Introduction: Glucocorticoids are key components of standard-of-care treatment regimens (e.g., R-CHOP, Hyper-CVAD) for several B-cell malignancies. However, prolonged systemic glucocorticoid treatment results in glucocorticoid-associated adverse events and acquired resistance that limit its therapeutic potential. ABBV-319 is a novel CD19-targeting ADC engineered to reduce glucocorticoid-associated toxicity observed with systemic glucocorticoids while possessing three distinct mechanisms of action (MoA) to increase efficacy: 1) antibody-mediated delivery of GRM to activate glucocorticoid receptor (GR) induced cell death in cancer cells, 2) inhibition of CD19 signaling, and 3) enhanced Fc-mediated cancer cell killing via afucosylation of the antibody backbone.

Results: We identified a GRM agonist that is 15 and 150 times more potent at driving GR transcriptional activation and cell death compared to clinical glucocorticoids dexamethasone and prednisolone, respectively. The conjugation of GRM agonist as the payload on ABBV-319 enables potent GRM-driven anti-cancer activity against malignant B-cell lines in vitro as well as in cell-line and patient derived xenograft (CDX and PDX) models in vivo. Remarkably, a single-dose of ABBV-319 induced sustained tumor regression and enhanced anti-tumor activity compared to repeat dosing of systemic glucocorticoids (e.g., prednisolone) at its maximum tolerated dose in mice. The CD19 monoclonal antibody (mAb) also reduced proliferation of a subset of B-cell malignant cell lines through inhibition of the PI3K/AKT pathway. Moreover, afucosylation of the CD19 mAb in ABBV-319 enhanced Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), and this activity was maintained after conjugation with GRM payloads. ABBV-319 bound similarly to both V158 (high-affinity) and F158 (low-affinity) FcγRIIIa allotypes and mediated potent ADCC in co-culture assays with human peripheral blood mononuclear cells (PBMCs). Notably, ABBV-319 displayed superior efficacy compared to afucosylated CD19 mAb in human CD34+ hematopoietic stem cell-engrafted NSG-Tg(Hu-IL15) mice, demonstrating that the three MoA (GR-driven cell death, CD19 signaling inhibition, and ADCC) collectively contribute to anti-tumor activity in vivo. ABBV-319 also displayed on-target depletion of normal human B-cells but did not affect peripheral NK cell counts in mice. Furthermore, CITE-seq profiling revealed that ABBV-319 treatment of human PBMCs activated GRM-induced signature genes restricted to B-cells, demonstrating the specificity of CD19-mediated delivery of GRM.

Conclusion: ABBV-319 has potent anti-tumor activity from three distinct MoA and exhibits safety improvements compared to systemic glucocorticoids, supporting its recent progression into Phase I clinical trial.

Citation Format: Chewei Anderson Chang, Ethan Emberley, Aloma L. D'Souza, Weilong Zhao, Cormac Cosgrove, Axel Hernandez Jr, Anatol Oleksijew, Paul Ellis, Luis Rodriguez, Gail Bukofzer, David Peetz, Wissam Assaily, Raghuveer Singh Mali, Wei Liu, Danqing Xu, Gregory K. Potts, Shaun McLoughlin, Kimberley McCarthy, Zhaomei Zhang, Jos Campbell, Isabella Sturdevant, Gloria Zhang, Tyler Curran, Jon D. Williams, Erwin Boghaert, Milan Bruncko, Christopher C. Marvin, Adrian Hobson, Michael Mcpherson, Tamar Uziel, Marybeth Pysz, Xi Zhao, Alex Bankovich, Kevin J. Freise, Susan Morgan-Lappe, James W. Purcell. Preclinical development of ABBV-319: a CD19-targeting glucocorticoid receptor modulator (GRM) agonist antibody-drug conjugate (ADC) for the treatment of B-cell malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6308.