Abstract PO-006: ABBV-319: A CD19–targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies

Abstract

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.