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1.
Drugs Today (Barc) ; 55(10): 605-613, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31720558

RESUMO

Plaque psoriasis is the commonest form of psoriasis affecting about 85% of those patients with the condition. Risankizumab was developed as a high-affinity humanized monoclonal antibody specific for the p19 subunit of interleukin-23 (IL-23p19). Clinical trials demonstrated that risankizumab was very effective in patients with moderate to severe plaque psoriasis causing total clearing of the condition as evidenced by Psoriasis Scalp Severity Index (PSSI100) and static Physician's Global Assessment (sPGA) of 0 in more than 50% of patients after 52 weeks of treatment. Risankizumab has been approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy as a dose of 150 mg administered by subcutaneous injection at week 0, week 4 and every 12 weeks thereafter.


Assuntos
Anticorpos Monoclonais/farmacologia , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Psoríase/terapia , Anticorpos Monoclonais Humanizados/farmacologia , Aprovação de Drogas , Humanos , Subunidade p19 da Interleucina-23/imunologia , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
2.
J Drugs Dermatol ; 18(10)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31603635

RESUMO

Dupilumab inhibits the interleukin-4 receptor subunit α and is FDA approved for treatment of moderate-to-severe atopic dermatitis. It is a relatively new drug, and whether it is efficacious for other diseases in dermatology is an area of increasing interest. We searched the literature and ClinicalTrials.gov database for uses of dupilumab beyond atopic dermatitis in dermatology and for ongoing studies on new uses for dupilumab. Off-label reports identified described use of dupilumab for several different dermatologic conditions, including allergic contact dermatitis, hand dermatitis, chronic spontaneous urticaria, prurigo nodularis, and alopecia areata. Overall, there is limited but promising data for dupilumab use beyond atopic dermatitis in dermatology. The relatively safe adverse effect profile of dupilumab may make it an option for certain recalcitrant diseases in dermatology, but further studies will be needed to assess its efficacy and determine its best possible use. J Drugs Dermatol. 2019;18(10):1053-1055.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Uso Off-Label , Dermatopatias/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Humanos , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Dermatopatias/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Resultado do Tratamento
3.
Clín. investig. arterioscler. (Ed. impr.) ; 31(5): 241-243, sept.-oct. 2019. graf
Artigo em Espanhol | IBECS | ID: ibc-184168

RESUMO

Se trata de un paciente con hipercolesterolemia familiar heterocigota y antecedentes de infarto agudo de miocardio, que es remitido a la unidad de lípidos de nuestro centro para ajuste del tratamiento hipocolesterolemiante. Dado que no alcanza los objetivos terapéuticos con tratamiento oral, comienza tratamiento con sesiones quincenales de aféresis de colesterol LDL, que mantiene durante 8 años. Con la introducción y disponibilidad de los inhibidores de la PCSK9, se presenta una nueva opción de tratamiento para este paciente


It is a patient with heterozygous familial hypercholesterolemia and a personal history of acute myocardial infarction, which is referred to our lipid unit for hypocholesterolemic treatment adjustment. Since he does not reach therapeutic goals with oral medication, he starts a treatment with fortnightly sessions of LDL-apheresis, which he keeps for 8 years. With the introduction and availability of PCSK9 inhibitors, a new treatment option is possible for this patient


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/antagonistas & inibidores , Hiperlipoproteinemia Tipo II/diagnóstico , Infarto do Miocárdio/complicações , Anticorpos Monoclonais/farmacologia , LDL-Colesterol/antagonistas & inibidores , Anticolesterolemiantes , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Pró-Proteína Convertase 9/administração & dosagem , Pró-Proteína Convertase 9/metabolismo , Lipoproteínas LDL/efeitos dos fármacos
4.
Internist (Berl) ; 60(10): 1043-1058, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31501913

RESUMO

Therapeutic regimens using monoclonal antibodies have been implemented in clinical daily practice for various gastroenterological diseases, for therapeutic strategies in gastrointestinal (GI) oncology, and infectious diseases of the gastrointestinal tract. The main indications remain the therapy of chronic inflammatory bowel disease and in GI oncology. A new field has opened for targeted therapy with monoclonal antibodies of recurrent Clostridium difficile infection. In the nomenclature of monoclonal antibodies, the endings of the substances indicate the production or degree of "humanization" of the respective antibodies ("umab": fully human, recombinant antibody; "ximab": chimeric antibody with variable murine domain). For chronic inflammatory bowel disease, monoclonal antibodies has been developed to interfere with molecular targets of the inflammatory cascade in the underlying pathogenesis (tumor necrosis factor­α, interleukin-12 and -23; α4ß7-integrins). The development of targeted therapies in the treatment of GI malignancies, monoclonal antibodies has been developed to interfere with substantial pathways of proliferation and apoptosis as well as neoplastic vascularization and neovascularization (e.g., vascular endothelial growth factor [VEGF] and VEGF receptor antibodies, epidermal growth factor receptor antibodies, HER2/neu antibodies). In the current review, we provide a summary of the current applications of monoclonal antibodies in the therapeutic treatment of gastroenterological diseases.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Gastroenteropatias/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos , Colite Ulcerativa/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Receptores ErbB/efeitos dos fármacos , Gastroenterologia , Humanos , Fatores Imunológicos/farmacologia , Camundongos , Receptores de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular
5.
Expert Rev Clin Pharmacol ; 12(10): 947-951, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31524530

RESUMO

Introduction: In September of 2018, the United States Federal Drug Administration (FDA) approved cemiplimab-rwlc (Libtayo) for advanced cutaneous squamous cell carcinoma (CSCC). Cemiplimab is an intravenous human monoclonal antibody directed against programmed cell death-1 receptor (PD-1). Cemiplimab blocks T-cell inactivation and enhances the immune system's anti-tumor response. Areas Covered: We review CSCC and the studies leading to cemiplimab's approval, including common side effects and safety issues experienced during the clinical trials. Expert Opinion: Immunotherapy, specifically checkpoint inhibitors, represents an increasingly utilized class of medications that is proving to be an effective treatment option for those with certain cancers. Over time, immunotherapy is likely to be the standard of care for immune-sensitive tumors. There are many challenges that the field faces, including the identification of reliable biomarkers to better predict response, decreasing toxicity, and the potential treatment of organ transplant patients.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Humanos , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/patologia , Resultado do Tratamento
6.
Expert Opin Investig Drugs ; 28(10): 821-826, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31526130

RESUMO

Introduction: The conventional management of most patients with metastatic urothelial carcinoma (UC) is platinum-based chemotherapy followed by immunotherapy. Erdafitinib is an option in post-platinum patients with activating mutations in fibroblast growth factor receptor (FGFR)-3 and -2. Salvage therapy with taxanes or vinflunine has demonstrated minimal efficacy. Enfortumab Vedotin (EV), a monoclonal antibody-drug conjugate (ADC) targeting nectin-4 is under investigation in patients with advanced UC. Areas covered: This review describes the epidemiology and unmet needs of patients with metastatic UC and is focused specifically on heavily treated patients. We explore the rationale for targeting nectin 4 and the clinical development of EV; efficacy and safety data from the completed phase I and II studies are examined. Ongoing trials to definitively assess clinical outcomes in comparison to current therapy and trials exploring EV in combination are also highlighted. Expert opinion: There is an unmet need for new therapies in most patients with advanced UC and who progress after platinum and immunotherapy. EV has shown promising efficacy and safety in this population in phase 1 and 2 trials including those with poor prognostic factors such as liver metastases. Ongoing trials exploring this agent in combination will continue to advance the treatment of UC.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/imunologia , Moléculas de Adesão Celular/imunologia , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Imunoterapia/métodos , Metástase Neoplásica , Oligopeptídeos/imunologia , Prognóstico , Neoplasias Urológicas/imunologia
7.
Lancet ; 394(10200): 793-804, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-31478503

RESUMO

Antibody-drug conjugates (ADCs) are immunoconjugates comprised of a monoclonal antibody tethered to a cytotoxic drug (known as the payload) via a chemical linker. The ADC is designed to selectively deliver the ultratoxic payload directly to the target cancer cells. To date, five ADCs have received market approval and over 100 are being investigated in various stages of clinical development. In this Therapeutics paper, we review recent clinical experience with the approved ADCs and other promising late-stage candidates on the horizon, following an overview of the biology and chemistry of ADCs and how the individual components of an ADC (antibody [or target], linker and conjugation chemistry, and cytotoxic payload) influence its activity. We briefly discuss opportunities for enhancing ADC efficacy, drug resistance, and future perspectives for this novel antibody-based molecular platform, which has great potential to make a paradigm shift in cancer chemotherapy.


Assuntos
Anticorpos Monoclonais , Antineoplásicos Imunológicos , Imunoconjugados , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia
8.
Expert Opin Investig Drugs ; 28(11): 931-940, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31549891

RESUMO

Introduction: Thymic stromal lymphopoietin (TSLP) is overexpressed in the airways of severe asthmatics and is an upstream cytokine that orchestrates inflammatory responses in asthma. TSLP exerts its effects by binding to a high affinity heteromeric receptor complex composed of TSLPR and IL-7Rα. An association of polymorphisms in TSLP with airway hyperresponsiveness, IgE, eosinophilia and asthma has been documented. TSLP has been implicated in asthma pathophysiology. Tezepelumab is a first-in-class human monoclonal antibody that binds to TSLP, thus inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety, tolerability and efficacy. Several trials are evaluating the long-term safety and the efficacy of tezepelumab in adults and adolescents with severe uncontrolled asthma.Areas covered: We provide an overview of the monoclonal antibody therapeutics market for severe uncontrolled asthma, examine the underlying pathophysiology that drives TSLP and discuss the use of tezepelumab for the treatment of severe uncontrolled asthma,Expert opinion: TSLP is a promising target for T2-high and perhaps some patients with T2-low asthma. The results of preliminary clinical trials are encouraging. Several unanswered questions concerning basic pathophysiological aspects of TSLP variants, the long-term safety and efficacy of tezepelumab with different phenotypes/endotypes of asthma should be addressed.


Assuntos
Antiasmáticos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Asma/tratamento farmacológico , Adolescente , Adulto , Animais , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Asma/imunologia , Asma/fisiopatologia , Citocinas/imunologia , Humanos , Índice de Gravidade de Doença
9.
Adv Exp Med Biol ; 1155: 543-553, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468430

RESUMO

Taurine transporter (TauT) has been identified as a target gene of p53 tumor suppressor. TauT is also found to be overexpressed in variety type of human cancers, such as leukemia. This study showed that expression of TauT was upregulated by c-Myc and c-Jun oncogenes. To explore whether blocking of TauT inhibits tumor development, the RNA interference (RNAi) and immune targeting approaches were tested in tumor cells in vitro and in p53 mutant mice in vivo. Knockdown of TauT expression by RNAi resulted in cell cycle G2 arrest and suppressed human breast cancer MCF-7 cells proliferation determined by colonies production and cell migration assays. Knockdown of TauT also rendered MCF-7 cells more susceptible to chemotherapeutic drug-induced apoptosis. An antibody specifically against TauT blocked taurine uptake and induced cell cycle G2 arrest leading to cell death of variety type of tumor cells without affecting the viability of normal mammalian cells. TauT peptide vaccination significantly increased median lifespan (1.5-fold) of the p53 null mice and rescued p53+/- mice by extending the median lifespan from 315 days to 621 days. Furthermore, single dose treatment of tumor-bearing (thymic lymphoma) p53 null mice with TauT peptide reduced tumor size by about 50% and significantly prolonged survival of these mice from average 7 days (after observing the thymic lymphoma) to 21 days. This finding demonstrates that a novel TauT peptide vaccine can delay, inhibit, and/or treat p53 mutation related spontaneous tumorigenesis in vivo. Therefore, TauT peptide may be used as a universal cancer vaccine to prevent and/or treat patients with p53 mutation-mediated cancers.


Assuntos
Vacinas Anticâncer , Imunoterapia , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Interferência de RNA , Proteína Supressora de Tumor p53/genética , Animais , Anticorpos Monoclonais/farmacologia , Pontos de Checagem do Ciclo Celular , Técnicas de Silenciamento de Genes , Genes jun , Genes myc , Humanos , Células MCF-7 , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Mutação , Taurina , Vacinas de Subunidades
10.
Expert Rev Clin Pharmacol ; 12(9): 851-857, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31460804

RESUMO

Introduction: The interleukin (IL)-23 and IL-17 pathway is closely related to the pathogenesis of psoriasis. This pathway is considered to be an important target for treating psoriasis. Risankizumab can selectively inhibit IL-23p19 subunit and for the treatment of psoriasis. This article aims to review risankizumab and provides reference for clinicians. Areas covered: The chemical property, mechanism of action, pharmacokinetics, clinical efficacy, safety of risankizumab was introduced in this paper. A PubMed search using the terms 'risankizumab,' 'IL-23,' 'p19 subunit,' and 'psoriasis,' was performed, and the results were screened for the most relevant English language publications. Expert opinion: Risankizumab is a humanized IgG monoclonal antibody that binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. Clinical trials showed that risankizumab was significantly more effective than ustekinumab. Risankizumab was well tolerated, upper respiratory tract infection was the common adverse reactions. Therefore, the market of risankizumab provides an important therapeutic means for psoriasis.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Humanos , Interleucina-23/imunologia , Psoríase/imunologia , Psoríase/patologia , Ustekinumab/administração & dosagem
11.
Paediatr Drugs ; 21(5): 389-395, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31463794

RESUMO

INTRODUCTION: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by interleukin (IL)-1 overproduction. Colchicine is the mainstay drug in the treatment of FMF; however, a minority of patients do not respond despite the highest tolerated doses. We aimed to share our experience with canakinumab, a human monoclonal antibody against IL-1ß, in pediatric FMF patients. METHODS: This historical, single-cohort study retrospectively evaluated the disease characteristics, indications, and treatment responses of 14 pediatric FMF patients treated with canakinumab in our pediatric rheumatology department. RESULTS: The median age at onset and diagnosis of 14 FMF patients (9 females, 5 males), were 3.5 (range 0.5-10) years and 6 (range 3-16) years, respectively. Indications for canakinumab treatment were renal amyloidosis (n = 1), colchicine resistance (n = 11), and persistent arthritis (n = 2). Only two (14.3%) patients had colchicine intolerance. Complete response was obtained in 10/14 (71.5%) among all patients and 10/12 (86%) in patients with typical phenotype. The patient with chronic oligoarthritis had a complete response, whereas the patient with rheumatoid factor (RF)-positive polyarthritis demonstrated an initial partial response to canakinumab treatment. We found that attack frequency, proteinuria, and acute phase reactants, including erythrocyte sedimentation rate and C-reactive protein, were significantly decreased after canakinumab treatment in children with FMF. CONCLUSION: Canakinumab may be an effective treatment option for pediatric FMF patients with colchicine resistance, renal amyloidosis, and chronic oligoarthritis. Further studies are needed to clarify the efficacy of canakinumab in patients with a second disease, RF-positive polyarticular juvenile idiopathic arthritis.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Interleucina-1beta/uso terapêutico , Adolescente , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Estudos de Coortes , Febre Familiar do Mediterrâneo/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-1beta/farmacologia , Masculino , Estudos Retrospectivos , Resultado do Tratamento
12.
Lancet ; 394(10199): 697-708, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31448741

RESUMO

Atherosclerosis and its clinical manifestation as ischaemic heart disease remains a considerable health burden. Given that many factors contribute to ischaemic heart disease, a multifactorial approach to prevention is recommended, starting with lifestyle advice, smoking cessation, and control of known cardiovascular risk factors, such as blood pressure and lipids. Within the lipid profile, the principal target is lowering LDL cholesterol, firstly with lifestyle interventions and subsequently with pharmacological therapy. Statins are the recommended first-line pharmacological treatment. Some individuals might require further lowering of LDL cholesterol or be unable to tolerate statins. Additional therapies targeting different pathways in cholesterol metabolism are now available, ranging from small molecules taken orally, to injectable therapies. Examples include ezetimibe, which targets Niemann-Pick C1-like protein, and monoclonal antibodies that target PCSK9. Phase 3 trials have also been completed for bempedoic acid (targeting ATP-citrate lyase) and inclisiran (an interference RNA-based therapeutic targeting hepatic PCSK9 synthesis). In addition to LDL cholesterol, mendelian randomisation studies support a causal role for lipoprotein(a) and triglycerides in ischaemic heart disease. In this Series paper, we appraise currently available and emerging therapies for lowering LDL cholesterol, lipoprotein(a), and triglycerides for prevention of ischaemic heart disease.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/farmacologia , LDL-Colesterol/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipoproteínas/efeitos dos fármacos , Isquemia Miocárdica/prevenção & controle , LDL-Colesterol/sangue , Humanos , Lipoproteínas/sangue , Isquemia Miocárdica/tratamento farmacológico , Pró-Proteína Convertase 9 , Fatores de Risco , Triglicerídeos/sangue
13.
Nat Immunol ; 20(9): 1138-1149, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31427775

RESUMO

Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1α, IL-1ß, IL-33, IL-36α, IL-36ß and IL-36γ). In many diseases, multiple cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.


Assuntos
Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/farmacologia , Proteína Acessória do Receptor de Interleucina-1/antagonistas & inibidores , Peritonite/imunologia , Pneumonia/imunologia , Psoríase/imunologia , Células A549 , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HEK293 , Humanos , Imiquimode/toxicidade , Inflamação/patologia , Interleucina-1/imunologia , Proteína Acessória do Receptor de Interleucina-1/imunologia , Interleucina-1beta/imunologia , Interleucina-33/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/toxicidade , Peritonite/tratamento farmacológico , Peritonite/patologia , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Psoríase/tratamento farmacológico , Psoríase/patologia , Transdução de Sinais/imunologia , Ácido Úrico/toxicidade
14.
Cancer Immunol Immunother ; 68(8): 1359-1368, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332464

RESUMO

Immune checkpoint inhibitors targeting coinhibitory pathways in T cells possess efficacy in combating cancer. In addition to PD-1/PD-L1 and CTLA-4 antibodies which are already established in tumor immunotherapy, immune checkpoints such as LAG-3 or BTLA are emerging, which may have the potential to enhance T-cell responses alone or in combination with PD-1 blockers. CD4+ T cells play a central role in the immune system and contribute to productive immune responses in multiple ways. The effects of immune checkpoint inhibitors on this cell subset may thus critically influence therapeutic outcomes. Here, we have used in vitro responses to tetanus toxoid (TT) as a model system to study the effects of immune checkpoint inhibitors on CD4+ T-cell responses. CFSE-labeled PBMCs of 65 donors were stimulated with TT in the presence of blocking antibodies to PD-L1, CTLA-4, LAG-3, or BTLA for 7 days. We found that the PD-L1 antibody greatly enhanced cytokine production and antigen-specific CD4+ T-cell proliferation, whereas blocking antibodies to BTLA or LAG-3 did not augment responses to TT. Surprisingly, the presence of the therapeutic CTLA-4 antibody ipilimumab resulted in a significant reduction of CD4+ T-cell proliferation and cytokine production. Stimulation experiments with an IgG4 variant of ipilimumab indicated that the inhibitory effect of ipilimumab was dependent on its IgG1 isotype. Our results indicate that the therapeutic CTLA-4 antibody ipilimumab can impair CD4+ effector T-cell responses and that this activity is mediated by its Fc part and CD16-expressing cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Ipilimumab/farmacologia , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/metabolismo , Ipilimumab/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Toxoide Tetânico/imunologia
15.
Crit Rev Oncol Hematol ; 142: 16-25, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326706

RESUMO

BACKGROUND: Two PD-1 (pembrolizumab, nivolumab) and one PD-L1(atezolizumab) inhibitors are approved for previously treated advanced non-small cell lung cancer but have not been compared in head-to-head trials. METHOD: A network meta-analysis was conducted to compare efficacy/safety of PD-1/PD-L1 inhibitors. RESULTS: In five-trials (including long-term updates) with docetaxel as common comparator there were no differences in OS and PFS between PD-1/PD-L1 inhibitors. Pembrolizumab (odds ratio(OR) = 2.22, 95%CrI = 1.28-3.70) and nivolumab (OR = 1.92, 95%CrI = 1.15-3.23) had higher ORRs than atezolizumab and at PD-L1 expression ≥50% and ≥1%. Probabilistically, pembrolizumab ranked first in OS and ORR, and in OS sub-analyses for adenocarcinoma, EGFR-mutant, ECOG-score-1, male, and age <65 years. Nivolumab ranked first in PFS, and in OS sub-analyses for squamous-cell disease, EGFR-wild-type, and ECOG-score-0. Pembrolizumab and nivolumab ranked the best option for most of adverse events. CONCLUSION: While pembrolizumab and nivolumab prevailed in rank in OS and ORR benefit, patient characteristics, safety and tolerance should be considered in treatment decision-making.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Meta-Análise em Rede , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Docetaxel/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resultado do Tratamento
16.
Expert Rev Clin Pharmacol ; 12(8): 741-748, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31220963

RESUMO

Introduction: The Calcitonin Gene-Related Peptide (CGRP) has been implicated in migraine pathophysiology due to its role in neurogenic inflammation and transmission of trigeminovascular nociceptive signal. New molecules targeting CGRP and its receptor have been developed as migraine-specific preventative treatments. Fremanezumab (or TEV-48,125, LBR-101), a human monoclonal antibody against CGRP, has been recently approved for clinical use by FDA and EMA. Areas covered: This paper briefly discusses the calcitonin family of neurotransmitters and resultant activation pathways and in-depth the chemical properties, pharmacodynamics, pharmacokinetics, clinical efficacy and safety of Fremanezumab for the prophylactic treatment of migraine. Expert opinion: Fremanezumab, a migraine-specific drug, is effective and safe as a prophylactic treatment of chronic and episodic migraine. As a monoclonal antibody, it was not associated to liver toxicity and is not expected to interact with other drugs. The long half-life might improve patients' compliance. Long-term effects of CGRP block in cardiovascular, grastrointestinal and bone functions should be evaluated in ongoing trials, since CGRP is involved in multiple biological activities in the human body. Nevertheless, targeting CGRP itself allows the receptor binding with other ligands involved in several physiological functions. Thus, the long-term treatment with Fremanezumab is expected to be associated with a lower risk of severe adverse effects.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Transtornos de Enxaqueca/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Humanos , Transtornos de Enxaqueca/fisiopatologia
17.
Eur J Pharm Biopharm ; 142: 49-60, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201855

RESUMO

Antibody drug conjugates (ADCs), which are obtained by coupling a potent cytotoxic agent to a monoclonal antibody (mAb), are traditionally bound in a random way to lysine or cysteine residues, with the final product's heterogeneity having an important impact on their activity, characterization, and manufacturing. A new antibody drug delivery system (ADS) based on a non-covalent linkage between a Fc-binding protein, in this case Protein A or Protein G, and a mAb was investigated in the effort to achieve greater homogeneity and to create a versatile and adaptable drug delivery system. Recombinant staphylococcal Protein A and streptococcal Protein G were chemically PEGylated at the N-terminus with a 5 kDa and a 20 kDa PEG, respectively, yielding two monoconjugates with a mass of ≈50 and ≈45 kDa. Circular dichroism studies showed that both conjugates preserved secondary structures of the protein, and isothermal titration calorimetry experiments demonstrated that their affinity for mAb was approximately 107 M-1. Upon complexation with a mAb (Trastuzumab or Rituximab), in vitro flow-cytometry analysis of the new ADSs showed high selectivity for the specific antigen expressing cells. In addition, the ADS complex based on Trastuzumab and Protein G, conjugated with a heterobifunctional 20 kDa PEG carrying the toxin Tubulysin A, had a marked cytotoxic effect on the cancer cell line overexpressing the HER2/neu receptor, thus supporting its application in cancer therapy.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Imunoconjugados/farmacologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Humanos , Células Jurkat , Receptor ErbB-2/metabolismo , Rituximab/farmacologia , Trastuzumab/farmacologia
18.
BMC Cancer ; 19(1): 634, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248373

RESUMO

BACKGROUND: Metastasis is a leading cause of breast cancer mortality. The induction of epithelial-to-mesenchymal transition (EMT) and complex oncogenic signaling is a vital step in the evolution of highly metastatic and therapeutically-intractable breast cancer; necessitating novel target discovery or development of therapeutics that target metastatic breast cells (MBCs). METHODS: To achieve this, this study employs a combination of in silico bioinformatics analyses, protein and transcript analyses, drug sensitivity assays, functional assays and animal studies. RESULTS: The present study identified CDH11 as an inductor and/or facilitator of metastatic signaling, and biomarker of poor prognosis in MBCs. Furthermore, we showed that in the presence of CDH11-rich cancer-associated fibroblasts (CAFs), MCF7 and MDA-MB-231 MBC cell lines acquired enhanced metastatic phenotype with increased CDH11, ß-catenin, vimentin, and fibronectin (FN) expression. We also demonstrated, for the first time to the best of our knowledge that exposure to anti-CDH11 antibody suppresses metastasis, reduces CDH11, FN and ß-catenin expression, and abrogate the cancer stem cell (CSC)-like traits of MBC cells. Interestingly, ectopic expression of miR-335 suppressed CDH11, ß-catenin and vimentin expression, in concert with attenuated metastatic and CSC potentials of the MBC cells; conversely, inhibition of miR-335 resulted in increased metastatic potential. Finally, corroborating the in silica and in vitro findings, in vivo assays showed that the administration of anti-CDH11 antibody or miR-335 mimic suppressed tumorigenesis and inhibited cancer metastasis. CONCLUSIONS: These findings validate our hypotheses that miR-335 mediates anti-CDH11 antibody therapy response and that an enhanced miR-335/CDH11 ratio elicits marked suppression of the MBC CSC-like and metastatic phenotypes, thus revealing a therapeutically-exploitable inverse correlation between CDH11-enhanced CSC-like and metastatic phenotype and miR-335 expression in MBCs. Thus, we highlight the therapeutic promise of humanized anti-CDH11 antibodies or miR-335-mimic, making a case for their clinical application as efficacious therapeutic option in patients with MBC.


Assuntos
Neoplasias da Mama/patologia , Caderinas/antagonistas & inibidores , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Caderinas/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/farmacologia , Metástase Neoplásica , Prognóstico , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Biochemistry (Mosc) ; 84(Suppl 1): S193-S205, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31213202

RESUMO

Cytokines of the IL-17 family play a key role in the host organism defense against bacterial and fungal infections. At the same time, upregulated synthesis of IL-17 cytokines is associated with immunoinflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and others. The members of this family are important therapeutic targets in the treatment of various human chronic inflammatory disorders. Elucidation of signaling pathways involving IL-17 family proteins and analysis of the structure of cytokine complexes with specific antibodies, inhibitors, and receptors are essential for the development of new drugs for the therapy of immunoinflammatory rheumatic diseases.


Assuntos
Doenças Autoimunes/imunologia , Interleucina-17 , Terapia de Alvo Molecular , Linfócitos T/imunologia , Anticorpos Monoclonais/farmacologia , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/química , Interleucina-17/fisiologia , Estrutura Quaternária de Proteína , Transdução de Sinais
20.
Molecules ; 24(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216704

RESUMO

The family of matrix metalloproteinases (MMPs) consists of a set of biological targets that are involved in a multitude of severe pathogenic events such as different forms of cancers or arthritis. Modulation of the target class with small molecule drugs has not led to the anticipated success until present, as all clinical trials failed due to unacceptable side effects or a lack of therapeutic outcome. Monoclonal antibodies offer a tremendous therapeutic potential given their high target selectivity and good pharmacokinetic profiles. For the treatment of a variety of diseases there are already antibody therapies available and the number is increasing. Recently, several antibodies were developed for the selective inhibition of single MMPs that showed high potency and were therefore investigated in in vivo studies with promising results. In this review, we highlight the progress that has been achieved toward the design of inhibitory antibodies that successfully modulate MMP-9 and MMP-14.


Assuntos
Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Desenho de Drogas , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacologia , Metaloproteinases da Matriz/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Humanos , Metaloproteinases da Matriz/classificação , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Relação Estrutura-Atividade
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