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Radiosensitizer Conjugation to the Carcinoma 19-9 Monoclonal Antibody¹

Hahnemann University, Philadelphia, Pennsylvania, 19102 [K. P. B., N. D. H., H. L. W., D. V. W.]; Lehigh University, Bethlehem, Pennsylvania 18015 [D. A. F., N. D. H., B. A. M., K. J. S.]; and Centocor Corporation, Malvern, Pennsylvania, 19355 [J. A. M., D. J. S.]

Misonidazole was covalently conjugated (3–68 mol drug/mol antibody) to 19-9 monoclonal antibody directed against a colorectal carcinoma tumor-associated antigen as a method for targeting radiosensitizing agents. This attachment was accomplished by the mixed anhydride method using the hemisuccinate derivative of misonidazole. Evaluation of conjugates in vitro shows a loss of antibody binding activity with increasing loading levels; however, significant binding activity is retained even at relatively high sensitizer/antibody ratios. This observation was consistent in three binding assays: a competitive radioimmunoassay; an enzyme immunoassay; and an affinity column assay. From these studies, it was concluded that the optimal loading factor for misonidazole-antibody conjugates, when it is used for immunochemotherapy lies between 8 and 15. In vitro release studies indicated that conjugates are hydrolytically stable (t = 4 days) under physiological conditions.

¹ This work was supported by grants from NIH (CA 31245), North-East Tier Ben Franklin Partnership of the State of Pennsylvania, the W. W. Smith Charitable Trust, and the Milheim Foundation for Cancer Research.

² Supported by a fellowship from the Mildred Sched Endowment (Federal Republic of Germany). Present address: Department of Internal Medicine II, Klinikum Grosshadern, University of Munich, Marchionini Str. 15, D8000 München 70, Federal Republic of Germany.

³ To whom requests for reprints should be addressed, at Center for Health Sciences, Lehigh University, Bethlehem, PA 18015.

Received 12/19/86. Revised 4/24/87. Accepted 5/ 1/87.