Exploring BAY-924: A Pioneering ADC for CXCR5-Positive B-Cell Malignancies with KSP Inhibitor Payload
BAY-924 is a groundbreaking antibody drug conjugate (ADC) that pairs a humanized anti-CXCR5 IgG1 antibody with a potent kinesin spindle protein inhibitor (KSPi). The ADC's structure is meticulously designed to facilitate a specific metabolic pathway, aligning with the KSPi's mechanism of action and ensuring maximum payload retention within tumor cells, as reported by Lerchen HG et al. in Angew. Chem. Int. Ed (2018). The antibody demonstrates a strong binding affinity to CXCR5, with a surface plasmon resonance assay indicating a value of 2.5 nM. Flow cytometry measurements reveal affinities ranging from 0.8 to 10 nM for the ADC across various CXCR5+ lymphoma cell lines.
In vitro tests have shown that BAY 924 possesses a high level of selective anti-proliferative activity against a range of tumor cell lines with varying CXCR5 expression levels, with IC50 values between less than 0.03 and 2 nM. The ADC also exhibits efficient internalization and lysosomal co-localization of the antibody in multiple cell lines, including the CXCR5+ MCL REC-1 cells.
In vivo studies have demonstrated BAY-924's high efficacy in several CXCR5+ lymphoma models, with a targeted payload accumulation in tumors compared to liver, spleen, and kidney, and negligible levels in plasma. In a subcutaneously implanted REC-1 model with large tumor size (500 mm3) in mice, BAY 924 induced long-lasting tumor regression following two intravenous injections at 10 mg/kg, Q7D, while the model showed insensitivity to ibrutinib, the current standard of care for MCL. In the advanced ABC DLBCL model OCI-LY1, a single injection of BAY-924 at 10 mg/kg resulted in complete responses in all tested mice (up to day 95 post-treatment). Comparative studies have shown BAY-924's superior activity to standard of care treatments such as rituximab (R)-CHOP, R/bendamustine, and R/lenalidomide. Additionally, BAY-924 induced a potent antitumor effect in the ABC DLBCL OCI-Ly3-2b model, which expresses weak to moderate levels of CXCR5.
The unique structure of BAY-924, along with data from related projects, suggests a favorable safety profile due to the ADC's high stability and the non-cell permeable free payload, which remains confined within the tumor cells. These findings support the continued development of BAY-924 as an innovative therapeutic strategy for CXCR5+ non-Hodgkin lymphoma.
The study was presented by 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, and Pascale Lejeune at the American Association for Cancer Research Annual Meeting in 2019, published in Cancer Research 2019;79(13 Suppl):Abstract nr 4825.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.
Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.
By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.
Click on the image below to go directly to the Translational Medicine search interface.
