Endothelin Receptors

[Google Scholar] 38

[Google Scholar] 38. a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus contamination in susceptible Rabbit polyclonal to Caspase 3 populations. (This study has been registered at under registration no. “type”:”clinical-trial”,”attrs”:”text”:”NCT01496755″,”term_id”:”NCT01496755″NCT01496755.) INTRODUCTION Cytomegalovirus (CMV) contamination is usually endemic worldwide with a seroprevalence ranging from 45 to 100% (1,C3). CMV persists as a lifelong latent contamination (4), similar to other members of the family. Although generally asymptomatic in immunocompetent hosts, CMV can cause serious and life-threatening disease in newborns infected and in immunocompromised individuals such as solid organ and hematopoietic stem cell transplant recipients (5, 6). Congenital CMV contamination occurs when a woman undergoes primary or recurrent CMV contamination during pregnancy and transmits CMV to the developing fetus (7). With an incidence of 0.6 to 5% of live births worldwide (8), CMV is the leading cause of congenital viral contamination and can result in death and permanent disabilities, such as hearing loss, vision loss, and mental retardation in infected newborns (9). Despite efforts to limit CMV exposure through proper hygiene, the prevention of maternal CMV contamination remains an elusive goal given the absence of a vaccine (10) and public awareness about its potential impact on DDR-TRK-1 the developing fetus (11). Combined with a lack of efficacy data, the concerns for teratogenicity and toxicity have precluded the use of antiviral brokers for the prevention of intrauterine CMV contamination (10, 12). In a nonrandomized study of pregnant women with primary CMV contamination, the administration of CMV-specific hyperimmune globulin (CMV-HIG) was associated with a lower risk of congenital CMV contamination and disease (13). DDR-TRK-1 However, in a recent larger and randomized study of pregnant women with primary CMV contamination, women who received CMV-HIG had a lower incidence of maternal-to-fetal transmission than those who received placebo (30% versus 44%), but this difference was not statistically significant (14). CMV contamination is the leading viral cause of morbidity and mortality in patients receiving solid organ or hematopoietic stem cell transplants (6, 15, 16). Antiviral medication has decreased the incidence of CMV disease in the first 6 months after solid organ transplantation (17, 18) and within 100 days after hematopoietic stem cell transplantation (19). However, antiviral brokers have significant toxicities, including neutropenia (15), and late-onset CMV disease, which is usually associated with allograft failure and mortality (20,C22), remains an important complication (23). Given DDR-TRK-1 the unmet medical need for treatments to prevent CMV contamination and in solid organ and hematopoietic stem cell transplant recipients, an anti-CMV monoclonal antibody therapy (RG7667) was developed (Genentech, Inc., South San Francisco, CA). CMV uses two different entry mechanisms to infect fibroblasts, epithelial cells, endothelial cells, and macrophages. Fibroblast entry is usually mediated by the glycoprotein complexes gB and gH/gL, which are conserved among herpesviruses, whereas entry into epithelial cells, endothelial cells, and macrophages requires the gH/gL/UL128/UL130/UL131 glycoprotein complex in addition to gB (24,C28). Several studies have shown that this most highly neutralizing antibodies in CMV-HIG are those that target the gH/gL/UL128/UL130/UL131 complex and not gB (29, 30). Moreover, the presence of maternal antibodies against the gH/gL/UL128/UL130/UL131 complex has been correlated with fetal protection during primary CMV contamination (31, 32). RG7667 consists of a combination of two monoclonal antibodies that binds neutralizing epitopes around the CMV complexes gH/gL and gH/gL/UL128/UL130/UL131, blocks entry into relevant cell types, and suppresses the emergence of viral resistance. In this paper, data from a phase 1 first-in-human trial is usually presented, characterizing the safety, tolerability, pharmacokinetics, and immunogenicity of RG7667 in healthy adult volunteers. MATERIALS AND METHODS Generation and characterization of RG7667. RG7667 is a combination of two monoclonal antibodies, MCMV5322A and MCMV3068A. MCMV5322A is usually a human immunoglobulin antibody (IgG1) that binds a neutralizing epitope on CMV glycoprotein H (gH) and is an affinity-matured version of MSL-109 (PDL Biopharma, Inc., Incline Village, NV) (33, 34). MCMV5322A Fab exhibits 10-fold higher affinity than MSL-109 to baculovirus-expressed gH/gL protein as determined by surface plasmon resonance (dissociation constant [of MCMV3068A was DDR-TRK-1 not able to be.