In patients with malignancies and immune disorders expressing Tac (⣠chain of the interleukin 2 receptor; CD25), physiologic shedding of this receptor may lead to high blood levels of the soluble form (sTac). This system was used to model the interaction of soluble antigen with antibody in therapeutic settings and to develop rational principles to optimize the delivery of antibody to tumor target cells. First, we confirmed that sTac in vivo can block anti-Tac binding sites and diminish antibody binding to TacŰ cells. Second, the bioactivity of antibody in vivo correlated directly with the amount of antibody infused and inversely with the sTac concentration. Third, bindability of antibody declined in the hours and days after anti-Tac infusion in patients. Finally, tumor targeting was achieved even in the presence of excess sTac, demonstrating a partition of antibody between soluble and cell-bound antigen. A role is proposed for the Brambell receptor (FcRB) to delay saturation of human or chimeric antibodies via differential catabolism of antigen-antibody complexes. Principles are developed for predicting activity of administered antibody in the presence of soluble antigen to assist in dose selection in passive, radioimmuno and immunotoxin therapies.Antigenemia occurs with several membrane-bound, tumorassociated antigens: e.g., CEA (1) and TAG-72 (2) in gastrointestinal cancers, Her2Íneu in breast carcinoma (3), CA125 in ovarian carcinoma (4), ganglioside in neuroblastoma (5), antibody idiotypes in B cell lymphomas (6), and others. The prototypical example of such shed molecules is the ⣠chain of the interleukin 2 receptor (IL-2RâŁ; Tac; ref. 7). Tac is up-regulated markedly during normal T cell activation and in several immune disorders and malignant states (8). Accompanying this upregulation is a concomitant active shedding of Tac from the membrane surface (7, 9, 10). In normal physiology, this shedding of receptors is thought to mediate rapid down-regulation of activated T cells when the activating stimulus is removed. In TacÏ© malignancies, however, the constitutive high expression of antigen and shedding leads to accumulations of soluble antigen (sTac) in plasma up to 1,000 times the normal levels (7).Since 1985, we have treated ÏŸ100 individuals with antibody to Tac (anti-Tac), both as unmodified antibody and as a carrier for isotopes or toxins. As a consequence of associated studies, we became aware that surface Tac antigen occasionally was unsaturated in some patients despite adequate plasma antibody concentrations, and this failure to saturate cellular Tac receptors appeared to correlate with high plasma levels of sTac. This system thus appeared to be a suitable model for a more quantitative study of the interaction of soluble antigen with antibody in therapeutic settings and with which to develop rational principles to optimize the delivery of antibody to tumor targets in vivo.
MATERIALS AND METHODSPatients and Treatment. Patients were enrolled according to eligibility criteria that included Tac-exp...