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.
The ultimate goal of this project is to create new anti-cancer agents with high selectivity, efficacy, and low systemic toxicity for the treatment of cancer. Currently, there are no major competitive products in the field because antibody-drug conjugates have been therapeutically ineffective. This proposal seeks to develop new technology to overcome the problems that have made current approaches to the antibody-mediated targeted delivery of drugs for cancer unsuccessful.
