The major aim of this proposal is to develop new methods to improve the immunodiagnostic and therapeutic potential of monoclonal antibodies for the treatment of the human malignant lymphomas and related diseases. Previous studies in experimental animals and man have shown that a monoclonal antibody developed in our laboratory, designated Lym-1, has marked specificity and reactivity for the human lymphomas. Clinical trials in man conducted with I-131 labeled Lym-1 and other radiolabeled monoclonal antibodies have shown that only a small amount of the injected antibody actually binds to the tumor (0.05-0.1% of the injected dose). Methods to enhance the extravascular penetration of monoclonal antibodies at the tumor site would significantly alter the in vivo diagnostic and therapeutic potential of these reagents. Moreover, methods that decrease the circulating residence time of radiolabeled monoclonal antibodies would improve imaging results and minimize the exposure of healthy tissues to radiation and other cytotoxic agents linked to monoclonal antibodies. In this proposal, we have focused our attention on the development of novel methods to improve antibody penetration and binding at the tumor site in order to increase the amount of antibody and radiolabel reaching the tumor. These methods include the use of vasoactive immunoconjugates which specifically increase the vascular permeability of the tumor endothelium. In particular, a novel vasoactive immunoconjugate, Lym-1/IL-2, has been developed which reversibly induces a 3-4 fold increase in the vascular permeability of the tumor. It is proposed that additional vasoactive peptides, including Tumor Necrosis Factor-alpha, Interleukin-1beta, physalaemin, and bradykinin be tested using the Lym-1/Raji lymphoma model for their proinflammatory and vasopermeability effects in vivo. Genetic engineering methods are currently being performed to generate a chimeric Lym-1/IL-2 fusion protein which will act as a prototype for the development of additional vasoactive and proinflammatory immunoconjugates. Finally, studies are planned to investigate the effects of vasoactive drugs on the enhancement of Lym-1/IL-2 and other immunoconjugates. The data generated by these investigations should be broadly applicable to monoclonal antibodies being used to treat other types of cancers and should provide the basis for future clinical studies with radiolabeled Lym-1 in man.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047334-06
Application #
2092508
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1992-06-01
Project End
1995-05-31
Budget Start
1994-06-01
Budget End
1995-05-31
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Epstein, Alan L; Mizokami, Myra M; Li, Jiali et al. (2003) Identification of a protein fragment of interleukin 2 responsible for vasopermeability. J Natl Cancer Inst 95:741-9
Khawli, L A; Glasky, M S; Alauddin, M M et al. (1996) Improved tumor localization and radioimaging with chemically modified monoclonal antibodies. Cancer Biother Radiopharm 11:203-15
Hu, P; Hornick, J L; Glasky, M S et al. (1996) A chimeric Lym-1/interleukin 2 fusion protein for increasing tumor vascular permeability and enhancing antibody uptake. Cancer Res 56:4998-5004
Hu, P; Glasky, M S; Yun, A et al. (1995) A human-mouse chimeric Lym-1 monoclonal antibody with specificity for human lymphomas expressed in a baculovirus system. Hum Antibodies Hybridomas 6:57-67
Epstein, A L; Khawli, L A; Hornick, J L et al. (1995) Identification of a monoclonal antibody, TV-1, directed against the basement membrane of tumor vessels, and its use to enhance the delivery of macromolecules to tumors after conjugation with interleukin 2. Cancer Res 55:2673-80
Khawli, L A; Miller, G K; Epstein, A L (1994) Effect of seven new vasoactive immunoconjugates on the enhancement of monoclonal antibody uptake in tumors. Cancer 73:824-31
Alauddin, M M; Khawli, L A; Epstein, A L (1992) An improved method of direct labeling monoclonal antibodies with 99mTc. Int J Rad Appl Instrum B 19:445-54
Najafi, A; Alauddin, M M; Sosa, A et al. (1992) The evaluation of 186Re-labeled antibodies using N2S4 chelate in vitro and in vivo using tumor-bearing nude mice. Int J Rad Appl Instrum B 19:205-12
LeBerthon, B; Khawli, L A; Alauddin, M et al. (1991) Enhanced tumor uptake of macromolecules induced by a novel vasoactive interleukin 2 immunoconjugate. Cancer Res 51:2694-8