RESUMO
PRO-169 is an anti-VEGF monoclonal antibody developed by Laboratorios Sophia that shares its sequence with Bevacizumab (BVZ); though, PRO-169 is intended for intravitreal administration. In this study, analytical characterization showed that PRO-169 had glycosylation differences in comparison to BVZ reference product (RP); since it had more content of G1F, G2F, sialic acid and high mannose. Further investigation was performed to evaluate if differences between both products would affect the efficacy and safety profile of PRO-169. PRO-169 had no alteration in its in vitro biological activity; moreover, no cytotoxicity or immunogenicity concerns should be expected as demonstrated by different orthogonal methods at analytical, in vitro and in vivo assays. These results support moving to the clinical testing of PRO-169 since no major complications will be expected with its clinical use for the treatment of ophthalmic diseases.
Assuntos
Anticorpos Monoclonais Humanizados , Fator A de Crescimento do Endotélio Vascular , Bevacizumab/farmacologia , Glicosilação , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêuticoRESUMO
PURPOSE: To evaluate the efficacy of a therapy on improving characteristics of laser-induced choroidal neovascularization (CNV) via single intravitreal injection of a humanized anti-human VEGF monoclonal antibody (PRO-169) versus bevacizumab in a rhesus monkey model. METHODS: To induce experimental CNV, small high-energy laser spots were used to treat several areas, around the macula in the retinas of monkeys at Day -21. Eighteen rhesus monkeys were used for CNV induction. The efficacy endpoints were fluorescein leakage by FFA and retinal thickness by OCT. FFA examinations were performed 19 days after induction. Appropriate animals were enrolled for treatment and randomly divided into 3 groups: bevacizumab (n=5, 7 eyes), PRO-169 (n=5, 7 eyes), and vehicle controls (n=4, 7 eyes). RESULTS: In 25 of 36 (69.4%) eyes, CNV lesions were identified. The average percent change of retinal thickness in the eyes of bevacizumab group was -159.3±62.2% and -154.0±45.1% (p<0.01 vs Vehicle) at Day 14 and Day 28, respectively; in the eyes of PRO-169 group it was -131.6±68.7% and -131.5±63.8% (p<0.01 vs Vehicle), respectively. The average percent change of leakage area in the eyes of bevacizumab group was -75.3±49.4% and -78.0±42.6% (p<0.01 vs Vehicle) at Day 14 and Day 28, respectively; in the eyes of PRO-169 group it was -82.0±19.3% and -81.4±21.0% (p<0.01 vs Vehicle), respectively. There were no abnormalities found in behavior, skin and hair, excretion and overall eye appearance before and after treatment in all groups. CONCLUSION: After photocoagulation, the eyes enrolled in this studio showed CNV related characteristics including increased retinal thickness, and fluorescein leakage at laser spots. PRO-169 (1.25 mg per eye) can reduce the retinal thickness and fluorescein leakage area after treatment for 14 and 28 days in this rhesus monkeys model, without toxic effect or adverse events. These findings suggested that PRO-169 can inhibit CNV.
Assuntos
Inibidores da Angiogênese/farmacologia , Anticorpos Neutralizantes/farmacologia , Bevacizumab/farmacologia , Neovascularização de Coroide/tratamento farmacológico , Modelos Animais de Doenças , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Neovascularização de Coroide/metabolismo , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Angiofluoresceinografia , Lasers , Macaca mulatta , Estrutura Molecular , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: To study the effect of different degrees of centrality on the carrying of identical group A streptococcus (GAS) clones in the nasopharynx of children from a Mexican public day-care center. MATERIAL AND METHODS: Nasopharyngeal cultures were performed in children from rooms B (RB) (n = 35) and C (RC) (n = 37). The Restriction Fragment Length Polymorphism (RFLP) patterns were compared among GAS isolates. A social networks questionnaire was filled out for each child and 10 classmates. Structure coefficients were compared among children with and without GAS. RESULTS: Four GAS clones were identified; clone I in five children from RC; clone II in two from RC and one from RB; clone III in one from RB and one from RC; and clone IV in one from RC. Social network structure: Density of RB and RC = 0.40 (+/- 0.87) and 0.35 (+/- 0.80), respectively. In RB, the homophily pattern of interaction was different in carriers (0.00), non-carriers (0.47) and both (0.47) p = 0.35. In RC, the homophily pattern was also different in carriers (0.46), non-carriers (0.68) and mixed (0.19), p = .001. In 4/5 with clone I, the values of degree, closeness and betweenness were above the group mean. In 3/3 with clone II, the values of degree and betweenness were also above the mean. In contrast, in those with clone III and IV, the values of degree, closeness and betweenness were below the group mean. CONCLUSION: The spread of specific GAS clones was associated with groups of children having a high proportion of ties and a high centrality level. This is evidence that spread of GAS strains among children attending day-care centers is not random but dependent on the degree of communication and physical contact between pairs.
Assuntos
Portador Sadio/microbiologia , Creches , Transmissão de Doença Infecciosa , Nasofaringe/microbiologia , Apoio Social , Infecções Estreptocócicas/transmissão , Streptococcus pyogenes/isolamento & purificação , Antibacterianos/uso terapêutico , Portador Sadio/epidemiologia , Creches/estatística & dados numéricos , Pré-Escolar , Células Clonais , Transmissão de Doença Infecciosa/estatística & dados numéricos , Feminino , Humanos , Masculino , México/epidemiologia , Polimorfismo de Fragmento de Restrição , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/epidemiologia , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/classificação , Streptococcus pyogenes/genéticaRESUMO
OBJECTIVE: To study the effect of different degrees of centrality on the carrying of identical group A streptococcus (GAS) clones in the nasopharynx of children from a Mexican public day-care center. MATERIAL AND METHODS: Nasopharyngeal cultures were performed in children from rooms B (RB) (n = 35) and C (RC) (n = 37). The Restriction Fragment Length Polymorphism (RFLP) patterns were compared among GAS isolates. A social networks questionnaire was filled out for each child and 10 classmates. Structure coefficients were compared among children with and without GAS. RESULTS: Four GAS clones were identified; clone I in five children from RC; clone II in two from RC and one from RB; clone III in one from RB and one from RC; and clone IV in one from RC. Social network structure: Density of RB and RC = 0.40 (± 0.87) and 0.35 (± 0.80), respectively. In RB, the homophily pattern of interaction was different in carriers (0.00), non-carriers (0.47) and both (0.47) p = 0.35. In RC, the homophily pattern was also different in carriers (0.46), non-carriers (0.68) and mixed (0.19), p = .001. In 4/5 with clone I, the values of degree, closeness and betweenness were above the group mean. In 3/3 with clone II, the values of degree and betweenness were also above the mean. In contrast, in those with clone III and IV, the values of degree, closeness and betweenness were below the group mean. CONCLUSION: The spread of specific GAS clones was associated with groups of children having a high proportion of ties and a high centrality level. This is evidence that spread of GAS strains among children attending day-care centers is not random but dependent on the degree of communication and physical contact between pairs.
OBJETIVO: Evaluar el efecto de grados diferentes de centralidad con la presencia de clonas idénticas de estreptococo del grupo A (EGA) en la nasofaringe de niños de una guardería pública de México. MATERIAL Y MÉTODOS: Se realizaron cultivos nasofaríngeos en niños de los salones B (SB) (n = 35) y C (SC) (n = 37). El patrón de polimorfismos de longitud de fragmento por restricción (Restriction Fragment Length Polymorphism, RFLP) fue comparado entre aislamientos de EGA. Un cuestionario de redes sociales fue llenado para cada niño y 10 compañeros. Los coeficientes de estructura fueron comparados entre niños con y sin EGA. RESULTADOS: Se identificaron cuatro clonas de EGA. Clona I en cinco niños del SC; clona II en dos del SC y en uno del SB; clona III en uno del SB y uno del SC; y clona IV en uno del SC. Estructura de redes sociales: Densidad SB y SC = 0.40 (± 0.87) y 0.35 (± 0.80), respectivamente. En SB, el patrón de homofilia de la interacción fue distinto en portadores (0.00), no portadores (0.47) y ambos (0.47) p = 0.35. En SC, el patrón de homofilia fue distinto en portadores (0.46), no portadores (0.68) y mixto (0.19), p = .001. En 4/5 con la clona I, los valores de grado, cercanía e intermediación estuvieron por arriba de la media grupal. En 3/3 con la clona II, los valores de grado e intermediación estuvieron por arriba de la media grupal. En contraste, en los niños con clonas III y IV, los valores de grado, cercanía e intermediación estuvieron por debajo de la media grupal. CONCLUSIONES: La diseminación de clonas específicas de EGA se asoció a grupos de niños con gran proporción de lazos entre ellos y un alto nivel de centralidad. Esto evidencia que la transmisión de EGA entre niños de guardería no ocurre al azar sino que depende del grado de comunicación y contacto físico entre éstos.