Potent Monoclonal Antibody Drug Conjugates

Phase I and II clinical trials with BR96-doxorubicin, an immunoconjugate that recognizes receptors on human carcinomas, have demonstrated that the monoclonal antibody component, BR96, is capable of safely delivering active doxorubicin to tumor masses, albeit at concentrations that are sub-optimal. We propose to construct and test significantly improved conjugates consisting of highly potent drugs attached to BR96 through a new generation of optimized peptide-based linkers. The resulting conjugates should be stable in serum, but labile inside tumor cell lysosomes, leading to the release of active drug at the target site. The drugs will consist of two classes. Minor groove binders containing a distamycin unit will be attached to the DNA alkylator cyclopropylpyrroloindole, forming a construct that will covalently modify the DNA of target cancer cells. The second drug will be combretastatin A4, a potent antimitotic agent that acts both on tumor cells and tumor vasculature. It is expected that conditionally stable conjugates prepared with these agents will be potent and capable of effecting antitumor activities at biologically relevant doses. The aims of the proposed study are to synthesize potent drug derivatives, link them to BR96 and to a ,monoclonal antibody against the CD40 antigen, and evaluate their stability characteristics in vitro cytotoxic activities, and in vivo toxicities and activities in nude mice with human tumor xenografts. PROPOSED COMMERCIAL APPLICATIONS: There is a very large unmet clinical need for treating carcinomas of the breast, lung, colon, and prostate. The BR96 antibody recognizes the Lewis-Y antigen, which is widely expressed on these tumors. Using the BR96 antibody for the delivery of potent drugs to tumors may lead to pronounced anticancer activity with acceptable levels of systemic toxicity. This would constitute a major advancement in the clinical treatment of cancer.