RESUMO
FDA-approved anti-PD-L1 antibody drug Atezolizumab is a human IgG1 without glycosylation by an N297A mutation. Aglycosylation of IgG1 has been used to completely remove the unwanted Fc-mediated functions such as antibody-dependent cytotoxicity (ADCC). However, aglycosylated Atezolizumab is very unstable and easy to form aggregation, which causes quick development of anti-drug antibody (ADA) in 41% of Atezolizumab-treated cancer patients, eventually leading to loss of efficacy. Here, we report the development of the anti-PD-L1 antibody drug Maxatezo, a glycosylated version of Atezolizumab, with no ADCC activity, better thermo-stability, and significantly improved anti-tumor activity in vivo. Using Atezolizumab as the starting template, we back-mutated A297N to re-install the glycosylation, and inserted a short, flexible amino acid sequence (GGGS) between G237 and G238 in the hinge region of the IgG1 heavy chain. Our data shows that insertion of GGGS, does not alter the anti-PD-L1's affinity and inhibitory activity, while completely abolishing ADCC activity. Maxatezo has a similar glycosylation profile and expression level (up to 5.4 g/L) as any normal human IgG1. Most importantly, Maxatezo's thermal stability is much better than Atezolizumab, as evidenced by dramatic increases of Tm1 from 63.55 °C to 71.01 °C and Tagg from 60.7 °C to 71.2 °C. Furthermore, the levels of ADA in mice treated with Maxatezo were significantly lower compared with animals treated with Atezolizumab. Most importantly, at the same dose (10 mg/kg), the tumor growth inhibition rate of Maxatezo was 98%, compared to 68% for Atezolizumab.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Animais , Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Glicosilação , Humanos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Receptores Fc/metabolismo , TemperaturaRESUMO
Complex immunological mechanisms underlie the pathogenesis of thyroid-associated ophthalmopathy (TAO). Historical models of Graves' disease and TAO have focused almost entirely on autoimmune reactivity directed against the thyrotropin receptor (TSHR). The insulin-like growth factor-I receptor (IGF-IR) has been proposed as a second participating antigen in TAO by virtue of its interactions with IGFs and anti-IGF-IR antibodies generated in Graves' disease. Furthermore, the IGF-IR forms with TSHR a physical and functional complex which is involved in signaling downstream from both receptors. Inhibition of IGF-IR activity results in attenuation of signaling initiated at either receptor. Based on the aggregate of findings implicating IGF-IR in TAO, the receptor has become an attractive therapeutic target. Recently, teprotumumab, a human monoclonal antibody IGF-IR inhibitor was evaluated in two clinical trials of patients with moderate to severe, active TAO. Those studies revealed that teprotumumab was safe and highly effective in reducing disease activity and severity. Targeting IGF-IR with specific biologic agents may result in a paradigm shift in the therapy of TAO.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Oftalmopatia de Graves/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Doença de Graves/tratamento farmacológico , Doença de Graves/imunologia , Oftalmopatia de Graves/imunologia , Humanos , Receptor IGF Tipo 1/efeitos dos fármacos , Receptor IGF Tipo 1/imunologiaAssuntos
Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Tratamento Farmacológico da COVID-19 , Diabetes Mellitus/tratamento farmacológico , Hipertensão/tratamento farmacológico , Linfócitos/patologia , Neutrófilos/patologia , Adulto , Idoso , Biomarcadores/análise , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/mortalidade , Comorbidade , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/imunologia , Diabetes Mellitus/mortalidade , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/imunologia , Hipertensão/mortalidade , Contagem de Leucócitos , Linfócitos/imunologia , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/virologia , Prognóstico , Fatores de Risco , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Análise de SobrevidaAssuntos
Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Família de Moléculas de Sinalização da Ativação Linfocitária/sangue , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Humanos , Mieloma Múltiplo/diagnóstico , Prognóstico , Resultado do TratamentoRESUMO
Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti-programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti-PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS <90 days (ORR, 49% vs. 35%, P = 0.12; CBR, 66% vs. 46%, P = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02-1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. Cancer Immunol Res; 4(7); 569-73. ©2016 AACR.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Antineoplásicos Imunológicos/uso terapêutico , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Terapia Combinada , Esquema de Medicação , Feminino , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Patients with inflammatory bowel diseases (IBD), a chronic inflammatory disease characterized by flares and remission, are prone to develop thrombosis. The mechanism behind this prothrombotic state is not completely understood but is definitely multifactorial and linked with excessive inflammation observed in these patients. So far, no biomarker exists to select among IBD patients those with and increased risk for thrombosis. Corticosteroid therapy, given as rescue IBD treatment, is known to increase the thrombotic risk, whereas for antitumor necrosis factor (TNF)-alpha therapy such as infliximab, given to induce and maintain remission in IBD, the results are inconclusive. Here, we describe a 31-year-old IBD patient who developed a deep vein thrombosis. We determined the clot lysis profiles before and after developing thrombosis. We showed that a global functional clot lysis assay can be used as a tool to identify IBD patients who may benefit from thromboprophylactic therapy.
Assuntos
Antirreumáticos/efeitos adversos , Doenças Inflamatórias Intestinais/diagnóstico , Infliximab/efeitos adversos , Trombose Venosa/diagnóstico , Adulto , Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Azatioprina/efeitos adversos , Feminino , Tempo de Lise do Coágulo de Fibrina , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/patologia , Metilprednisolona/efeitos adversos , Fatores de Risco , Trombose Venosa/sangue , Trombose Venosa/induzido quimicamente , Trombose Venosa/patologiaAssuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Alzheimer/psicologia , Ensaios Clínicos Fase II como Assunto , Cognição , Humanos , Neuroimagem , NeurociênciasRESUMO
AIMS: Identify sensitive end points and populations for similarity studies of trastuzumab and biosimilar monoclonal antibodies. METHODS: We performed meta-analyses of trastuzumab clinical trials data: overall response rate (ORR) and progression-free survival in metastatic breast cancer (MBC), and total pathologic complete response (tpCR) and event-free survival in the neoadjuvant setting. Fitted models predicted the maximum loss in long-term efficacy for different similarity trial designs. Immunogenicity rates were investigated in different early breast cancer (EBC) study phases. RESULTS: Using the same equivalence margins for ORR (MBC) and tpCR (EBC), the predicted maximum loss in long-term efficacy with a biosimilar candidate versus the reference product is smaller for tpCR than for ORR. In EBC this predicted loss could be controlled with feasible patient numbers for a typical clinical trial. Analyses suggested that a treatment-free follow-up phase is preferable for immunogenicity characterization. CONCLUSION: Treatment of patients with neoadjuvant breast cancer represents a sensitive setting for establishing biosimilarity of efficacy and immunogenicity. tpCR is a sensitive end point in this setting to establish biosimilarity between a biosimilar candidate and its reference product.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Neoplasias da Mama/epidemiologia , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , TrastuzumabRESUMO
BACKGROUND/AIM: Increased concentrations of neopterin, a biomarker of systemic immune response, have been reported after administration of cytokines, cytotoxic chemotherapy or external-beam radiation, but little is known about the effects of targeted-agents on neopterin. PATIENTS AND METHODS: Urinary neopterin was studied in pre-treated patients with metastatic colorectal carcinoma during therapy with cetuximab, administered mostly in combination with irinotecan, 5-fluorouracil and leucovorin. Urinary neopterin was determined by high-performance liquid chromatography. RESULTS: High initial urinary neopterin concentrations predicted poor prognosis. A significant correlation was observed between urinary neopterin and peripheral blood leukocyte count, hemoglobin and carcinoembryonic antigen concentrations. Urinary neopterin concentrations significantly increased during therapy only in patients with initially low neopterin concentrations. CONCLUSION: Urinary neopterin concentrations predict prognosis in patients with metastatic colorectal carcinoma treated with cetuximab. Rising neopterin concentrations indicate an activation of systemic immune response that could be responsible for the antitumor activity of cetuximab.