Monoclonal antibodies targeting the B-cell receptor complex directly induce widespread kinase inhibition and B-cell killing for the treatment of leukemia and lymphoma

Welt Bio-Molecular Pharmaceutical (WBMP) aims to develop cytotoxic monoclonal antibody (mAb) therapies binding driver membrane receptors on malignant cells. Such membrane targets control growth, survival, and proliferation signals in healthy cells and their increased activity is often implicated in the oncogenesis of tumor cells. In B-cells, the B-cell Receptor Complex (BCRC), a signalosome comprising several membrane proteins, is involved in transmitting signals that determine cellular fate. Dysregulation of BCRC proteins, or those in downstream signaling pathways, result in a diversity of B-cell cancer subtypes, making the BCRC a rational drug target. WBMP has previously described WBMP-4, a pro-apoptotic anti-membrane IgM antibody. Using a proprietary mAb-target-discovery platform, we have developed mAbs against two additional sites across the BCRC. All pipeline mAbs mediate apoptosis individually upon target binding. Here we investigate the therapeutic potential of this suite of mAbs via in vitro kinase and cytotoxicity analyses. Antibodies against designated regions of the BCRC, identified via WBMP's drug-discovery platform, were developed using hybridoma technology. Candidate mAbs were selected for their target-reactivity, and biologic effect was measured via preliminary growth assays of various lymphoma cell lines treated with hybridoma supernatant. These mAb supernatants have been tested for their ability to modulate B-cell kinase activity using the Pamgene phosphotyrosine kinome assay. Biacore assays will select unique, high affinity mAbs binding at distinct BCRC epitopes. Cell growth, MTT, and additional kinome assays will define the cytotoxicity characteristics of mAbs at varying doses and compared to existing B-cell therapeutics (i.e. ibrutinib, acalabrutinib, venetoclax, rituximab). WBMP has successfully applied a drug discovery system to develop a pipeline of B-cell cancer therapeutics. Each candidate mAb in this pipeline binds to a specific BCRC epitope and modulates the function of this signalosome. Here we show the potent effect of each of these mAbs as monotherapies, in vitro , in inducing widespread kinase inhibition, and, at sufficient doses, apoptosis. Activity of these mAbs will be studied in mouse xenograft systems and safety will be assessed with comprehensive normal tissue and non-target protein cross-reactivity assays. Those mAbs which are determined to be safe and effective will be considered for further clinical development. Together, this pipeline of novel mAbs covers the spectrum of B-cell malignancies, and the availability of multiple, distinct, directly effective mAbs against B-cells offers the potential for combination treatment strategies that can be optimized for specific tumor-types.