The remarkable commercial and medical success of monoclonal antibodies has led to the exploration of variations of this therapeutic modality. One approach, which is particularly suited for anticancer therapy, involves Antibody-Drug Conjugates (ADCs), or immunoconjugates, and has experienced limited success in the past two decades. The combination of tumor specific selectivity of monoclonal antibodies (mAbs), with highly potent cytotoxins, makes the discovery and development of ADCs a very logical and worthwhile pursuit. However, even as many problems related to the creation of useful conjugates have been solved via creative chemistry, there still remain barriers to success that are based solely on the selection of the active drug in the ADC. We provide here novel chemical compounds that may be ideally suited as immunoconjugate payloads. Several mAbs are available that are directed to target antigens selectively expressed or over expressed on the surface of malignant cells and are known to be internalized into the cancer cell. These mAbs present excellent opportunities for the development of ADCs employing our anticancer compounds. Two examples of particular interest are Herceptin(r) (a commercial mAb used to treat HER2 (+) breast cancer) and the anti- CD138 mAb, B-B4 (a potential mAb treatment for multiple myeloma). As a preclinical development model, we will focus efforts towards the development of antibody conjugates with these two mAbs employing two novel benzyl styryl sulfone compounds, ON 01500 and ON 013100. ON 01500 and ON 013100 are patented, highly potent and selective compounds which induced apoptosis in tumor cells with low nanomolar IC50. We have developed strategies for the conjugation of these molecules to mAbs using serum stable, self-immolating linkers that are designed for release of intracellular cytotoxic payloads. The key advantages for using compounds ON 01500 and ON 013100 are: they are highly potent (low nanomolar) against a broad spectrum of cancer cell types, have a relatively high therapeutic index, are not substrates for multi-drug resistance (MDR) genes, and are inexpensive to manufacture on multi-kilo scale. We propose to evaluate the novel immunoconjugates of Herceptin and anti-CD138 mAb in comparison to literature benchmarks describing Herceptin(r)-Geldanamycin and the maytansinoid-based immunoconjugate B-B4-DM1. The key objective of this program is to identify one or more highly potent ADCs for future evaluation in clinical trials. Another objective is to create enabling technology that can be applied to the increasing supply of good mAbs and potentially useful for a large number of anticancer applications. Antibody-drug conjugates (ADCs) covalently linked to highly potent toxic agents are rapidly gaining acceptance as improved anticancer treatments. The availability of humanized antibodies to a growing number of tumor specific surface antigens is providing the """"""""magic bullet"""""""" for cancer therapy. The development of novel highly potent synthetic molecules from Onconova Therapeutics, Inc. that can be linked to tumor specific antibodies will provide enhanced treatment options for cancer patients. ? ? ?
