Povetacicept, an Enhanced Dual APRIL/BAFF Antagonist That Modulates B Lymphocytes and Pathogenic Autoantibodies for the Treatment of Lupus and Other B Cell-Related Autoimmune Diseases.

OBJECTIVE: Dysregulated APRIL/BAFF signaling is implicated in the pathogenesis of multiple autoimmune diseases, including systemic lupus erythematosus and lupus nephritis. We undertook this study to develop and evaluate a high-affinity APRIL/BAFF antagonist to overcome the clinical limitations of existing B cell inhibitors. METHODS: A variant of TACI-Fc generated by directed evolution showed enhanced binding for both APRIL and BAFF and was designated povetacicept (ALPN-303). Povetacicept was compared to wild-type (WT) TACI-Fc and related molecules in vitro and in vivo. RESULTS: Povetacicept inhibited APRIL and BAFF more effectively than all evaluated forms of WT TACI-Fc and selective APRIL and BAFF inhibitors in cell-based reporter assays and primary human B cell assays, mediating potent suppression of B cell proliferation, differentiation, and immunoglobulin (Ig) secretion. In mouse immunization models, povetacicept significantly reduced serum immunoglobulin titers and antibody-secreting cells more effectively than anti-CD20 monoclonal antibodies, WT TACI-Fc, or APRIL and BAFF inhibitors. In the NZB × NZW mouse lupus nephritis model, povetacicept significantly enhanced survival and suppressed proteinuria, anti-double-stranded DNA antibody titers, blood urea nitrogen, glomerulonephritis, and renal immunoglobulin deposition. In the bm12 mouse lupus model, povetacicept significantly reduced splenic plasmablasts, follicular helper T cells, and germinal center B cells. In non-human primates, povetacicept was well tolerated, exhibited high serum exposure, and significantly decreased serum IgM, IgA, and IgG levels after a single dose. CONCLUSION: Enhanced APRIL and BAFF inhibition by povetacicept led to greater inhibition of B cell populations critical for autoantibody production compared to WT TACI-Fc and CD20-, APRIL-, or BAFF-selective inhibitors. Potent, dual inhibition by povetacicept has the potential to significantly improve clinical outcomes in autoantibody-related autoimmune diseases.

Laboratory simulations of mate-guarding as a component of the pair-bond in male titi monkeys, Callicebus cupreus.

Mate-guarding and territorial aggression (both intra- and inter-sexual) are behavioral components of social monogamy seen in male coppery titi monkeys (Callicebus cupreus) both in the field and in the laboratory. Methodology for studying these behaviors in captivity facilitates the translation of questions between field and laboratory. In this study, we tested whether exposure to a mirror would stimulate mate-guarding behavior in male titi monkeys, and whether this exposure was accompanied by hormonal changes. Eight males were exposed to a mirror condition (treatment) or the back of the mirror (control) for five sessions, and behavioral responses were filmed. Blood samples were taken to measure levels of cortisol, oxytocin, and vasopressin. Lipsmacks (P < 0.0001), arching (P < 0.0001), tail-lashing (P = 0.009), restraining (P = 0.015), and approaches to the female (P = 0.0002) were all higher during the mirror condition, while tail-twining tended to decline during the mirror condition (P = 0.076). Hormones did not vary by experimental treatment, but were correlated with certain behaviors during the presentation of the mirror. While social behaviors changed with mirror exposure, self-directed and mirror-guided behaviors did not, indicating a lack of self-recognition. Use of a mirror was a safe and effective means of investigating mate-guarding behavior in response to a simulated intrusion, with the added benefit of not needing another animal to serve as an intruder; and thus may be of use in providing a laboratory model for natural behavior. Especially, as it eliminates the need for a stimulus animal, it would also be of possible use in investigating responses to a simulated intruder in wild populations of titis and other pithecines.

Natural variation in early parental care correlates with social behaviors in adolescent prairie voles (Microtus ochrogaster).

Natural variation in early parental care may contribute to long-term changes in behavior in the offspring. Here we investigate the role of variable early care in biparental prairie voles (Microtus ochrogaster). Total amounts of parental care were initially quantified for 24 breeder pairs and pairs were ranked in relation to one another based on total contact. Consistency in key components of care suggested a trait-like quality to parental care. Based on this ranking, breeder pairs from the top (high-contact) and bottom (low-contact) quartiles were selected to produce high- and low-contact offspring to investigate adolescent behavior after varying early care. Parental care of subject offspring was again observed postnatally. Offspring of high-contact parents spent more time passively nursing and received more paternal non-huddling contact while low-contact offspring spent more time actively nursing and received more paternal huddling and pseudohuddling in the first postnatal days (PNDs). Low-contact offspring also displayed faster rates of development on a number of physical markers. Post-weaning, offspring were evaluated on anxiety-like behavior, social behavior and pre-pulse inhibition (PPI) to a tactile and an acoustic startle. High-contact offspring spent more time sniffing a juvenile and less time autogrooming. With an infant, high-contact offspring spent more time in non-huddling contact and less time autogrooming and retrieving than did low-contact offspring. Considering sexes separately, high-contact females spent more time sniffing a novel juvenile than low-contact females. High-contact males spent more time in non-huddling contact with an infant than low-contact males; while low-contact females retrieved infants more than high-contact females. In both measures of social behavior, high-contact males spent less time autogrooming than low-contact males. These results suggest a relationship between early-life care and differences in social behavior in adolescence.

CART peptide following social novelty in the prairie vole (Microtus ochrogaster).

Prairie voles (Microtus ochrogaster) are monogamous rodents that display high levels of affiliative behaviors, including pair-bonding, biparental care, and cooperative breeding. Species differences in basal cocaine- and amphetamine-regulated transcript (CART) mRNA and peptide expression have been found between prairie voles and polygamous meadow voles. Therefore, we hypothesized that the CART system may play a role in the regulation of social behavior in this species. Male and female adult prairie voles were placed in a cage either alone, or with a novel social partner of the same or opposite sex. After 45 min, subjects were sacrificed and CART peptide expression was examined using immunohistochemistry. We examined fifteen hypothalamic, limbic, and hindbrain regions of interest, focusing on areas that show species-specific patterns of expression. We found that subjects paired with a novel conspecific had lower levels of peptide in the bed nucleus of the stria terminalis (BNST) than isolated animals. This may reflect increased peptide release following increased dopaminergic activity in animals exposed to a novel conspecific. Additionally, CART peptide was higher in the nucleus accumbens (NAc) of subjects paired with an opposite sex partner compared to those paired with a same-sex conspecific, although there was no difference between isolated subjects and either socially housed group. These findings suggest that CART in the NAc is differentially responsive to the sex of adult conspecifics and that the social environment influences CART expression in the prairie vole in a region- and stimulus-specific manner.