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1.
Nat Commun ; 11(1): 4611, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929072

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Interleucinas/antagonistas & inibidores , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Resultado do Tratamento , Triglicerídeos/sangue , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Zhonghua Zhong Liu Za Zhi ; 42(8): 624-628, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867452

RESUMO

Small cell lung cancer (SCLC), a special type of lung cancer, is a highly malignant neuroendocrine tumor with strong invasiveness and rapid progression. SCLC is sensitive to radiotherapy and chemotherapy, so radiotherapy and chemotherapy have been the main first-line treatment of SCLC. However, it is easy to develop drug resistance after treatment. Therefore, the study of anti-angiogenic therapy has attracted more and more attention. At present, anti-angiogenic drugs mainly focus on four categories: monoclonal antibodies (such as bevacizumab), endogenous angiogenesis inhibitors (such as endostar), anti-angiogenic fusion protein (such as aflibercept) and small molecular tyrosine kinase inhibitors (such as anlotinib). There are still some bottlenecks in the research and clinical application of antiangiogenic drugs. It is the right direction to explore better combination therapy and effective dual-field and multi-target drugs.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Neovascularização Patológica/patologia , Medicina de Precisão , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento
3.
MAbs ; 12(1): 1804241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804015

RESUMO

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain of the viral Spike (S) glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain of S. This molecule shows exceptional performance in vitro, inhibiting the interaction of recombinant S1 to ACE2 and transduction of ACE2-overexpressing cells by S-pseudotyped lentivirus with IC50s substantially below 100 pM, and with potency approximately 100-fold greater than ACE2-Fc itself. Moreover, 89C8-ACE2 was able to neutralize authentic viral infection in a standard 96-h co-incubation assay at low nanomolar concentrations, making this class of molecule a promising lead for therapeutic applications.


Assuntos
Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral , Anticorpos Monoclonais/farmacologia , Desenho de Fármacos , Descoberta de Drogas , Humanos , Proteínas Recombinantes , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos
4.
Adv Exp Med Biol ; 1252: 115-124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32816270

RESUMO

Available data on systemic treatments in pregnancy-associated breast cancer (PABC) is reviewed in this section. These treatments include chemotherapy, endocrine therapy (ET), small molecule inhibitors, monoclonal antibodies against human epidermal growth factor receptor 2 (EGFR-2) also known as HER2; and human epidermal growth factor receptor 3 (EGFR-3), also known as HER3.In local disease, systemic treatment can be delivered as neoadjuvant (before surgery) or adjuvant (after surgery) treatment. In metastatic disease, systemic therapy is the main modality of treatment.Approach to PABC is based on available data in the general population, limited only by safety issues for use of medications during gestation and lactation. Therefore, treatments are similar to non-PABC patients while trying to minimize the risk to the fetus. Available data on different chemotherapies, anti-HER2 monoclonal antibodies, ET and small molecule inhibitors are discussed in detail.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Terapia Neoadjuvante , Metástase Neoplásica/tratamento farmacológico , Gravidez , Complicações Neoplásicas na Gravidez/patologia , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico
5.
Int J Mol Sci ; 21(15)2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32718020

RESUMO

The ongoing pandemic of coronavirus disease-2019 (COVID-19) is being caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease continues to present significant challenges to the health care systems around the world. This is primarily because of the lack of vaccines to protect against the infection and the lack of highly effective therapeutics to prevent and/or treat the illness. Nevertheless, researchers have swiftly responded to the pandemic by advancing old and new potential therapeutics into clinical trials. In this review, we summarize potential anti-COVID-19 therapeutics that block the early stage of the viral life cycle. The review presents the structures, mechanisms, and reported results of clinical trials of potential therapeutics that have been listed in clinicaltrials.gov. Given the fact that some of these therapeutics are multi-acting molecules, other relevant mechanisms will also be described. The reviewed therapeutics include small molecules and macromolecules of sulfated polysaccharides, polypeptides, and monoclonal antibodies. The potential therapeutics target viral and/or host proteins or processes that facilitate the early stage of the viral infection. Frequent targets are the viral spike protein, the host angiotensin converting enzyme 2, the host transmembrane protease serine 2, and clathrin-mediated endocytosis process. Overall, the review aims at presenting update-to-date details, so as to enhance awareness of potential therapeutics, and thus, to catalyze their appropriate use in combating the pandemic.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Pandemias , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
6.
Cancer Treat Rev ; 89: 102065, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32653806

RESUMO

To date, much progress has been made in early-stage extranodal NK/T-cell lymphoma (ENKTCL), and risk-adapted therapy with radiotherapy (RT) alone for the low-risk group and RT combined with asparaginase-based chemotherapy (CT) for the high-risk group yields favorable outcomes. However, optimal treatment strategies have not been defined yet for advanced-stage ENKTCL. Historically, ENKTCL responded poorly to conventional anthracycline-based chemotherapy probably because of inherent multidrug resistance (MDR). The fact that ENKTCL cells lack asparagine synthetase (ASNS) activity warranted the use of L-asparaginase or pegaspargase as frontline chemotherapies. Even though, due to high mortality of the disease, approximately 50% patients failing the frontline therapy arrived at dismal clinical outcomes with a median progression-free survival (PFS) less than 8 months. As distinctive molecular and biological subgroups are increasingly discovered within the disease entity of ENKTCL, novel targeted therapies and immunotherapy are of the urgent need for those heterogeneous subgroups. In this review, we sought to summarize the preclinical and clinical results of 6 categories of promising targeted therapy and immunotherapy for the treatment of ENKTCL, including monoclonal antibodies, immune checkpoint inhibitors, small-molecular inhibitors, epigenetic therapy, immunomodulatory drugs, and adoptive T-cell therapy, and these might change the landscape of treatment for ENKTCL in the near future.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/terapia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Imunoterapia/métodos , Imunoterapia Adotiva , Terapia de Alvo Molecular/métodos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/farmacologia
7.
Anticancer Res ; 40(7): 3793-3799, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620618

RESUMO

BACKGROUND/AIM: Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of cancer worldwide. Our study focused on the axon guidance receptor roundabout guidance receptor 1 (ROBO1) as a target for monoclonal antibody therapy of HNSCC. We previously showed that saporin-conjugated anti-ROBO1 (B5209B) immunotoxin (IT-ROBO1) enhanced cytotoxic effects on HNSCC cells in combination with the photosensitizer aluminum phthalocyanine disulphonate (AlPcS2a) and illumination. We examined the effects of this combination therapy in a mouse xenograft model. MATERIALS AND METHODS: IT-ROBO1 was intraperitoneally administered to HSQ-89 (derived from Japanese maxillary sinus squamous carcinoma, RCB0789; RIKEN, Tsukuba, Japan) xenografted mice. After 3 days, AlPcS2a was injected subcutaneously around the tumor and the area was illuminated at 650 nm for 30 min. The growth of the tumor was evaluated and the effects on the tumor were examined. RESULTS: Pronounced anti-tumor effects were elicited by the administration of IT-ROBO1 and AlPcS2a with light illumination on tumor size and pathological characteristics. CONCLUSION: The results showed that photosensitizer treatment with illumination robustly enhanced the antitumor effect of the IT-ROBO1 immunotoxin.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Imunotoxinas/metabolismo , Seio Maxilar/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Receptores Imunológicos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Seio Maxilar/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
PLoS Pathog ; 16(7): e1008560, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32667948

RESUMO

Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Citomegalovirus/imunologia , Vacinas contra Citomegalovirus/imunologia , Imunização Passiva , Imunoglobulina G/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Antígenos Virais/imunologia , Citomegalovirus/imunologia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Imunoglobulina G/farmacologia , Camundongos
9.
Mol Immunol ; 125: 140-150, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32682148

RESUMO

Successful transplantation outcome is the final goal in most end stage and nonfunctional organs; however, despite using different therapeutic strategies, antibody-mediated rejection is still a big obstacle. B cells have a key role in transplant rejection by several functions, such as antibody production, antigen presenting, contribution in T cell activation, forming the germinal center, and tertiary lymphoid organs. Therefore, B cells modulation seems to be very crucial in transplant outcome. A double-edged sword function is considered for B cells during transplantation; On the one hand, antibody production against the transplanted organ induces antibody-mediated rejection. On the other hand, IL10 production by regulatory B (Breg) cells induces graft tolerance. Nowadays, several monoclonal antibodies (mAb) are available for B cell modulation that are routinely used in transplant recipients, among which rituximab (anti-CD20 mAb) act in eliminating B cells. However, there are some other monoclonal antibodies, such as epratuzumab and Inotuzumab ozogamicin (IO), which exert anti-CD22 activity, resulting in disruption of B cell functions and induction of tolerance in autoimmune disease or B cell malignancies; that notwithstanding, these mAbs have not yet been tried in transplantation. In this review, we focus on different methods for modulating the activity of B cells as well as induction of Breg cells, aiming to prevent the allograft rejection.


Assuntos
Anticorpos Monoclonais/farmacologia , Linfócitos B/efeitos dos fármacos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Tolerância ao Transplante/efeitos dos fármacos , Tolerância ao Transplante/imunologia , Animais , Linfócitos B/imunologia , Humanos , Transplante Homólogo
10.
Int J Mol Sci ; 21(15)2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32718086

RESUMO

The role of interleukin (IL)-6 in health and disease has been under a lot of scrutiny in recent years, particularly during the recent COVID-19 pandemic. The inflammatory pathways in which IL-6 is involved are also partly responsible of the development and progression of rheumatoid arthritis (RA), opening interesting perspectives in terms of therapy. Anti-IL-6 drugs are being used with variable degrees of success in other diseases and are being tested in RA. Results have been encouraging, particularly when anti-IL-6 has been used with other drugs, such as metothrexate (MTX). In this review we discuss the main immunologic aspects that make anti-IL-6 a good candidate in RA, but despite the main therapeutic options available to target IL-6, no gold standard treatment has been established so far.


Assuntos
Artrite Reumatoide/imunologia , Interleucina-6/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Progressão da Doença , Humanos , Interleucina-6/antagonistas & inibidores , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos
11.
Eur Rev Med Pharmacol Sci ; 24(13): 7475-7484, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32706087

RESUMO

The pandemic caused by the new SARS-CoV2 coronavirus has led to an effort to find treatments that are effective against this disease that the World Health Organization calls COVID-19. In severe cases of COVID-19, there is an increase in cytokines, among which IL-6 seems to play an important role. A search has been performed for studies using IL-6 blocking drugs (tocilizumab, siltuximab, and sarilumab) in PubMed, Web of Science, and Scopus. Also, a search of ongoing trials registered at clinicaltrials.gov was performed. We found very little published clinical experience with these drugs, consisting mainly of case reports or case series with few patients. The results of clinical trials are necessary to clarify the role of these drugs in patients with COVID-19.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Betacoronavirus/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Humanos , Interleucina-6/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia
12.
Adv Cancer Res ; 147: 303-317, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32593404

RESUMO

Receptor tyrosine kinases (RTKs) are integral membrane sensors that govern cell differentiation, proliferation and mobility, and enable rapid communication between cells and their environment. Of the 20 RTK subfamilies currently known, Eph receptors are the largest group. Together with their corresponding ephrin ligands, Eph receptors regulate a diverse array of physiologic processes including axonal guidance, bone remodeling, and immune cell development and trafficking. Deregulation of Eph signaling pathways is linked to cancer and other proliferative diseases and, because RTKs play critical roles in cancer development, the specific targeting of these molecules in malignancies provides a promising treatment approach. Monoclonal antibodies targeting RTKs represent a potentially attractive modality for pharmaceutical development due to their relatively high target specificity and low off-target binding rates. Therefore, new technologies to generate antibodies able to target RTKs in their native in vivo context are likely to facilitate pre-clinical and clinical development of antibody-based therapies. Our group has recently reported a platform discovery methodology termed Selection of Phage-displayed Accessible Recombinant Targeted Antibodies (SPARTA). SPARTA is a novel and robust stepwise method, which combines the attributes of in vitro screenings of a naïve human recombinant antibody library against known tumor targets with those features of in vivo selections based on tumor-homing capabilities of a pre-enriched antibody pool. This unique approach overcomes several rate-limiting challenges to generate human monoclonal antibodies amenable to rapid translation into medical applications.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Receptores da Família Eph/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Receptores da Família Eph/metabolismo , Transdução de Sinais
13.
Scand J Immunol ; 92(3): e12915, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32533866

RESUMO

Systemic lupus erythematosus is an autoimmune syndrome characterized by the development of autoantibodies to a wide range of antigens. Together with B cells, respective self-reactive T cells have an important contribution in disease progression as being responsible for inflammatory cytokines secretion, B cell activation and promoting amplification of the autoimmune response. Annexin A1 is expressed by many cell types and binds to phospholipids in a Ca2+ -dependent manner. Abnormal expression of annexin A1 was found on activated B and T cells in both murine and human autoimmunity suggesting its potential role as a therapeutic target. In the present study, we have investigated the possibility to suppress autoimmune manifestation in spontaneous mouse model of lupus using anti-annexin A1 antibody. Groups of lupus-prone MRL/lpr mice were treated with the anti-annexin A1 monoclonal antibody, and the disease activity and survival of the animals were following up. Flow cytometry, ELISA assays, and histological and immunofluorescence kidney analyses were used to determine the levels of Annexin A1 expression, cytokines, anti-dsDNA antibodies and kidney injuries. The administration of this monoclonal antibody to MRL/lpr mice resulted in suppression of IgG anti-dsDNA antibody production, modulated IL-10 secretion, decreased disease activity and prolonged survival compared with the control group.


Assuntos
Anexina A1/antagonistas & inibidores , Anexina A1/imunologia , Anticorpos Monoclonais/farmacologia , Fatores Imunológicos/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Animais , Autoanticorpos/imunologia , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Proteinúria/etiologia , Proteinúria/urina , Baço/imunologia , Baço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
14.
Cancer Treat Rev ; 88: 102043, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32505806

RESUMO

Autophagy is a self-degradative cellular process, involved in stress response such as starvation, hypoxia, and oxidative stress. This mechanism balances macro-molecule recycling to regulate cell homeostasis. In cancer, autophagy play a role in the development and progression, while several studies describe it as one of the key processes in drug resistance. In the last years, in addition to standard anti-cancer treatments such as chemotherapies and irradiation, targeted therapy became one of the most adopted strategies in clinical practices, mainly due to high specificity and reduced side effects. However, similar to standard treatments, drug resistance is the main challenge in most patients. Here, we summarize recent studies that investigated the role of autophagy in drug resistance after targeted therapy in different types of cancers. We highlight positive results and limitations of pre-clinical and clinical studies in which autophagy inhibitors are used in combination with targeted therapies.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Humanos , Imunotoxinas/farmacologia , Terapia de Alvo Molecular , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia
15.
Expert Rev Cardiovasc Ther ; 18(6): 355-361, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32511037

RESUMO

INTRODUCTION: The prevalence of hypertriglyceridemia (HTG) is increasing. Elevated triglyceride (TG) levels are associated with an increased cardiovascular disease (CVD) risk. Moreover, severe HTG results in an elevated risk of pancreatitis, especially in severe HTG with an up to 350-fold increased risk. Both problems emphasize the clinical need for effective TG lowering. AREAS COVERED: The purpose of this review is to discuss the currently available therapies and to elaborate the most promising novel therapeutics for TG lowering. EXPERT OPINION: Conventional lipid lowering strategies do not efficiently lower plasma TG levels, leaving a residual CVD and pancreatitis risk. Both apolipoprotein C-III (apoC-III) and angiopoietin-like 3 (ANGPTL3) are important regulators in TG-rich lipoprotein (TRL) metabolism. Several novel agents targeting these linchpins have ended phase II/III trials. Volanesorsen targeting apoC-III has shown reductions in plasma TG levels up to 90%. Multiple ANGPLT3 inhibitors (evinacumab, IONIS-ANGPTL3-LRx, ARO-ANG3) effectuate TG reductions up to 70% with concomitant potent reduction in all other apoB containing lipoprotein fractions. We expect these therapeutics to become players in the treatment for (especially) severe HTG in the near future.


Assuntos
Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Apolipoproteína C-III/efeitos dos fármacos , Hipertrigliceridemia/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Ensaios Clínicos como Assunto , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/metabolismo , Lipoproteínas/metabolismo , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Pancreatite/etiologia , Pancreatite/prevenção & controle
16.
Nat Commun ; 11(1): 2992, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532974

RESUMO

Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Based on the hypothesis that specific inhibition of APC's anticoagulant but not its cytoprotective activity can be beneficial for hemophilia therapy, 2 types of inhibitory monoclonal antibodies (mAbs) are tested: A type I active-site binding mAb and a type II mAb binding to an exosite on APC (required for anticoagulant activity) as shown by X-ray crystallography. Both mAbs increase thrombin generation and promote plasma clotting. Type I blocks all APC activities, whereas type II preserves APC's cytoprotective function. In normal monkeys, type I causes many adverse effects including animal death. In contrast, type II is well-tolerated in normal monkeys and shows both acute and prophylactic dose-dependent efficacy in hemophilic monkeys. Our data show that the type II mAb can specifically inhibit APC's anticoagulant function without compromising its cytoprotective function and offers superior therapeutic opportunities for hemophilia.


Assuntos
Anticorpos Monoclonais/farmacologia , Hemofilia A/prevenção & controle , Fragmentos Fab das Imunoglobulinas/imunologia , Inibidor da Proteína C/farmacologia , Proteína C/antagonistas & inibidores , Animais , Anticorpos Monoclonais/classificação , Anticorpos Monoclonais/imunologia , Tempo de Sangramento , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Cultivadas , Cristalografia por Raios X , Hemofilia A/sangue , Hemorragia/prevenção & controle , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Fragmentos Fab das Imunoglobulinas/metabolismo , Macaca fascicularis , Masculino , Proteína C/química , Proteína C/imunologia , Proteína C/metabolismo , Inibidor da Proteína C/sangue , Inibidor da Proteína C/farmacocinética
17.
Cancer Immunol Immunother ; 69(11): 2345-2355, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32514619

RESUMO

The cross-talk between cancer cells and monocyte-derived alveolar macrophages (Mo-AMs) promotes non-small cell lung carcinoma (NSCLC) progression. In this study, we report that both cancer cells and Mo-AMs robustly express beta 3-adrenergic receptor (ADRB3) in NSCLC. ADRB3 supports lung cancer cells proliferation and promotes chronic inflammation. Genetic and pharmacologic inhibition of ADRB3 reverses tumor growth and inflammation in mouse. Furthermore, we demonstrate that M5D1, a novel anti-ADRB3 monoclonal antibody, inhibits human lung cancer cells proliferation and inflammation via affecting the intracellular mTOR pathway and activating p53. In NSCLC patients, we confirmed that upregulation of ADRB3 expression correlates with tumor progression and poor prognosis. Altogether, these results shed light on the role of ADRB3 in NSCLC and suggest that M5D1 could become powerful antitumor weapons.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Macrófagos Alveolares/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Prognóstico
18.
J Immunol ; 205(4): 915-922, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32591393

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for millions of infections and hundreds of thousands of deaths globally. There are no widely available licensed therapeutics against SARS-CoV-2, highlighting an urgent need for effective interventions. The virus enters host cells through binding of a receptor-binding domain within its trimeric spike glycoprotein to human angiotensin-converting enzyme 2. In this article, we describe the generation and characterization of a panel of murine mAbs directed against the receptor-binding domain. One mAb, 2B04, neutralized wild-type SARS-CoV-2 in vitro with remarkable potency (half-maximal inhibitory concentration of <2 ng/ml). In a murine model of SARS-CoV-2 infection, 2B04 protected challenged animals from weight loss, reduced lung viral load, and blocked systemic dissemination. Thus, 2B04 is a promising candidate for an effective antiviral that can be used to prevent SARS-CoV-2 infection.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/farmacologia , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Mapeamento de Epitopos , Feminino , Células HEK293 , Humanos , Epitopos Imunodominantes/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Domínios e Motivos de Interação entre Proteínas/genética , Domínios e Motivos de Interação entre Proteínas/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Transfecção , Células Vero
19.
Nat Commun ; 11(1): 2251, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: covidwho-164588

RESUMO

The emergence of the novel human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture. This cross-neutralizing antibody targets a communal epitope on these viruses and may offer potential for prevention and treatment of COVID-19.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/farmacologia , Afinidade de Anticorpos/imunologia , Betacoronavirus/química , Betacoronavirus/efeitos dos fármacos , Chlorocebus aethiops , Sequência Conservada , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Reações Cruzadas/imunologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Modelos Moleculares , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos/imunologia , Receptores Virais/química , Receptores Virais/metabolismo , Vírus da SARS/química , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Células Vero
20.
J Immunother Cancer ; 8(1)2020 05.
Artigo em Inglês | MEDLINE | ID: covidwho-220167

RESUMO

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as 'cytokine storm'. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Imunoterapia , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/complicações , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Sociedades Médicas , Transferência Adotiva , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Interferon gama/antagonistas & inibidores , Interleucina-1/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Janus Quinases/antagonistas & inibidores , Neoplasias/imunologia , Neoplasias/terapia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Fatores de Transcrição STAT/antagonistas & inibidores , Síndrome Respiratória Aguda Grave/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores
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