ABBV-319: A First-In-Class CD19-targeting Glucocorticoid Receptor Modulator (GRM) Agonist Antibody-Drug Conjugate (ADC) for the Treatment of B-cell Malignancies [CITE-seq]
Glucocorticoids are key component of the immuno-chemotherapy regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for the treatment of B-cell non-Hodgkin lymphoma (NHL). However, prolonged systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) engineered to reduce glucocorticoid-associated toxicity 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 B-cell NHL 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 different MOAs are combined. ABBV-319 also showed durable anti-tumor activity across multiple preclinical B-cell lymphoma models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing testing of ABBV-319 in Phase I clinical trial (NCT05512390) Overall design: PBMC samples from two different donors were collected and treated with ABBV-319, CD19 mAb, or DMSO. Genomic materials were collected at 24hr post treatment and profiled for CITE-seq to investigate treatment effect of ABBV-319 on different myeloid and lymphoid cell lineages.