Impact of antigenemia on the bioactivity of infused anti-Tac antibody: Implications for dose selection in antibody immunotherapies

Abstract

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 Tac؉ 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, Her2͞neu 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-2R␣; 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 Tacϩ 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 Ͼ100 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...

Antigen Shedding May Improve Efficiencies for Delivery of Antibody-Based Anticancer Agents in Solid Tumors

“…The model presented here is consistent with this data and indicates that the RIT-mesothelin complex in tumor ECS is this reservoir. The model is also consistent with the report of Junghans et al(9) that the shed antigen-antibody complex can supply the antibody to bind leukemic cells and solid tumors when free antibody is depleted.…”

“…Such shedding can be expected to significantly influence the delivery of anti-cancer agents that use these antigens as the delivery target(9). However, no theoretical study has been reported on the effect of antigen shedding on the delivery of these agents in solid tumors.…”

In vivobehaviour of antibody–drug conjugates for the targeted treatment of cancer

“…In a third example, researchers treated patients with an anti-CD25 antibody (anti-Tac antibody) and studied the amount of circulating antibody that was available for binding ex vivo to target cells. In one patient, because of shed antigen, initially only a fraction of the infused antibody bound ex vivo to target cells; however, after the infusion of a total dose of ∼ 30 mg, the ex vivo activity reached a plateau at its maximal theoretical level [36]. This suggests that pretreatment with naked antibody to neutralise the shed antigen may lead to an increase in delivery to tumours and, ultimately, in the antitumour activity of the subsequently administered immunoconjugate.…”

Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma

“…Previously we published [18, 19] analyses of the impact of soluble TAC (IL-2R alpha) on the bindability of administered anti-IL-2R alpha and on the impact of tumor burden on antibody dosing. There we indicated that in situations such as with high specific activity radiolabeled antibody one must use the soluble circulating IL-2R alpha levels to provide the optimized dose of unlabeled dacliuzumab.…”