Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is only 15%. Continued efforts with newer, more efficacious, therapies are warranted. Monoclonal-antibody (MAb)-directed cancer chemotherapy, using MAb-drug immunoconjugates, is an active area of exploration. The goal of the proposed work is to produce a safe and effective MAb-drug conjugate for the treatment of non-small-cell lung cancer (NSCLC). To this end, a rapidly internalizing, humanized, anti-EGP-1 MAb, hRS7, will be covalently linked to a potent topoisomerase 1 inhibitor, SN-38, which is the pharmacologically active form of the anti-cancer drug, CPT-11, and evaluated in human NSCLC xenografts in nude mice. Internalizing hRS7 MAb offers the opportunity to selectively accumulate a high concentration of the drug at the tumor sites, while the linker between the MAb and the drug will ensure that the drug is released in its native form. The choice of the drug, which is the active form of an already approved cancer drug, will be advantageous in that the safety issues related to the drug are already well documented. One objective of the SBIR Phase I project is to optimize the already designed hRS7- SN-38 conjugate preparation, while the central goal is to document that the immunoconjugate is efficacious in the therapy of subcutaneous human lung adenocarcinoma xenografts growing in athymic nude mice. The project feasibility will be documented by (1) achieving an optimized conjugate preparation with a substitution of 6-8 drug molecules per hRS7 MAb molecule, (2) demonstrating the similarity of the conjugate and the unmodified MAb in terms of antigen-binding and internalizing characteristics, (3) establishing that the conjugate is stable to incubation under physiological conditions, and (4) the finding of specific and significant efficacy of hRS7-SN-38 conjugate in the therapy of nude mice bearing human lung tumor xenografts. Successful achievement of these goals will set the stage for SBIR Phase II program for more detailed characterizations of the immunoconjugate, expanded preclinical therapy studies, toxicology studies in non-human primate species expressing the EGP-1 antigen in normal tissues, and the submission of an IND application for a pilot clinical Phase I trial in NSCLC patients. Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is only 15%. Continued efforts with newer, more efficacious, therapies are warranted. The ultimate goal of the proposed project is to develop a safer and more efficacious targeted therapy of non-small-cell lung cancer using a tumor-selective antibody and the active drug form of the cancer therapeutic, CPT-11. ? ? ?
|Cardillo, Thomas M; Govindan, Serengulam V; Sharkey, Robert M et al. (2011) Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res 17:3157-69|