Tanabe Research Laboratories

Systemic sclerosis (SSc) is a complex autoimmune disorder characterized by extensive fibrosis, vascular abnormalities, and immune dysregulation, affecting clinical outcomes such as skin thickness and pulmonary function with high mortality rates. B cells play a pivotal role in the pathogenesis of SSc. This study aimed to develop a systems model for B cell differentiation and tissue distribution to characterize the therapeutic responses to CD19+ (inebilizumab) and CD20+ cell depletion (rituximab) in patients with SSc. We integrated real-world data (RWD) of B cell subsets from 61 patients with untreated SSc using this model. Upon successful model validation, virtual clinical simulations revealed uniform dynamics of CD19 cells but distinct patterns of antibody-secreting cells (ASCs) among patients, with significant variabilities due to CD20 treatment. The ratio of plasma cells to plasmablasts (PC/PB) was identified as a crucial factor, with a high ratio correlating with a poor response to CD20 treatment but stable depletion by CD19 treatment. Furthermore, the CD20-binding affinity of rituximab and its elimination rate constant were also suggested to contribute to the therapeutic variabilities of CD20 treatment. This study addressed ASC responses as a marker of a proof-of-mechanism; nonetheless, the model must be extended to further address the aforementioned clinical outcomes. Overall, the systems model provided mechanistic insights into the contrasting responses of ASCs depending on the study drugs and identified potential predictors of treatment efficacy. By integrating RWD, our study provides a mechanistic framework to optimize dosing strategies and guide personalized treatment approaches to refine B-cell depletion therapies for SSc.

B0AT1 is a neutral amino acid transporter responsible for the (re)absorption in the intestine and kidney. Here, we developed small-molecule inhibitors of B0AT1 as a therapeutic strategy to a transient pocket, located ~17 angstrom away from the substrate-binding site and unique to the outward-open conformation, and stabilize an outward-occluded conformation that prevents the conformational transitions required for transport. Guided by structural insights, we optimized an initial inhibitor (Cinromide) to improve potency and cross-species activity, yielding compound 3, which inhibits both human and mouse B0AT1 with submicromolar IC_50 values. In a PKU mouse model (Pahenu2), oral administration of compound 3 increased urinary Phe excretion and significantly reduced plasma Phe. Our findings identify a druggable allosteric site in B0AT1, demonstrate its utility for achieving potent and selective inhibition in vivo, and establish allosteric blockade as a therapeutic approach for PKU and other SLC6-family transporters.

Abstract Glucocorticoids such as prednisone (P) and dexamethasone (D) are key components in standard-of-care immuno-chemotherapy regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for the treatment of B-cell malignancy. However, prolonged systemic glucocorticoid treatment is associated with several adverse events that often result in dose reduction and reduced therapeutic efficacy. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) with a glucocorticoid receptor modulator (GRM) payload engineered to reduce glucocorticoid-associated toxicities while possessing three distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) CD19 receptor-mediated delivery of potent glucocorticoid receptor modulator (GRM) payload to induce apoptosis, (2) inhibition of B-cell receptor (BCR) stimulated CD19 signaling, and (3) enhanced Fc-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven anti-tumor activity against multiple malignant B-cell lines in vitro as well as in cell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) in vivo. Remarkably, a single-dose of ABBV-319 induced sustained tumor regression and enhanced anti-tumor activity compared to repeat dosing of systemic prednisolone at the maximum tolerated dose (MTD) in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed anti-proliferative activity on a subset of B-cell lymphoma cell lines through the inhibition of PI3K signaling. Moreover, afucosylation of the CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), and this activity was maintained after conjugation with GRM payload. Notably, ABBV-319 displayed superior efficacy compared to afucosylated CD19 mAb in human CD34+ PBMC-engrafted NSG-tg(Hu-IL15) transgenic mice, demonstrating enhanced anti-tumor activity in vivo when multiple MOAs are enabled concurrently. ABBV-319 also showed potent anti-tumor activity across multiple B-cell lymphoma models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma treated with R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 for the treatment of B-cell malignancy in Phase I clinical trial (NCT05512390). Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Chewei (Anderson) Chang. ABBV-319: A CD19–targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-006.

To determine real-world treatment retention, safety, and tolerability from edaravone-treated patients with amyotrophic lateral sclerosis (ALS) in the MTP-Patient Support® (MTP-PS) program.

Este trabalho relata as experiências vivenciadas por uma discente negra, no mestrado e suas perspectivas frente às demandas da matriz curricular do curso e a convivência com os docentes e os demais discentes do programa. O estudo descritivo é do tipo relato de experiência, cujo contexto se dá no Programa de Pós-Graduação, Mestrado Profissional e Interdisciplinar em Extensão Rural- PPGExR, da Universidade Federal do Vale do São Francisco. Foram analisados os editais dos processos seletivos do Mestrado em Extensão Rural entre os anos de 2017 e 2022 quanto a sua adoção e aplicabilidade no que tange a política de cotas raciais. Foram descritas as atividades acadêmicas desenvolvidas, no primeiro semestre letivo do curso, entre março de 2022 e julho de 2022. Foram apresentadas as percepções quanto à receptividade e a interação advindas das relações interpessoais que ocorreram durante este período e que foram vivenciadas dentro e fora da academia. Compreendeu-se que o ambiente educacional além de ser altamente propício para desenvolvimento de diversos processos inclusivos, ainda peca em integrar de forma eficiente os saberes epistemológicos do povo negro. É preciso que o povo negro se insira nas universidades de forma quantitativa e também qualitativa de forma a contribuir para desmistificar o mito da democracia racial com interlocuções promovidas dentro e fora das instituições.

Free fatty acid receptors (FFA, nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors [116, 27]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14.0 (myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3, (α-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA) and C22:6,n-3 (docosahexaenoic acid)) activate FFA1 [9, 54, 64] and FFA4 receptors [45, 52, 94], while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA2 [10, 66, 90] and FFA3 [10, 66] receptors. The crystal structure for agonist bound FFA1 has been described [113].

Tanabe Hajime développa sa philosophie dans la perspective d’une « ontologie sociale » à travers la « logique de l’espèce » et la « logique de l’Amour ». La première, développée de 1934 à 1941, vise la rationalisation de la société japonaise en temps de guerre, la seconde le salut de la société japonaise après la Seconde Guerre mondiale dans le cadre d’une philosophie de la religion. Le but de cet article est de mettre au jour le développement de la logique de l’espèce vers la logique de l’Amour et de présenter l’histoire de l’ontologie sociale tanabéenne dans le cadre de la « métanoétique ».

Aims/IntroductionSodium–glucose cotransporter 2 inhibitors (SGLT2i) have been shown to display excellent renoprotective effects in diabetic kidney disease with macroalbuminuria/proteinuria. Regarding the renoprotective mechanism of SGLT2i, a sophisticated hypothesis was made by explaining the suppression of glomerular hypertension/hyperfiltration through the adenosine/adenosine type 1 receptor (A1R) signaling‐mediated restoration of the tubuloglomerular feedback mechanism; however, how such A1R signaling is relevant for renoprotection by SGLT2i in diabetic kidney disease with proteinuria has not been elucidated.Materials and MethodsStreptozotocin‐induced diabetic CD‐1 mice were injected with bovine serum albumin (BSA) and treated with SGLT2i in the presence/absence of A1R inhibitor administration.ResultsWe found that the influences of SGLT2i are essentially independent of the activation of A1R signaling in the kidney of BSA‐overloaded streptozotocin‐induced diabetic mice. BSA‐overloaded diabetic mice showed the trend of kidney damage with higher glomerular filtration rate (GFR) and the significant induction of fibrogenic genes, such as transforming growth factor‐β2 and collagen type III. SGLT2i TA‐1887 suppressed diabetes‐induced GFR in BSA‐overloaded diabetic mice was associated with the significant suppression of transforming growth factor‐β2 and collagen type III; A1R‐specific inhibitor 8‐cyclopentyl‐1,3‐dipropylxanthine did not cancel the effects of TA‐1887 on either GFR or associated gene levels. Both TA‐1887 and 8‐cyclopentyl‐1,3‐dipropylxanthine‐treated BSA‐overloaded diabetic mice showed suppressed glycated hemoglobin levels associated with the increased food intake. When analyzing the association among histological evaluation, GFR and potential fibrogenic gene levels, each group of mice showed distinct correlation patterns.ConclusionsA1R signaling activation was not the dominant mechanism on the influence of SGLT2i in the kidney of BSA‐overloaded diabetic mice.

Phosphate binders, such as iron （III） citrate hydrate （FCH）, are essential medications for hemodialysis patients. Some in vivo studies have demonstrated that FCH prevented induction of oxidative stress in the presence of transferrin. However, how FCH affects iron-related oxidative stress in the absence of transferrin remains unclear. In the current study, we investigated the effects of ferric citrate （FC） on oxidative stress in the absence of transferrin in vitro to address this question. Human U937 monocytes were pretreated with FC, iron （II） chloride tetrahydrate （FeCl2・4H2O）, iron （III） chloride hexahydrate （FeCl3・6H2O）, or saccharated ferric oxide for 24 h and then treated with 10-mM hydrogen peroxide （H2O2） for 30 min. The final Fe concentrations were adjusted to approximately 200µg/dl. Iron concentration, intracellular reactive oxygen species （ROS） levels, and intracellular lipid peroxidation of the cell membrane were measured. After treatment with FC, iron concentration and ROS levels increased. Change in lipid peroxidation after treatment with FC was not observed. However, after treatment with H2O2, no change was observed in the intracellular ROS levels in FC-pretreated cells, whereas lipid peroxidation of the cell membrane was decreased. Despite the high iron concentration in FC-pretreated cells, neither intracellular ROS nor cell membrane lipid peroxidation levels were increased with H2O2 treatment. Their results might represent antioxidative effects of FC. The results of this study may contribute to a better understanding of the effects of oxidative stress in hemodialysis patients treated with FCH.