Abstract ND01: ABBV-319: A first-in-class Glucocorticoid Receptor Modulator (GRM) agonist ADC for the treatment of B-cell malignancies

Abstract

Abstract ABBV-319 is a novel CD19-targeting multi-modal antibody drug conjugate (ADC) for the treatment of B-cell malignancies. The ADC is engineered to have 3 distinct mechanisms of action to maximize anti-cancer activity while reducing systemic toxicities: (1) targeted GRM payload delivery, (2) signaling inhibition of CD19/BCR and (3) enhanced ADCC via afucosylation. Unlike traditional cytotoxic ADCs, the GRM payload is a high potency agonist (sub nM EC50) of the intracellular glucocorticoid receptor (GR) which then traffics to the nucleus resulting in sustained GR-driven transcriptional events leading to cancer cell death. CD19 is a clinically validated B-cell target (approved antibodies, ADCs, CARTs) known to be highly expressed even following multiple lines of therapy, making it an appropriate target for this novel approach. The CD19 antibody in ABBV-319 is an optimized high affinity IgG1 that can inhibit CD19/BCR downstream signaling events including AKT, leading to inhibition of growth in certain B-cell lines. Given ADCC/ADCP is a highly effective mechanism in B-cell malignancies (e.g., rituximab, tafasitamab) the CD19 antibody was engineered to have increased FcγR binding via afucosylation, that retains its enhanced ADCC activity as a GRM drug conjugate. By engineering the molecule in this way, the multi-modal ADC is not solely reliant on one mechanism of action for activity and therefore has the potential for broader activity. Sustained regressions/cures have been observed in multiple B-cell malignancy xenograft model systems (cell-line, PDX, humanized) after a single ADC dose that compares favorably against approved benchmark antibodies, systemic steroids and ADCs. ABBV-319 targets clinically validated mechanisms of action that are known to combine well with multiple standard-of-care agents. This combination potential together with its favorable safety profile, suggests ABBV-319 will be a highly effective combination treatment for B-cell malignancies. ABBV-319 was well tolerated in cynomolgus monkey studies with favorable drug-like properties and antibody-like pharmacokinetics, enabling a high mg/kg clinical starting dose. A first in-human Phase 1 clinical trial evaluating ABBV-319 in B-cell malignancies (DLBCL, FL, CLL) was recently initiated in late 2022 (clinicaltrials.gov, NCT05512390). Citation Format: James W. Purcell. ABBV-319: A first-in-class Glucocorticoid Receptor Modulator (GRM) agonist 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 ND01.