Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is only 15%. As existing therapies do not significantly increase survival rate, there is an urgent need to develop newer therapies that can augment the existing treatments. The goal of the proposed work is to produce a safe and effective targeted chemotherapy for the treatment of non-small cell lung cancer (NSCLC). To this end, a rapidly internalizing, humanized, anti-EGP-1 MAb, hRS7, linked to a potent topoisomerase 1 inhibitor, SN-38, was designed and evaluated in the SBIR Phase I study. The immunoconjugate, which was designed to allow for the intact intratumoral liberation of the drug, maintained its antigen-binding property and drug potency, and produced significant and specific therapeutic efficacy in a nude mouse model of lung adenocarcinoma. In addition, a 7-fold greater dose than that used for therapy was nontoxic. The drug component is the pharmacologically active form of an already approved cancer drug, CPT-11, which is advantageous in that the safety issues related to the drug are already well documented. The successful SBIR Phase I feasibility research portends a high potential for translation to novel therapeutic strategies. The Phase II program will focus on cGMP manufacture and expanded preclinical studies. Specifically, the conjugate manufacture will be optimized, its storage format will be finalized, and a non-GMP lot (2 g) and two cGMP lots (2W5 g) of the conjugate will be prepared and evaluated for shelf-life stability. The product will be evaluated in a second model of non-small cell lung cancer and a CPT-11-refractory model, tested for potential immunogenicity due to the drug and the linker, and assessed for therapeutic window and toxicity in nude mice. Most importantly, the product safety will be determined in a non-human primate species, which will delineate the safe starting dose in human. Finally, an Investigational New Drug application will be submitted to the FDA for approval to start a clinical Phase I dose-escalation trial in NSCLC patients in the SBIR Phase III period.

Public Health Relevance

Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is just 15%. Continued efforts with newer therapies are urgently needed. The ultimate goal of the proposed project is to develop a safer and more efficacious targeted chemotherapy of non-small cell lung cancer using a tumor-selective monoclonal antibody and the highly potent form of the cancer drug, CPT-11. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44CA114802-02
Application #
7611218
Study Section
Special Emphasis Panel (ZRG1-ONC-L (10))
Program Officer
Andalibi, Ali
Project Start
2005-03-01
Project End
2010-08-31
Budget Start
2008-09-18
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$724,653
Indirect Cost
Name
Immunomedics, Inc.
Department
Type
DUNS #
115350605
City
Morris Plains
State
NJ
Country
United States
Zip Code
07950
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
Govindan, Serengulam V; Cardillo, Thomas M; Moon, Sung-Ju et al. (2009) CEACAM5-targeted therapy of human colonic and pancreatic cancer xenografts with potent labetuzumab-SN-38 immunoconjugates. Clin Cancer Res 15:6052-61