RecombiMAb human IgG4 (S228P) isotype control, anti-hen egg lysozyme

Background: Neuropathic pain remains difficult to treat because current analgesics often provide insufficient efficacy or dose-limiting adverse effects. Nav1.7 is genetically validated as a key regulator of human pain sensation, but the development of selective small-molecule Nav1.7 inhibitors has been limited by the high similarity among voltage-gated sodium channel subtypes. Methods: We generated monoclonal antibodies selectively targeting Nav1.7, humanized them for therapeutic development, and evaluated their binding, selectivity, functional channel inhibition, systemic analgesic efficacy, and effects on neuronal activity in a rat model of partial sciatic nerve ligation-induced neuropathic pain. Results: The humanized antibodies showed high-affinity and selective binding to Nav1.7 and functionally inhibited the channel in cellular assays. After systemic administration to neuropathic pain model rats, the lead antibody produced robust analgesia lasting at least 96 h. Electrophysiological analyses demonstrated reduced mechanically evoked and spontaneous neuronal activity, and immunohistochemistry showed decreased mechanical stimulus-induced phosphorylation of extracellular signal-regulated kinase in dorsal root ganglion neurons. The antibodies did not impair physiological nociception or motor function under the tested conditions. Conclusions: These findings provide preclinical proof of concept that humanized anti-Nav1.7 antibodies can act as systemically administered, long-acting biologic analgesics for neuropathic pain while preserving normal nociceptive and motor functions. The clinical advancement of S-151128 further supports the translational potential of this modality.

BACKGROUNDCoccidioidomycosis ranges from self-limiting uncomplicated Valley fever (UVF) in most cases to life-threatening disseminated coccidioidomycosis (DCM) in rare individuals. A few patterns of immunologic deficits allowing for dissemination have been identified, although the specific defects in most individuals with DCM remain undefined. We hypothesized that chronic antigen exposure in DCM engenders a state of T cell exhaustion.METHODSFrom a cohort of over 300 individuals with confirmed diagnoses of coccidioidomycosis, circulating T cell phenotypes were characterized via flow cytometry and Coccidioides-specific T cell responses were measured by activation-induced marker (AIM) assay.RESULTSMale sex was significantly associated with disseminated disease (OR 2.5, 95% CI 1.5-4.0). A majority (52%) of individuals showed Coccidioides-specific T cell responses in our AIM assay. We noted a significant difference in patients sampled in the first year of diagnosis, where only 8% of patients with DCM had T cell responses during this time, as compared with 44% of individuals with UVF (P = 0.04). Among DCM patients with detectable AIM responses, CD4+ T cells demonstrated an exhausted phenotype with elevated PD-1 expression compared with UVF individuals. In vitro PD-1 blockade augmented IFN-γ production in most tested individuals with DCM.CONCLUSIONThese findings suggest that dissemination may occur in some individuals during a period of impaired antigen-specific T cell activity. Importantly, these responses can be augmented in vitro by PD-1-blocking antibodies, supporting further study of immune checkpoint therapy as an adjunct to antifungal treatment in disseminated coccidioidomycosis.FUNDINGNational Institute of Allergy and Infectious Diseases grants U19 AI166059 and R21 AI149654 and University of California Office of the President grant VFR-19-633386.

The underlying immunopathogenesis of inflammatory arthritis (IA) immune-related adverse event (irAE) remains obscure. Unlike rheumatoid arthritis (RA), where autoantibodies and B cell dysfunction are central features, the contribution of humoral immunity to IA-irAE is unclear. Here, we performed immunophenotyping of peripheral blood from patients with IA-irAE and compared them with patients with seronegative RA, immune checkpoint inhibition-treated patients without irAE, and healthy controls. IA-irAE was marked with increased cytotoxic gene expression and metabolic activation in T cells and reduced CXCR3 and CCR6 expression in CD4+ T cells. Contrary to seronegative RA, patients with IA-irAE displayed no substantial elevation in autoantibody levels or atypical CD11c+CD21- B cells. IA-irAE was further characterized by elevated levels of interleukin-6 (IL-6), IL-12, and type I interferon, which correlated with the T cell activation phenotypes. Together, our findings define IA-irAE as a disease with certain immunological features distinctive from RA, representing a potentially T cell-driven, autoantibody-independent autoimmunity. These results offer insights into immune tolerance breakdown and therapeutic targeting in irAEs.

Pancreatic ductal adenocarcinoma (PDAC) remains refractory to chimeric antigen receptor (CAR) T-cell therapies because of its immunosuppressive microenvironment and a dense extracellular matrix deposited by cancer-associated fibroblasts (CAF), which impair CAR T-cell infiltration. To address these barriers, we previously developed a dual-targeting CAR-TEAM platform in which mesothelin-specific CAR T cells secrete a fibroblast activation protein (FAP)-targeting T-cell engager antibody molecule (TEAM) to simultaneously kill tumor cells and CAF. In this study, we leveraged mesothelin-targeting CAR T cells and tested rational drug combinations and optimal delivery strategies to enhance therapeutic efficacy and guide potential combinations that could be incorporated into a clinical study.