Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.

The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.

Chronic anti-phencyclidine monoclonal antibody therapy decreases phencyclidine-induced in utero fetal mortality in pregnant rats.

Illicit drug use during pregnancy is a serious social and public health problem inflicting an array of deleterious effects on both mother and offspring. We investigated the hypothesis that a murine anti-phencyclidine (PCP) monoclonal antibody (mAb6B5; K(D)=1.3 nM) can safely protect mother and fetus from PCP-induced adverse health effects in pregnant rats. Pregnant Sprague-Dawley rats (n=4-5) were intravenously administered bolus injections of PCP (1mg/kg) on multiple days during pregnancy. They were also chronically treated with anti-PCP mAb6B5 at 45 mg/kg as a PCP antagonist. This dose provided one mAb-PCP binding site for every four PCP molecules. Therapeutic and safety study endpoints included pregnancy outcome (litter size, number of live vs. dead pups), maternal hemodynamic status and locomotor activity. Maternal hemodynamic changes (i.e., blood pressure and heart rate) and locomotor activity were measured in dams from gestation days 6-21 (one day antepartum) using a radiotelemetry-tracking device with a femoral arterial pressure catheter. This mAb6B5 treatment regimen significantly (p=0.008) reduced the number of PCP-induced in utero fetal deaths (odds ratio=3.2; 95%CI 1.3 to 7.9) and significantly (p<0.05) reduced acute PCP-induced maternal locomotor effects in the second trimester. Maternal hemodynamic responses to PCP were not significantly affected by mAb6B5 treatment. In conclusion, these data suggest that anti-PCP mAb treatments administered during pregnancy can safely protect a mother and her fetus(es) from PCP-related morbidity and mortality even when the mAb dose is too low to significantly prevent other PCP-induced maternal pharmacological effects.

Association between mannan-binding lectin and impaired lung function in cystic fibrosis may be age-dependent.

An association between mannan-binding lectin (MBL) status and severity of lung function impairment in cystic fibrosis (CF) has been found in several studies, but not in others. To explore the possible basis for discrepancies in the literature, we related both MBL and L-ficolin concentrations to lung function and examined the results in relation to the age of the patients. For patients under 15 years of age, those with MBL < 200 ng/ml had better lung function than those with MBL > 200 ng/ml [median forced expiratory volume in 1 s (FEV(1)), 99% versus 83%; P = 0.05]. For patients over 15 years of age, those with MBL < 200 ng/ml had poorer lung function than those with MBL > 200 ng/ml (median FEV(1), 44% versus 55%; P = 0.1). Also, for the over 15-year-olds, the proportion of patients with FEV(1) values below the median was greater in the MBL-insufficient subgroup (P < 0.04). In other words, relative deficiency of MBL appears to accelerate the age-related decline in lung function in CF patients. No corresponding relationships could be found between L-ficolin concentration and lung function. These findings and interpretation lend support to the potential value of MBL replacement therapy in a small minority of cystic fibrosis patients.

Competence in the context of adversity: pathways to resilience and maladaptation from childhood to late adolescence.

Competent outcomes in late adolescence were examined in relation to adversity over time, antecedent competence and psychosocial resources, in order to investigate the phenomenon of resilience. An urban community sample of 205 (114 females, 90 males; 27% minority) children were recruited in elementary school and followed over 10 years. Multiple methods and informants were utilized to assess three major domains of competence from childhood through adolescence (academic achievement, conduct, and peer social competence), multiple aspects of adversity, and major psychosocial resources. Both variable-centered and person-centered analyses were conducted to test the hypothesized significance of resources for resilience. Better intellectual functioning and parenting resources were associated with good outcomes across competence domains, even in the context of severe, chronic adversity. IQ and parenting appeared to have a specific protective role with respect to antisocial behavior. Resilient adolescents (high adversity, adequate competence across three domains) had much in common with their low-adversity competent peers, including average or better IQ, parenting, and psychological well-being. Resilient individuals differed markedly from their high adversity, maladaptive peers who had few resources and high negative emotionality. Results suggest that IQ and parenting scores are markers of fundamental adaptational systems that protect child development in the context of severe adversity.