Abstract 1566: A novel drug discovery platform identifies epitopes on driver receptors that can be targeted to induce widespread kinase inhibition and cancer cell death

Abstract Welt Bio-Molecular Pharmaceutical (WBMP) has developed a drug discovery platform that identifies critical peptide segments of membrane receptors, which, when targeted with an antibody, block transmembrane signal transmission, leading to widespread kinase inhibition. This platform was first used to generate our lead monoclonal antibody (mAb), WBMP-4, which binds to a region on membrane-bound IgM, a subunit of the B-cell Receptor (BCR), and induces cell growth inhibition (at low doses) and apoptosis (at high doses) in IgM-expressing B-cell malignancies. Here we present the results of kinome and protein expression studies that characterize the mechanism of action of WBMP-4 and validate the algorithm underlying our platform. We evaluated kinase activity in lymphoma cells treated with WBMP-4 (at 5 and 20 ug/mL, and at 6 and 24 hours) via the PamGene phosphotyrosine kinase assay. This assay measures kinase activity in cell lysates using a microarray chip containing peptide sequences that serve as substrate for 189 phosphotyrosine sites on well-characterized signaling proteins. Additionally, we measured protein expression and phosphorylation of key targets downstream of the BCR with western blot analyses of WBMP-4 treated and untreated IgM-expressing B-cells. Our detailed kinome analysis reveals widespread kinase modulation following WBMP-4 treatment, with >180 of 189 phosphosites showing a significant change in phosphorylation signal intensity (>153 significantly decreased) upon treatment. Western blot analyses similarly show changes in phosphorylation of kinases (ZAP70, mTOR, AKT, and MEK). However, we also find decreased protein expression of CD79b, ZAP70, BTK, MEK, Myc, and increased LCK following WBMP-4 treatment. These results show that kinase activity across signaling pathways is altered upon WBMP-4 binding to the BCR’s mIgM, with the vast majority exhibiting a downregulation of phosphorylation. We also find that protein expression is impacted in several kinases directly downstream of the BCR. We hypothesize that kinase inhibition induced by WBMP-4 modulates transcription factor activity, and resultantly, protein expression, which maintains growth inhibition signaling and prevents recovery signals, determining the fate of the cells. Further analysis will assess earlier time points and lower dosages to examine the more immediate effect of WBMP-4 inhibition. WBMP-4’s global kinase inhibition encompasses the effects of approved kinase inhibitor drugs (i.e. BTK, PI3K, and Bcl-2 inhibitors), and is designed to be more tumor-restrictive; WBMP-4 only affects IgM-expressing B-cells, sparing healthy B-cells that express other classes of Ig (i.e. IgG, IgA, IgD, or IgE). This tumor specificity and potent inhibitory effects make WBMP-4 a promising clinical candidate. Citation Format: Rachel S. Welt, Virginia Raymond, David Kostyal, Sydney Welt. A novel drug discovery platform identifies epitopes on driver receptors that can be targeted to induce widespread kinase inhibition and cancer cell death. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1566.