ABBV-319: A CD19-targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies.

Glucocorticoids are key components of the current standard-of-care regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for treatment of B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. CD19 displays restricted expression in normal B-cells and is up-regulated in B-cell malignancies. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) engineered to reduce glucocorticoid-associated toxicities while possessing three distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of 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 payloads. 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 when multiple MOAs are enabled. ABBV-319 also showed durable anti-tumor activity across multiple B-cell lymphoma PDX models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma post R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in Phase I clinical trial (NCT05512390).

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Nursing Home Length of Stay in 3 Canadian Health Regions: Temporal Trends, Jurisdictional Differences, and Associated Factors.

OBJECTIVES: To assess (1) temporal changes (2008-2015) in nursing home (NH) length of stay (LoS) in 3 Canadian health jurisdictions (Edmonton, Calgary, Winnipeg), (2) resident admission characteristics associated with LoS, and (3) temporal changes of admission characteristics in each of the 3 jurisdictions. DESIGN: Retrospective cohort study using data previously collected in Translating Research in Elder Care (TREC), a longitudinal program of applied health services research in Canadian NHs. SETTING AND PARTICIPANTS: 7817 residents admitted between January 2008 and December 2015 to a stable cohort of 18 NHs that have consistently participated in TREC since 2007. METHODS: LoS was defined as time between a resident's first NH admission and final discharge from the NH sector. Analyses included descriptive statistics, Kaplan Meier estimates (unadjusted LoS), and Cox proportional hazard regressions (adjusted LoS), adjusted for resident characteristics (eg, age, cognitive performance, and health instability). We also controlled for NH size and ownership. RESULTS: In jurisdictions with increasing care needs, unadjusted median LoS [95% confidence interval (CI)] decreased over time (2008 and 2009 vs 2014 and 2015 admissions); in Calgary from 1.837 (95% CI 1.618, 2.275) to 1.328 (95% CI 1.185, 1.489) years and in Edmonton from 1.927 (95% CI 1.725, 2.188) to 1.073 (95% CI 0.936, 1.248) years. In Winnipeg, care needs and LoS remained constant (2.163, 95% CI 1.867, 2.494, vs 2.459, 95% CI 2.155, 2.883, years). Resident characteristics including higher physical dependency [hazard ratio (HR) 1.205, 95% CI 1.133, 1.282], higher cognitive impairment (HR 1.112, 95% CI 1.042, 1.187), or higher health instability (HR 1.333, 95% CI 1.224, 1.452) were associated with lower LoS. Adjustment for resident characteristics reduced jurisdictional LoS differences and rendered temporal LoS differences within jurisdictions statistically nonsignificant. CONCLUSIONS/IMPLICATIONS: In jurisdictions where care needs at admission have increased since 2008, resident LoS has decreased. Jurisdictional differences in care needs and LoS indicate that health policies may affect these outcomes. Variations of resident outcomes by policy environment require additional scrutiny.