant- and product-specific changes in bioactivity under oxidizing conditions, along with differential oxidation on the molecular subunits of monoclonal antibodies. CONCLUSION: Our results highlight the need for product-specific optimization and selection of orthogonal, relevant oxidizers when characterizing stress responses in biopharmaceuticals.


Assuntos
Produtos Biológicos/química , Estresse Oxidativo , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Humanos , Indicadores e Reagentes/química , Metionina/química , Oxidantes/química , Oxirredução , Espécies Reativas de Oxigênio/química , Rituximab/química , Rituximab/farmacologia , Trastuzumab/química , Trastuzumab/farmacologia
12.
Praxis (Bern 1994) ; 108(7): 469-476, 2019.
Artigo em Alemão | MEDLINE | ID: mdl-31136272

RESUMO

Benralizumab: Targeting the IL-5 Receptor in Severe Eosinophilic Asthma Abstract. For patients with difficult-to-control, severe bronchial asthma, highly effective, targeted treatment options are available in addition to inhaled medication. In the presence of eosinophilia, inhibition of the interleukin-5 (IL­5) axis with specific monoclonal antibodies promises to be an effective alternative to continuous systemic steroid therapy with few side effects. This review summarizes the data on benralizumab, a specific antibody against the IL-5 receptor alpha preventing receptor stimulation by IL-5 and activating a NK-cell mediated cytotoxic reaction with apoptosis of eosinophils. The s.c.-application of benralizumab leads within days to a virtually complete depletion of blood eosinophils with consecutive improvement in lung function and stabilization of asthma. For selected severe asthmatics, this is a promising therapy option.


Assuntos
Antiasmáticos , Anticorpos Monoclonais Humanizados , Asma , Receptores de Interleucina-5 , Antiasmáticos/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Asma/tratamento farmacológico , Eosinófilos , Humanos , Receptores de Interleucina-5/efeitos dos fármacos
13.
Praxis (Bern 1994) ; 108(7): 1-8, 2019.
Artigo em Alemão | MEDLINE | ID: mdl-31136278

RESUMO

Benralizumab: Targeting the IL-5 Receptor in Severe Eosinophilic Asthma Abstract. Abstract:For patients with difficult-to-control, severe bronchial asthma, highly effective, targeted treatment options are available in addition to inhaled medication. In the presence of eosinophilia, inhibition of the interleukin-5 (IL-5) axis with specific monoclonal antibodies promises to be an effective alternative to continuous systemic steroid therapy with few side effects. This review summarizes the data on benralizumab, a specific antibody against the IL-5 receptor alpha preventing receptor stimulation by IL-5 and activating a NK-cell mediated cytotoxic reaction with apoptosis of eosinophils. The s.c.-application of benralizumab leads within days to a virtually complete depletion of blood eosinophils with consecutive improvement in lung function and stabilization of asthma. For selected severe asthmatics, this is a promising therapy option.


Assuntos
Antiasmáticos , Anticorpos Monoclonais Humanizados , Asma , Receptores de Interleucina-5 , Antiasmáticos/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Asma/tratamento farmacológico , Eosinófilos , Humanos , Receptores de Interleucina-5/efeitos dos fármacos
14.
Nat Commun ; 10(1): 2141, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31105267

RESUMO

Costimulation of T cell responses with monoclonal antibody agonists (mAb-AG) targeting 4-1BB showed robust anti-tumor activity in preclinical models, but their clinical development was hampered by low efficacy (Utomilumab) or severe liver toxicity (Urelumab). Here we show that isotype and intrinsic agonistic strength co-determine the efficacy and toxicity of anti-4-1BB mAb-AG. While intrinsically strong agonistic anti-4-1BB can activate 4-1BB in the absence of FcγRs, weak agonistic antibodies rely on FcγRs to activate 4-1BB. All FcγRs can crosslink anti-41BB antibodies to strengthen co-stimulation, but activating FcγR-induced antibody-dependent cell-mediated cytotoxicity compromises anti-tumor immunity by deleting 4-1BB+ cells. This suggests balancing agonistic activity with the strength of FcγR interaction as a strategy to engineer 4-1BB mAb-AG with optimal therapeutic performance. As a proof of this concept, we have developed LVGN6051, a humanized 4-1BB mAb-AG that shows high anti-tumor efficacy in the absence of liver toxicity in a mouse model of cancer immunotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Imunoterapia/métodos , Melanoma Experimental/terapia , Receptores de IgG/metabolismo , Neoplasias Cutâneas/terapia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/antagonistas & inibidores , Células 3T3 , Animais , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Linhagem Celular Tumoral/transplante , Ensaios de Seleção de Medicamentos Antitumorais , Técnicas de Introdução de Genes , Humanos , Fígado/efeitos dos fármacos , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de IgG/genética , Neoplasias Cutâneas/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
15.
N Engl J Med ; 380(16): 1535-1545, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30995373

RESUMO

BACKGROUND: Administration of a single broadly neutralizing human immunodeficiency virus (HIV)-specific antibody to HIV-infected persons leads to the development of antibody-resistant virus in the absence of antiretroviral therapy (ART). It is possible that monotherapy with UB-421, an antibody that blocks the virus-binding site on human CD4+ T cells, could induce sustained virologic suppression without induction of resistance in HIV-infected persons after analytic treatment interruption. METHODS: We conducted a nonrandomized, open-label, phase 2 clinical study evaluating the safety, pharmacokinetics, and antiviral activity of UB-421 monotherapy in HIV-infected persons undergoing analytic treatment interruption. All the participants had undetectable plasma viremia (<20 copies of HIV RNA per milliliter) at the screening visit. After discontinuation of ART, participants received eight intravenous infusions of UB-421, at a dose of either 10 mg per kilogram of body weight every week (Cohort 1) or 25 mg per kilogram every 2 weeks (Cohort 2). The primary outcome was the time to viral rebound (≥400 copies per milliliter). RESULTS: A total of 29 participants were enrolled, 14 in Cohort 1 and 15 in Cohort 2. Administration of UB-421 maintained virologic suppression (<20 copies per milliliter) in all the participants (94.5% of measurements at study visits 2 through 9) during analytic treatment interruption, with intermittent viral blips (range, 21 to 142 copies per milliliter) observed in 8 participants (28%). No study participants had plasma viral rebound to more than 400 copies per milliliter. CD4+ T-cell counts remained stable throughout the duration of the study. Rash, mostly of grade 1, was a common and transient adverse event; one participant discontinued the study drug owing to a rash. A decrease in the population of CD4+ regulatory T cells was observed during UB-421 monotherapy. CONCLUSIONS: UB-421 maintained virologic suppression (during the 8 to 16 weeks of study) in participants in the absence of ART. One participant discontinued therapy owing to a rash. (Funded by United Biomedical and others; ClinicalTrials.gov number, NCT02369146.).


Assuntos
Antirretrovirais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos , Exantema/induzido quimicamente , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores , Carga Viral , Viremia/tratamento farmacológico
16.
EBioMedicine ; 42: 157-173, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30910484

RESUMO

BACKGROUND: Bringing antibodies from pre-clinical studies to human trials requires humanization, but this process may alter properties that are crucial for efficacy. Since pathological tau protein is primarily intraneuronal in Alzheimer's disease, the most efficacious antibodies should work both intra- and extracellularly. Thus, changes which impact uptake or antibody binding will affect antibody efficacy. METHODS: Initially, we examined four tau mouse monoclonal antibodies with naturally differing charges. We quantified their neuronal uptake, and efficacy in preventing toxicity and pathological seeding induced by human-derived pathological tau. Later, we generated a human chimeric 4E6 (h4E6), an antibody with well documented efficacy in multiple tauopathy models. We compared the uptake and efficacy of unmodified and chimeric antibodies in neuronal and differentiated neuroblastoma cultures. Further, we analyzed tau binding using ELISA assays. FINDINGS: Neuronal uptake of tau antibodies and their efficacy strongly depends on antibody charge. Additionally, their ability to prevent tau toxicity and seeding of tau pathology does not necessarily go together. Particularly, chimerization of 4E6 increased its charge from 6.5 to 9.6, which blocked its uptake into human and mouse cells. Furthermore, h4E6 had altered binding characteristics despite intact binding sites, compared to the mouse antibody. Importantly, these changes in uptake and binding substantially decreased its efficacy in preventing tau toxicity, although under certain conditions it did prevent pathological seeding of tau. CONCLUSIONS: These results indicate that efficacy of chimeric/humanized tau antibodies should be thoroughly characterized prior to clinical trials, which may require further engineering to maintain or improve their therapeutic potential. FUND: National Institutes of Health (NS077239, AG032611, R24OD18340, R24OD018339 and RR027990, Alzheimer's Association (2016-NIRG-397228) and Blas Frangione Foundation.


Assuntos
Anticorpos Monoclonais/farmacologia , Proteínas tau/antagonistas & inibidores , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Transporte Biológico , Biomarcadores , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Agregados Proteicos , Agregação Patológica de Proteínas/metabolismo , Ligação Proteica , Multimerização Proteica , Relação Estrutura-Atividade , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Proteínas tau/imunologia
17.
BMC Cancer ; 19(1): 278, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922327

RESUMO

BACKGROUND: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3), which is expressed in hepatocellular carcinoma (HCC), was tested in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. Biomarker analysis was performed to identify a responder population that benefits from treatment. METHODS: A novel statistical method based on the Indian buffet process (IBP) was used to identify biomarkers predictive of response to treatment with Codrituzumab. The IBP is a novel method that allows flexibility in analysis design, and which is sensitive to slight, but meaningful between-group differences in biomarkers in very complex datasets RESULTS: The IBP model identified several subpopulations of patients having defined biomarker values. Tumor necrosis and viable cell content in the tumor were identified as prognostic markers of disease progression, as were the well-known HCC prognostic markers of disease progression, alpha-fetoprotein and Glypican-3 expression. Predictive markers of treatment response included natural killer (NK) cell surface markers and parameters influencing NK cell activity, all related to the mechanism of action of this drug CONCLUSIONS: The Indian buffet process can be effectively used to detect statistically significant signals with high sensitivity in complex and noisy biological data TRIAL REGISTRATION: NCT01507168 , January 6, 2012.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glipicanas/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Modelos Estatísticos , Análise de Sobrevida , Resultado do Tratamento , alfa-Fetoproteínas/metabolismo
18.
Iran J Immunol ; 16(1): 26-42, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30864553

RESUMO

BACKGROUND: We have recently produced an inhibitory mouse anti-human HER2 mAb (2A8) which displayed potent anti-tumor activity in combination with trastuzumab. OBJECTIVE: To describe chimerization and functional characterization of 2A8 mAb. METHODS: The VH and VL genes of 2A8 mAb were amplified from cDNA of the mouse hybridoma, ligated to constant regions of human immunoglobulin, and expressed in CHO cell line. Reactivity with four members of human HER family, the inhibitory effects and antibody-dependent cell cytotoxicity (ADCC) of purified chimeric mAb (c2A8) were assessed by ELISA, XTT, H3-tymidine incorporation and lactate dehydrogenase assays. Inhibition of ERK and AKT downstream signaling pathways by the chimeric antibody were analyzed by Western blotting. RESULTS: Chimeric 2A8 mAb bound to recombinant human HER2 and did not cross-react with the other members of HER family. Moreover, c2A8 was able to recognize HER2-overexpressing cancer cell line and inhibited growth and proliferation of these cells. The binding affinity of c2A8 was comparable to the mouse parental mAb. ADCC and Western blotting results showed that the mouse 2A8 mAb was successfully chimerized and could significantly inhibit phosphorylation of AKT in combination with trastuzumab. CONCLUSION: The c2A8 mAb is potentially a valuable tool for targeted immunotherapy of HER2 positive cancers.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/genética , Anticorpos Monoclonais Humanizados/imunologia , Especificidade de Anticorpos/genética , Especificidade de Anticorpos/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Células CHO , Linhagem Celular Tumoral , Cricetulus , Reações Cruzadas/imunologia , Mapeamento de Epitopos , Epitopos/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica , Vetores Genéticos/genética , Humanos , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Cadeias Leves de Imunoglobulina/genética , Cadeias Leves de Imunoglobulina/imunologia , Macaca fascicularis , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Transfecção , Trastuzumab/farmacologia
20.
Drugs ; 79(3): 341-346, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30742278

RESUMO

Sintilimab (Tyvyt®) is a fully human IgG4 monoclonal antibody that binds to programmed cell death receptor-1 (PD-1), thereby blocking the interaction of PD-1 with its ligands (PD-L1 and PL-L2) and consequently helping to restore the endogenous antitumour T-cell response. It has been co-developed by Innovent Biologics and Eli Lilly and Company, and was recently approved in China for the treatment of classical Hodgkin's lymphoma in patients who have relapsed or are refractory after ≥ 2 lines of systemic chemotherapy. Sintilimab is undergoing phase I, II and III development for use in various solid tumours, including non-small cell lung cancer and oesophageal cancer, in China. Phase I/II development of sintilimab for use in solid tumours is underway in the USA, with the US FDA accepting an Investigational New Drug application for sintilimab in January 2018. This article summarizes the milestones in the development of sintilimab leading to this first approval for the treatment of classical Hodgkin's lymphoma in patients who have relapsed or are refractory after ≥ 2 lines of systemic chemotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Doença de Hodgkin/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , China , Aprovação de Drogas , Quimioterapia Combinada , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos , United States Food and Drug Administration
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