TARGETING THE B-CELL RECPTOR COMPLEX AND DOWNSTREATM KINASES

DESCRIPTION (provided by applicant): Targeting the B-cell Receptor Complex and Downstream Kinases The B-cell Receptor Complex (BCRC) comprises a cell-surface membrane bound Ig (mIg) and closely associated co-signaling molecules. Previous strategies to target the BCRC molecules in B-cell malignancies have focused on the unique CDR sequences specific for each monoclonal tumor. However, as a consequence of the uniqueness of each CDR, this approach necessitated the generation of a specific drug for each patient. While this scheme is not feasible in the clinic, as proof of principle it is important to note that these early clinical studies targeting the BCRC demonstrated anti-tumor activity. Recently, the focus has shifted to targeting BCRC associated molecules such as the Syk tyrosine kinase, a downstream mediator of the BCRC signaling pathway. However, the Syk tyrosine kinase pathway is not restricted to B-cell lineage tissue and its inhibition leads to unwanted immune effects, possible pro-oncogenic effects and other toxicities. Here we describe a strategy to specifically modulate the BCRC by generation of specific monoclonal antibodies (mAbs) targeting the mIg molecule at its linker peptide (the extra-cellular proximal domain [ECPD]). Thus far, we have generated a large panel of peptide-specific mAbs detecting the 13-mer peptide sequence (EGEVSADEEGFEN) specific for the membrane IgM (mIgM) molecule and the 18-mer peptide sequence (ELQLEESCAEAQDGELDG) specific for mIgG. We have demonstrated peptide specific binding and preliminary evidence of target cell binding (proof of principle). The goal of this phase 1 application is to generate comparative binding data, epitope analysis, define immune mediating effects and specificity of reactivity of our large panel of mAbs. These data will streamline the selection of clinic candidate mAbs from the large number of clones collected. The selected set of high avidity mAbs representing reactivity to each epitope contained in the 13-mer mIgM ECPD and the mIgG ECPD will then be used in future studies to determine their biologic effects and select the best therapeutic strategy to employ in their clinical development. PUBLIC HEALTH RELEVANCE: Targeting the B-cell Receptor Complex and Downstream Kinases B-cell malignancies comprise the major subtype of lymphomas today with over 80,000 new cases per year. The vast majority of patients are not curable despite the apparent sensitivity of these diseases to a number of drugs commonly in use. The B-cell Receptor Complex (BCRC) is the central differentiation signaling element of the B-cell arm of the immune system and this molecule is expressed on the surface of all B-cell malignancies. Here we describe a strategy to target the BCRC and thus theoretically target every cell in these malignancies. The ability to cure these diseases will be dependent on the success of eradication of all tumor cells.