Effects of target antigen competition on distribution of monoclonal antibody to solid tumors.
Monoclonal antibody (MoAb) 11A and MoAb 13A recognize normal murine cell surface glycoproteins, which are also expressed in high concentrations on Line 1 lung carcinoma. Studies were initiated to examine the competition in vivo for radiolabeled MoAb between sites on the tumor versus sites on normal tissue. Quantitative 2-site assay of the alpha 6 beta 4 integrin recognized by MoAb 11A showed that major sites of expression are tumor, intestine, and skin. Microdistribution studies show that at doses of 125I-labeled MoAb 11A less than the total body antigen load, the MoAb bound to beta 4 endothelial cells with little extravasation to epithelial sites. As the MoAb dose was increased, and endothelial sites became saturated, deposition at epithelial sites including skin and tumor became apparent. Quantitative radioimmunoassay with MoAb 13A, recognizing CD44 (P100), demonstrated major sites of expression as tumor, intestine, liver and, to a lesser extent, spleen and skin. Microdistribution studies at low doses of 125I-labeled MoAb showed deposition mainly in the liver and spleen sinusoids, whereas higher doses were necessary to maximize MoAb accumulation in tumor. The rapid access of MoAb to target antigen is the most important parameter in efficient localization of MoAb. Access of antigen outside the vascular space is regulated at least in part by the permeability of the endothelial barrier. Of the organs studied, antigen accessibility increases in the following order: lung epithelium less than skin epithelium less than intestine and uterus epithelium less than epithelial tumors less than liver and spleen sinusoids less than intervascular sites. Antigens in easily accessible sites interact with MoAb first and must be saturated before MoAb will penetrate to less accessible areas. Thus, the extent of competition of antigen for available MoAb depends not only on the amount of antigen, but also on the site at which it is expressed. Doses that achieve maximum binding to tumor sites can be predicted if accurate target antigen quantities and sites of expression are known.
Kennel
S J
SJ
Biology Division, Oak Ridge National Laboratory, Tennessee 37831-8077.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D001345:Autoradiography; D001667:Binding, Competitive; D005260:Female; D016023:Integrins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D016023:Integrins; D016201:Receptors, Lymphocyte Homing