Bacterial biofilms on orthopedic implants are resistant to the host immune response and to traditional systemic antibiotics. Novel therapies are needed to improve patient outcomes. TRL1068 is a human monoclonal antibody (mAb) against a biofilm anchoring protein. For assessment of this agent in an orthopedic implant infection model, efficacy was measured by reduction in bacterial burden of Staphylococcus aureus, the most common pathogen for prosthetic joint infections (PJI). Systemic treatment with the biofilm disrupting mAb TRL1068 in conjunction with vancomycin eradicated S. aureus from steel pins implanted in the spine for 26 of 27 mice, significantly more than for vancomycin alone. The mechanism of action was elucidated by two microscopy studies. First, TRL1068 was localized to biofilm using a fluorescent antibody tag. Second, a qualitative effect on biofilm structure was observed using scanning electron microscopy (SEM) to examine steel pins that had been treated in vivo. SEM images of implants retrieved from control mice showed abundant three-dimensional biofilms, whereas those from mice treated with TRL1068 did not. Clinical Significance: TRL1068 binds at high affinity to S. aureus biofilms, thereby disrupting the three-dimensional structure and significantly reducing implant CFUs in a well-characterized orthopedic model for which prior tested agents have shown only partial efficacy. TRL1068 represents a promising systemic treatment for orthopedic implant infection.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by a deficiency in functional C1 esterase inhibitor (C1-INH), a serpin family protein that blocks the activity of plasma kallikrein. Insufficient inhibition of plasma kallikrein results in the overproduction of bradykinin, a vasoactive inflammatory mediator that produces both pain and unpredictable swelling during HAE attacks, with potentially life-threatening consequences. We describe the generation of STAR-0215, a humanized immunoglobulin G1 (IgG1) antibody with a long circulating half-life (t1/2) that potently inhibits plasma kallikrein activity, with a >1000-fold lower affinity for prekallikrein and no measurable inhibitory activity against other serine proteases. The high specificity and inhibitory effect of STAR-0215 is demonstrated through a unique allosteric mechanism involving N-terminal catalytic domain binding, destabilization of the activation domain, and reversion of the active site to the inactive zymogen state. The YTE (M252Y/S254T/T256E) modified fragment crystallizable (Fc) domain of STAR-0215 enhances pH-dependent neonatal Fc receptor (FcRn) binding, resulting in a prolonged t1/2 in vivo (⁓34 days in cynomolgus monkeys) compared to antibodies without this modification. A single subcutaneous dose of STAR-0215 ({greater than or equal to} 100 mg) was predicted to be active in patients for 3 months or longer, based on simulations using a minimal physiologically based pharmacokinetic (mPBPK) model. These data indicate that STAR-0215, a highly potent and specific antibody against plasma kallikrein with extended t1/2, is a potential agent for long-term preventative HAE therapy administered every 3 months or less frequently. Significance Statement STAR-0215 is a YTE-modified immunoglobulin G1 monoclonal antibody with a novel binding mechanism that specifically and potently inhibits the enzymatic activity of plasma kallikrein and prevents the generation of bradykinin. It has been designed to be a long-lasting prophylactic treatment to prevent attacks of HAE and to decrease the burden of disease and the burden of treatment for people with HAE.

The respiratory syncytial virus (RSV) causes significant respiratory disease in young infants and the elderly. Immune prophylaxis in infants is currently limited to palivizumab, an anti-RSV fusion (F) protein monoclonal antibody (mAb). While anti-F protein mAbs neutralize RSV, they are unable to prevent aberrant pathogenic responses provoked by the RSV attachment (G) protein. Recently, the co-crystal structures of two high-affinity anti-G protein mAbs that bind the central conserved domain (CCD) at distinct non-overlapping epitopes were solved. mAbs 3D3 and 2D10 are broadly neutralizing and block G protein CX3C-mediated chemotaxis by binding antigenic sites γ1 and γ2, respectively, which is known to reduce RSV disease. Previous studies have established 3D3 as a potential immunoprophylactic and therapeutic; however, there has been no similar evaluation of 2D10 available. Here, we sought to determine the differences in neutralization and immunity to RSV Line19F infection which recapitulates human RSV infection in mouse models making it useful for therapeutic antibody studies. Prophylactic (24 h prior to infection) or therapeutic (72 h post-infection) treatment of mice with 3D3, 2D10, or palivizumab were compared to isotype control antibody treatment. The results show that 2D10 can neutralize RSV Line19F both prophylactically and therapeutically, and can reduce disease-causing immune responses in a prophylactic but not therapeutic context. In contrast, 3D3 was able to significantly (p < 0.05) reduce lung virus titers and IL-13 in a prophylactic and therapeutic regimen suggesting subtle but important differences in immune responses to RSV infection with mAbs that bind distinct epitopes.

Results of the first ASHP national survey of clinical services provided by health-system specialty pharmacies (HSSPs) are presented. A survey questionnaire was developed by 26 HSSP contacts after reviewing available literature on the role and services of HSSPs. After pilot and cognitive testing resulting in a final questionnaire of 119 questions, a convenience sample of 441 leaders in HSSPs was contacted using email and invited to participate in the survey. The survey response rate was 29%. Almost half of respondents (48%) had offered pharmacy services for 7 years or more, and most (60%) dispensed more than 15,000 prescriptions annually. Respondents most commonly (42%) reported a specialist model wherein staff are dedicated to specific specialty disease states. Over half of respondents reported providing several medication access, pretreatment assessment, and initial counseling services to patients referred to them, regardless of whether the HSSP was used for medication fulfillment. All HSSP activities were noted to be documented in the electronic health record and visible to providers frequently or always. Almost all respondents noted that HSSP pharmacists have a role in specialty medication selection. Disease-specific outcomes were tracked in 95% of responding HSSPs, with 67% reporting that outcomes were used to drive patient monitoring. HSSPs were often involved in continuity of care services such as transitions of care (reported by 89% of respondents), referral to other health-system services (53%), and addressing social determinants of health (60%). Most respondents (80%) reported providing clinical education to specialty clinic staff, including medicine learners (62%). Though only 12% of respondents had dedicated outcomes research staff, many reported annually publishing (47%) or presenting (61%) outcomes research. HSSPs are a clinical and educational resource for specialty clinics and have developed robust patient care services that encompass the patient journey from before specialty medication selection through treatment monitoring and optimization.

Respiratory syncytial virus (RSV) is a poor inducer of antiviral interferon (IFN) responses which result in incomplete immunity and RSV disease. Several RSV proteins alter antiviral responses, including the non-structural proteins (NS1, NS2) and the major viral surface proteins, that is, fusion (F) and attachment (G) proteins. The G protein modifies the host immune response to infection linked in part through a CX3 C chemokine motif. Anti-G protein monoclonal antibodies (mAbs), that is, clones 3D3 and 2D10 that target the G protein CX3C chemokine motif can neutralize RSV and inhibit G protein-CX3CR1 mediated chemotaxis. Determine how monoclonal antibodies against the RSV F and G proteins modify the type I and III IFN responses to RSV infection. As the G protein CX3 C motif is implicated in IFN antagonism, we evaluated two mAbs that block G protein CX3C-CX3CR1 interaction and compared responses to isotype mAb control using a functional cellular assay and mouse model. Mouse lung epithelial cells (MLE-15 cells) and BALB/c mice were infected with RSV Line19 F following prophylactic mAb treatment. Cell supernatant or bronchoalveolar lavage fluid (BALF) were assayed for types I and III IFNs. Cells were interrogated for changes in IFN-related gene expression. Treatment with an anti-G protein mAb (3D3) resulted in improved IFN responses compared with isotype control following infection with RSV, partially independently of neutralization, and this was linked to upregulated SOCS1 expression. These findings show that anti-G protein antibodies improve the protective early antiviral response, which has important implications for vaccine and therapeutic design. RSV is a leading cause of respiratory disease in infants and the elderly. The only Food and Drug Administration-approved prophylactic treatment is limited to an anti-F protein monoclonal antibody (mAb), that is, palivizumab which has modest efficacy against RSV disease. Accumulating evidence suggests that targeting the RSV attachment (G) protein may provide improved protection from RSV disease. It is known that the G protein is an IFN antagonist, and IFN has been shown to be protective against RSV disease. In this study, we compared IFN responses in mouse lung epithelial (MLE-15) cells and in mice infected with RSV Line19 F treated with anti-G protein or anti-F protein mAbs. The levels of type I and III IFNs were determined. Anti-G protein mAbs improved the levels of IFNs compared with isotype-treated controls. These findings support the concept that anti-G protein mAbs mediate improved IFN responses against RSV disease, which may enable improved treatment of RSV infections.

The actions of the immune system are finely tuned, involving complex communication and coordination between diverse immune and non-immune cells across the tissues of the body. A healthy immune system requires a precise balance between immunity and tolerance. Regulatory T cells (Tregs) have long been appreciated as one of the master regulators of this balance; their importance is underscored by the autoimmunity that develops in mice and humans when Tregs are missing or dysfunctional. In addition to the immunoregulatory roles of Tregs in suppressing autoimmunity and inflammation via control of adaptive and innate immune responses, several non-immune modulatory functions of Tregs have been identified in recent years. In this review, we have highlighted the growing literature on the action of Tregs in metabolism, stem cell maintenance, tissue repair, and angiogenesis. Alongside Tregs' immune suppressive role, these non-suppressive activities comprise a key function of Tregs in regulating health and disease. As Tregs receive increasing attention as therapeutic targets, understanding their non-canonical functions may become an important feature of Treg-directed interventions.

This paper introduces distributed spatial multiplexing (DSM) with cooperative communications based on clustering of single-antenna radios. Clusters co-transmit their shared messages toward a destination radio equipped with multiple antennas. In the baseline configuration, there is no coordination beyond message sharing, and the resulting incoherent DSM scheme offers user cooperation diversity for each data stream. A second, novel variant of clustered DSM leverages distributed beamforming (DBF) techniques, wherein each cluster independently coordinates for RF phase alignment at a different destination radio antenna. In sample topologies, the resulting clustered coherent DSM outperforms the baseline incoherent variant by a large margin, and operates with close proximity to the idealized capacity-achieving (yet impractical) DSM based on singular value decomposition (SVD) of the distributed channel matrix.

ABSTRACT This study employs quantitative and qualitative data from a large diverse sample of scientists and professionals active in Greater Boston’s environmental and community development movements to pursue two lines of inquiry regarding experts and expertise in social movements. Statistical analysis and supporting qualitative analysis investigate, first, the extent to which expert’s professional training and employment predict their mobilization into different social movements (a measure of embodied expertise) and, second, the more specific ways that experts’ embeddedness in Boston-area businesses, law firms, and colleges and universities provide distinct mobilization pathways. Finding support for both, our conclusions emphasize the strategic value and heterogeneity of expert activists as a group and the importance of institutional analysis in understanding the dynamics and impacts of expert activism.

Abstract The study investigates the way local social movements respond to structural transformations in city politics. Drawing from archival research, published scholarship, and 51 in-depth interviews, we characterize the mobilization of experts into social movements in Greater Boston since the 1960s as a long-term shift from “protecting places” to “providing services.” Consonant with a shift from centralized to decentralized municipal government, we show how an initially unified resistance to urban renewal morphed into two diverging and opposing movements. One focused on housing affordability and relied on market-driven tactics; the other sought to enhance the “production of nature” through grassroots community organizing. These findings support two contributions to the scholarship on expert activism by showing that: (1) social movement organizations (SMOs) respond to structural shifts epistemologically, as well as organizationally; and (2) expert activism can alter the conditions and context of knowledge production in neighborhoods and the movements that rise in their defense.