Abstract 4825: Preclinical characterization of BAY-924, a first in class ADC targeting CXCR5-positive B-cell malignancies, with a KSP inhibitor as novel payload

Abstract

Abstract Despite recent progress in the treatment of B-cell malignancies, patients are still in need of innovative therapeutic approaches. CXCR5 is a chemokine receptor expressed in a majority of B-cell malignancies including diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL), follicular lymphoma and chronic lymphocytic leukemia. Evaluation of tumor biopsies from relapsed DLBCL patients shows that CXCR5 staining remains high, suggesting altogether that it could be a relevant target to explore for the treatment of non-Hodgkin lymphoma. BAY-924 is a novel first-in-class antibody drug conjugate (ADC) consisting of a humanized anti-CXCR5 IgG1 antibody (Ab) linked to a potent proprietary kinesin spindle protein inhibitor (KSPi). Of importance, the structure of the ADC is optimized for a specific metabolism, matching the KSPi mode of action and enabling a maximal retention of the payload within the tumor cells (Lerchen HG et al.; Angew. Chem. Int. Ed, 2018). Surface plasmon resonance assay showed a high binding affinity of the Ab to CXCR5 (2.5 nM). Affinities of 0.8 to 10 nM were measured by flow cytometry for the ADC in different CXCR5+ lymphoma cell lines. In vitro, BAY 924 had high and selective anti-proliferative activity in a panel of tumor cell lines with different levels of CXCR5 expression (<0.03 - 2 nM IC50). Efficient internalization and lysosomal co-localization of the Ab was observed in a variety of cell lines including the CXCR5+ MCL REC-1 cells. In vivo, BAY-924 was highly active in several CXCR5+ lymphoma models with a specific accumulation of the payload in tumor versus liver, spleen and kidney and almost undetectable levels in plasma. In the REC-1 model implanted subcutaneously (SC) in mice and treated at large tumor size (500 mm3), long lasting tumor regression was observed after 2 intravenous injections of BAY 0924 at 10 mg/kg, Q7D, whereas the model was insensitive to ibrutinib, a current standard of care (SoC) for the MCL indication. In the advanced ABC DLBCL model OCI-LY1 (SC), a single injection of BAY-924 at 10 mg/kg induced complete responses in 10/10 mice (up to day 95 post-treatment). In this model, head-to-head comparison showed superior activity of BAY-924 compared to the SoCs rituximab (R)-CHOP, R/bendamustine and R/lenalidomide. Also, BAY-924 induced potent antitumor effect with a 4% ΔT/ΔC (day 55) in the ABC DLBCL OCI-Ly3-2b model, expressing weak to moderate levels of CXCR5 in vivo. Given its unique structure, and based on supportive data from other projects, it is anticipated that BAY-924 shows a favorable safety profile, due to the high stability of the ADC and a non-cell permeable free payload which is trapped inside the tumor cells. Overall, these results support further development of BAY-924 as an innovative approach for the treatment of CXCR5+ non-Hodgkin lymphoma. Citation Format: Sarah Johannes, Stefanie Hammer, Stephan Maersch, Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Hannah Joerissen, Oliver von Ahsen, Christoph Schatz, Simone Greven, Christoph Mahlert, Dominik Mumberg, Pascale Lejeune. Preclinical characterization of BAY-924, a first in class ADC targeting CXCR5-positive B-cell malignancies, with a KSP inhibitor as novel payload [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4825.