SBIR-STTR Award

Currently used anti-cancer agents have limited selectivity for the tumor. Immunoconjugates that have been prepared from these drugs are not potent enough to be therapeutically effective. We will use 100 to 1000-fold more cytotoxic drugs and endow them with tumor-selectivity by linking them to antibodies. Thus, drugs that are too toxic to be used alone can be rendered therapeutically useful. Effective immunoconjugates will be generated by a) substituting the moderately cytotoxic anti-neoplastic agents in current use in antibody-drug conjugates with CC-1065 analogs which are 100 to 1000-fold more potent and b) linking these CC- 1065 analogs to antibodies via disulfide bonds that should be stable in circulation, but efficiently cleaved inside the cell to release fully active drug. In order to realize this goal, new disulfide-containing CC-1065 analogs will be synthesized without affecting the high cytotoxicity of the parent drug. Preliminary experiments indicate that the presence of a disulfide functionality preserves the potency of the drug. The most cytotoxic of these drugs will be linked to antibodies via disulfide bonds, and the in vitro cytotoxicity and specificity of these conjugates will be determined. The antibodies we will use in this study are already being used in human clinical trials.Awardee's statement of the potential commercial applications of the research: The ultimate goal is to create new therapeutic agents with high selectivity and low systemic toxicity for cancer treatment. Currently, there are no major competitive products in the field because antibody-drug conjugates tested so far have been therapeutically ineffective. We seek to develop new technology to resolve the problems that have made current approaches for the targeted delivery of drugs for cancer unsuccessful.National Cancer Institute (NCI)

The highly cytotoxic CC-1065 analog bis-indolyl-(seco)-CBI has been conjugated to monoclonal antibodies via disulfide bonds. These immunoconjugates have been shown to be highly potent in vitro, in a target specific manner, at concentrations readily achievable in vivo. Significant efficacy was demonstrated in an established human tumor xenograft survival model in immunodeficient mice. This proposal now seeks to translate these exciting results into new anti-cancer agents to be used in clinical trails in humans.In order to realize this goal, the specific aims to be achieve in Phase II include:1) development of processes that allow the scaled up production of drug and 'humanized' antibody;2) incorporation of substituent groups that will provide maximum solubility to the drug and its conjugates, without losing potency;3) development of linkers that will provide optimal in vivo stability to these conjugates;4) optimization of conjugation and purification processes to enable larger scale production of conjugates;5) extensive in vitro and in vivo evaluation of final conjugates.It is expected that the completion of the Phase II proposal will lead to the production of clinically and commercially important new anti-cancer agents with high target specific potency, efficacy, and low systemic toxicity.National Cancer Institute (NCI)