Abstract 5672: Pharmacodynamics and potential predictive biomarkers of ABBV-428, a first-in-class mesothelin (MSLN)-CD40 bispecific, in patients with advanced solid tumors
Authors: Fang Hua , Ye Shiming , Reddy Anita , Turan Tolga , Woolley Andrew , Chao Debra T. , Ramathal Cyril , Henner William R. , Hew Kinjal , McDevitt Michael , Hayflick Joel , Fan Frances , Allaire Kathryn , Fong Lawrence 
Published: September 2020

Abstract
Background: ABBV-428 is a first-in-class bispecific antibody against CD40 and MSLN designed to stimulate CD40 for tumor-specific immune activation with limited systemic toxicity (Cancer Immunol Res 2019;7:1864). In phase I findings, ABBV-428 was well tolerated up to 3.6mg/kg; 3/50 patients had long-term stable disease (SD; Luke et al. ESMO 2019). Here, pharmacodynamic and potential predictive biomarkers were assessed in the blood and tumor tissues in this phase I open-label, multicenter study (NCT02955251).
Methods: Patients ≥18 y had advanced solid tumors and progression/intolerance to standard therapies. ABBV-428 (≤3.6 mg/kg) was administered biweekly. CD40 receptor occupancy, absolute B cell counts, immune costimulatory activation markers, and serum cytokines were assessed at baseline and after treatment. MSLN expression (H-score) by IHC was reported at baseline. CD40/MSLN colocalization was assessed with a fluorescent multiplex assay. Paired tumor biopsy samples were collected at baseline and after treatment (C1D1, C2D1) to measure CD8+ T cells and PD-L1+ cells (IHC) and gene expression (NanoString Pancancer immune profiling panel). Immunologic constant of rejection (ICR) gene signature scores (J Immunother Cancer 2018;6:50) and IFNγ signatures (J Clin Invest 2017;127:2930) were used to characterize the tumor immune inflammatory microenvironment. BAP1 gene was sequenced (Sanger) in mesothelioma samples in 3 patients with long-term SD.
Results: In peripheral blood, there was &gt;90% CD40 receptor occupancy starting at 0.8 mg/kg. There was a transient decrease in circulating B cells 2-24 hrs after administration of ABBV-428, followed by an increase in B cell costimulatory activation markers (CD80, CD86, CD69) across dose groups with no evidence of cytokine response (IFNγ, IL-10, IL-12p70, IL-6, IL-8, TNFα, IL-1β, IL-2). There was no consistent change in tumor-infiltrating CD8+ T cells or PD-L1+ cells after ABBV-428 treatment in paired tumor biopsy samples from 13 patients. Patients with SD had higher ICR scores and a higher IFNγ gene signature at baseline than those with progressive disease. There was no correlation between baseline MSLN expression level and clinical response. Wide intertumor variability of MSLN/CD40 colocalization was observed from 4 tumor biopsy samples. No well-established recurrent mutations were seen in BAP1, which are correlated with better prognosis in mesothelioma patients.
Conclusions: These data show that ABBV-428 binds and activates CD40 in the blood leading to B cell activation with no evidence of systemic cytokine production or significant change in the tumor immune microenvironment. Evidence of inflamed immune tumor microenvironment was observed at baseline from long-term SD patients. These results may explain the clinical observations from the current ABBV-428 clinical trial.
Citation Format: Hua Fang, Shiming Ye, Anita Reddy, Tolga Turan, Andrew Woolley, Debra T. Chao, Cyril Ramathal, William R. Henner, Kinjal Hew, Michael McDevitt, Joel Hayflick, Frances Fan, Kathryn Allaire, Lawrence Fong. Pharmacodynamics and potential predictive biomarkers of ABBV-428, a first-in-class mesothelin (MSLN)-CD40 bispecific, in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5672.