PDL BioPharma (United States)

The gut microbiota plays an essential role in mucosal immunity, with secretory immunoglobulin A (IgA) acting as a key effector in neutralizing pathogens and maintaining host-microbiota homeostasis. IgA production occurs via T cell-dependent (TD) and -independent pathways, with T follicular helper (Tfh) cells driving high-affinity, antigen-specific IgA responses. However, the specific microbial taxa and metabolites that regulate Tfh-mediated IgA responses under steady-state conditions remain poorly understood. This study investigated how gut microbiota-derived signals shape Tfh responses and IgA production, with implications for enhancing mucosal vaccine efficacy. We demonstrate that Peyer's patches (PP)-derived Tfh cells exhibit superior IgA-inducing capacity compared to splenic Tfh cells. RNA sequencing revealed distinct transcriptional profiles in PP-Tfh cells, including upregulation of the genes associated with Tfh differentiation and activation (Bcl6, Cd40lg, Maf), T-B cell interactions (Il21, Sh2d1a, Fyn), and migration (Ccr6, Cxcr5). Functionally, PP-Tfh cells formed larger T-B cell contact areas and induced significantly higher IgA secretion in co-culture than their splenic counterparts. Microbiota depletion experiments revealed that eliminating neomycin-depleted bacteria reduced fecal IgA levels and diminished PP-Tfh cell frequencies. Fecal microbiota transplantation from neomycin-treated mice restored both IgA production and Tfh responses in germ-free (GF) mice. Bioinformatic analysis (PICRUSt2 and LEfSe) identified butyrate-producing Lachnospiraceae and Ruminococcaceae as key drivers of the Tfh-IgA axis. Butyrate supplementation enhanced Tfh differentiation and IgA⁺ germinal center B cell development in vitro and increased fecal IgA levels in vivo. Mechanistically, butyrate promoted IgA production via GPR43 signaling, as its effect was lost in co-cultures with Gpr43⁻/⁻ Tfh cells. Moreover, treatment with tributyrin, a butyrate prodrug, enhanced vaccine-induced IgA and protected mice against Salmonella Typhimurium infection, reducing bacterial burden and tissue damage. These findings define a functional microbiota-Tfh-IgA axis sustained by neomycin-depleted, butyrate-producing bacteria. Our study underscores the crucial role of the gut microbiota, particularly neomycin-depleted butyrate producing taxa, in regulating PP-Tfh cell function and IgA production. Butyrate emerges as a metabolite linking microbial metabolism to Tfh differentiation and IgA class switching. Together, these findings establish a microbiota-metabolite-Tfh cell axis essential for mucosal immune homeostasis and suggest novel strategies for enhancing vaccine efficacy and protection against enteric infections. Video Abstract.

Azedra is the name given to high specific activity/ high molar activity MIBG (m-[131I]-(iodobenzylguanindinium); iobenguane (131I) produced commercially for the treatment of adrenal carcinoma: neuroblastoma, pheochromocytoma and paraganglioma. Azedra was patented in 2007; human clinical testing began in 2009 and the drug was approved by the FDA in 2018 and discontinued in 2024. Herein, we describe the lifeline of Azedra from concept to its discontinuation as an example of the challenges involved in the development, production and distribution of a radiopharmaceutical.

Abstract Francisella tularensis poses considerable public health risk due to its high infectivity and potential for bioterrorism. Francisella‐like lipoprotein (Flpp3), a key virulence factor unique to Francisella, plays critical roles in infection and immune evasion, making it a promising target for therapeutic development. However, the lack of well‐defined binding pockets and structural information on native interactions has hindered structure‐guided ligand discovery against Flpp3. Here, we used a combination of physics‐based and deep‐learning methods to design high‐affinity miniprotein binders targeting two distinct sites on Flpp3. We identified four binders for site I with binding affinities ranging between 24–110 nM. For the second site, an initial binder showed a dissociation constant (KD) of 81 nM, and subsequent site saturation mutagenesis yielded variants with sub‐nanomolar affinities. Circular dichroism confirmed the topology of designed miniproteins. The X‐ray crystal structure of Flpp3 in complex with a site I binder is nearly identical to the design model (Cα root‐mean‐square deviation (RMSD): 0.9 Å). These designed miniproteins provide research tools to explore the roles of Flpp3 in tularemia and should enable the development of new therapeutic candidates.

In the version of the article initially published, in the key to Fig. 2f the colors were swapped and have now been amended so that "W guidance" is purple and "Unconditional" is grey. In Fig. 5a , the color of "Child B" has been corrected from pink to purple, and in Fig. 5d , "β-helix" has now been amended to "β-sheet". These corrections have been made to the HTML and PDF versions of the article.

Abstract Ongoing declines in insect populations have led to substantial concern and calls for conservation action. However, even for relatively well studied groups, like butterflies, information relevant to species‐specific status and risk is scattered across field guides, the scientific literature, and agency reports. Consequently, attention and resources have been spent on a minuscule fraction of insect diversity, including a few well studied butterflies. Here we bring together heterogeneous sources of information for 396 butterfly species to provide the first regional assessment of butterflies for the 11 western US states. For 184 species, we use monitoring data to characterize historical and projected trends in population abundance. For another 212 species (for which monitoring data are not available, but other types of information can be collected), we use exposure to climate change, development, geographic range, number of host plants, and other factors to rank species for conservation concern. A phylogenetic signal is apparent, with concentrations of declining and at‐risk species in the families Lycaenidae and Hesperiidae. A geographic bias exists in that many species that lack monitoring data occur in the more southern states where we expect that impacts of warming and drying trends will be most severe. Legal protection is rare among the taxa with the highest risk values: of the top 100 species, one is listed as threatened under the US Endangered Species Act and one is a candidate for listing. Among the many taxa not currently protected, we highlight a short list of species in decline, including Vanessa annabella, Thorybes mexicanus, Euchloe ausonides, and Pholisora catullus. Notably, many of these species have broad geographic ranges, which perhaps highlights a new era of insect conservation in which small or fragmented ranges will not be the only red flags that attract conservation attention.

Internal radiation therapy using Iodine-131 metaiodobenzylguanidine (131I-MIBG) for neuroblastoma has been discussed whether a special application scheme for off-labeled drugs called "Kouchi-Shinsei" could be applied to neuroblastoma or not by the Evaluation Committee on Unapproved or Off-labeled Drug with High Medical Needs (the Committee); if the Committee determines that Kouchi-Shinsei is applicable, neuroblastoma indication is expected to be regulatory approved within a year. Since a NHI medical technical fee is not yet set for neuroblastoma, the Japanese Society of Nuclear Medicine surveyed health resource use via a questionnaire survey of medical institution that has conducted a Japanese Advanced Medical Care B clinical study in neuroblastoma. Results showed that the necessary total cost per patient is 1,847,451 JPY when calculated based on the Draft Proposal for Medical Examination Value (Ver. 7.3) of the Japanese Health Insurance Federation for Surgery. Because follow-up is necessary for 3 months after administration, it was considered that an appropriate fee per patient is 1,847,451 JPY and an appropriate NHI medical technical fee per patient is 46,186 points which can be claimed up to once a month for 4 times including the initial month of the treatment.

A voltage-based method is proposed to correct battery pack state of charge (SOC) estimation at the charge-end. Two main characteristics make the charge-end time span a good opportunity to correct SOC estimation: first, it is easy to detect when the battery is at the last stage of charging because the charging profile is known to the BMS designer and also during the charge-end time span the amount of current is low, and the terminal voltage of the battery cells are high; second, as the battery reaches the charge-end stage, we know that the true SOC is approaching to 100%. This paper presents a method to utilize these important features to correct the SOC estimation error. Using a voltage threshold method, the algorithm detects when the battery is close to the charge-end to activate the charge-end SOC correction strategy. Once activated, the strategy corrects the SOC using the maximum cell voltage to guarantee that SOC is 100% when charging is complete. The amount of correction is a function of maximum cell voltage and the charge current C-rate.

Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer's disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month.

Antibody-drug conjugates (ADCs) are a therapeutic modality that traditionally enable the targeted delivery of highly potent cytotoxic agents to specific cells such as tumor cells. More recently, antibodies have been used to deliver molecules such as antibiotics, antigens, and adjuvants to bacteria or specific immune cell subsets. Site-directed mutagenesis of proteins permits more precise control over the site and stoichiometry of their conjugation, giving rise to homogeneous chemically defined ADCs. Identification of favorable sites for conjugation in antibodies is essential as reaction efficiency and product stability are influenced by the tertiary structure of immunoglobulin G (IgG). Current methods to evaluate potential conjugation sites are time-consuming and labor intensive, involving multistep processes for individually produced reactions. Here, we describe a highly efficient method for identification of conjugatable genetic variants by analyzing pooled ADC libraries using mass spectrometry. This approach provides a versatile platform to rapidly uncover new conjugation sites for site-specific ADCs.