The long-term objectives of this project are to determine those sites on a monoclonal antibody that may be chemically modified without significantly altering its biological properties, and to use that knowledge to develop advanced radiopharmaceuticals. Attachment of metal ions to antibodies by means of bifunctional chelating agents can add the nuclear, physical, and chemical properties of the metallic elements to these target-selective proteins. As the clinical use of radiolabeled monoclonal antibodies proceeds, a few antibodies have been found to be useful in vivo for diagnosis and therapy of human patients. The focus of our initial efforts is an antibody (Lym-1) produced against Burkitt's lymphoma. This mouse lgG2a antibody binds to a membrane-bound glycoprotein which is strongly expressed on many human lymphoma and lymphocytic leukemia cells. Using this antibody labeled with l-131, Cu-67 or ln-111, patients with these diseases have been imaged successfully. 111ln-Lym-1 and 67Cu-Lym-1, labeled via bifunctional chelating agents, have many potential advantages for imaging, and 90Y-or 67Cu-Lym-1 have nuclear properties superior to 131l-Lym-1 for therapy. In order to enhance the properties of chelate- tagged antibodies for radioimmunoimaging and radioimmunotherapy, we need to improve the delivery of the radioimmunoimaging and radioimmunotherapy, we need to improve the delivery of the radiopharmaceutical to the tumor, as well as speed the removal of radioactivity from normal tissues. To accomplish these goals, the basic chemistry of the radiopharmaceutical must allow the immunoglobulin molecule to retain all its biological properties. Only then can the biologic activation mechanisms of normal immunoglobulins be utilized to aid in tumor targeting. A direct approach is proposed: to treat the monoclonal antibody as a chemical reagent, and analyze the resulting conjugates for their biological properties. We will explore new methods to modify Lym-1 at different sites, and ultimately determine which positions in the amino acid sequence may be modified with minimal loss of biological activity. Since antibodies exhibit biological activity beyond simply binding to antigen, such as cytotoxicity, complement fixation, receptor binding, etc., it is important to assay for such biological activity in addition to antigen binding. Other monoclonal antibodies, such as the human/mouse chimeric L6, will be compared using the same methods. We will make use of new bifunctional chelating agents currently under development in our laboratory, so that advances in our understanding of antibody chemistry may be combined with advanced chelate chemistry.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
United States
Zip Code
Schellinger, Joan G; Kudupudi, Avinash; Natarajan, Arutselvan et al. (2012) A general chemical synthesis platform for crosslinking multivalent single chain variable fragments. Org Biomol Chem 10:1521-6
Saludes, Jonel P; Natarajan, Arutselvan; DeNardo, Sally J et al. (2010) The remarkable stability of chimeric, sialic acid-derived alpha/delta-peptides in human blood plasma. Chem Biol Drug Des 75:455-60
Kumaresan, Pappanaicken R; Luo, Juntao; Lam, Kit S (2009) On-demand cleavable linkers for radioimmunotherapy. Methods Mol Biol 539:191-211
DeNardo, G L; Mirick, G R; Hok, S et al. (2009) Molecular specific and cell selective cytotoxicity induced by a novel synthetic HLA-DR antibody mimic for lymphoma and leukemia. Int J Oncol 34:511-6
Balhorn, Rod; Hok, Saphon; DeNardo, Sally et al. (2009) Hexa-arginine enhanced uptake and residualization of selective high affinity ligands by Raji lymphoma cells. Mol Cancer 8:25
Sulchek, Todd; Friddle, Raymond; Ratto, Timothy et al. (2009) Single-molecule approach to understanding multivalent binding kinetics. Ann N Y Acad Sci 1161:74-82
DeNardo, Gerald L; Natarajan, Arutselvan; Hok, Saphon et al. (2008) Nanomolecular HLA-DR10 antibody mimics: A potent system for molecular targeted therapy and imaging. Cancer Biother Radiopharm 23:783-96
Natarajan, Arutselvan; Xiong, Cheng-Yi; Gruettner, Cordula et al. (2008) Development of multivalent radioimmunonanoparticles for cancer imaging and therapy. Cancer Biother Radiopharm 23:82-91
Lehmann, Joerg; Natarajan, Arutselvan; Denardo, Gerald L et al. (2008) Short communication: nanoparticle thermotherapy and external beam radiation therapy for human prostate cancer cells. Cancer Biother Radiopharm 23:265-71
Kumaresan, Pappanaicken R; Luo, Juntao; Song, Aimin et al. (2008) Evaluation of ketone-oxime method for developing therapeutic on-demand cleavable immunoconjugates. Bioconjug Chem 19:1313-8

Showing the most recent 10 out of 187 publications