The specific aims of this project is to interact with Projects 1 and 2 to develop improved bifunctional chelating agent technology for clinical use, and to characterize immunoconjugates not only by standard methods, but also by determining the exact sites of attachment of bifunctional chelating agents to monoclonal antibodies. Our plans for the next grant period are: 1. To develop large-scale clinical pre-labeling with the new bifunctional chelating agents DOTA-peptide and -isothiocyanate, so that therapeutic amounts of 90Y can be administered to patients with minimal amounts of antibody. To study a set of rationally chosen peptide linkers to optimize the biological properties of these molecules. The pre- labeling approach promises to greatly improve the biological properties of yttrium immunoconjugates, and others as well. 2. To explore the advantages of TETA-peptide reagents for 67Cu radioimmunotherapy. It is expected that the peptide linker can lead to lower levels of radioactivity in the liver than ar currently obtained with the 2-iminothiolane linker. 3. Using the methods developed during the current period, to map the peptide sites on the antibodies conjugated with reagents employed during the next grant period. This degree of characterization will allow us to correlate biodistribution patterns and modified sites. 4. To begin biological testing of engineered proteins that we have produced. This will lead to targeting molecules with selected properties, which may be tailored to the physiology of each target. Many metal ions form chelate complexes. Stable 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 both diagnosis and therapy of human patients. A prime example is the antibody Lym-1. this mouse lgG2a(k) antibody, produced against Burkitt's lymphoma, binds to a membrane-bound glycoprotein which is strongly expressed on many human lymphoma and lymphocytic leukemia cells. We have successfully imaged patients with these diseases using this antibody labeled with 131I, 67Cu, 111In. We have also delivered effective radioimmunotherapy on this antibody to lymphoma patients using 131I and 67Cu.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA047829-11
Application #
6269341
Study Section
Project Start
1998-05-01
Project End
1999-09-29
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
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