Targeted Treatment of Recurrent Small Cell Lung Cancer with Anti-AbnV2 Antibodies

DESCRIPTION (provided by applicant): There is currently no effective treatment for recurrent small-cell lung cancer (rSCLC). The objective of this project is to utilize a monoclonal antibody, Abner, to develop new, rational, and successful treatment of rSCLC. The hypothesis being tested is that an abnormal vasopressin type 2 receptor (AbnV2R) present on these tumors will provide a sensitive, tumor-specific, and reliable target for the effective treatment by Abner antibodies. The data from the studies of Phase 1 of the project clearly show that treatment of variant SCLC tumor xenografts, with native and 90Yttrium-labelled mouse Abner significantly slows growth, but this growth is completely impaired when antibody treatment follows cyclophosphamide. Our data indicate AbnV2R expression is a feature common to all, or most, SCLC and that AbnV2R is a surface protein. Phase 2 is directed at advancing treatment of rSCLC with Abner by developing a human chimeric form (cAbner) of the mouse monoclonal antibody, and thena humanized form (hAbner) as potential clinical candidates. The ability of cAbner and hAbner to target and prevent growth of human variant SCLC xenografts in mice will then be tested. Phase 2 goals are directed towards (i) generating a chimeric form (cAbner) of mouse Abner with the constant regions of human IgG1; (ii) establishing that the targeting, recognition, and treatment profiles of mAbner are retained by cAbner; (iii) modeling a humanized form (hAbner) of Abner from the cAbner with genetically grafting CDRs from the VH and VL regions of mMAG-1 into the DNA framework of a human antibody; (iv) establishing that the targeting, recognition, and treatment profiles of mAbner are retained by hAbner. These investigations will employ, RT-PCR, ligation, and cloning, DNA recombinance, DNA sequencing, immunohistochemistry, antibody modification, Northern and Western analysis with densiometric quantitation, ELISA, RIA, tumor-directed targeting, whole-body scintigraphy for 99mTechnetium, cytofluorographic and radiometric quantitation, confocal microscopy, radioligand binding, flow cytometry, and cell and tumor growth assessments with mechanism analysis in vitro and for nu/nu mice. A successful end-point of our Phase 2 studies would be the generation of cAbner and/orhAbner forms of our antibody that show a similar binding affinity as mAbner, recognize all or most recurrent (and primary) cancers, do not react with normal tissues, and can reduce the size of tumors, and/or prevent their growth in vivo. The proposed research is expected to rapidly lead to new and successful therapeutic approaches for managing recurrent small-cell lung cancer. PUBLIC HEALTH RELEVANCE: This project will introduce a new targeted therapeutic approach for the treatment of recurrent small-cell lung cancer, a disease that is refractory to all current treatments. This refractoriness means lt 10% expected 5 year survival rate for patients representing gt 40,000 new cases of SCLC that arise in the USA each year. Our targeted approach is directed at a newly discovered abnormal receptor which seems to be a tumor-specific surface marker of recurrent small-cell lung cancer. Targeting will employ an available monoclonal antibody to treat this deadly disease. This antibody recognizes a unique extracellular portion of the marker. Currently patients with recurrent SCLC usually succumb to the disease in 3 to 6 months. The proposed research is expected to lead to new successful therapies for managing recurrent SCLC, thereby leading to a higher long-term survival rate for these patients.