Antibody-induced intracellular signaling works in combination with radiation to eradicate lymphoma in radioimmunotherapy

Abstract

Radioimmunotherapy (RIT) has emerged as an effective treatment for lymphoma, however the underlying mechanisms are poorly understood. We therefore investigated the relative contributions of antibody and targeted radiation to the clearance of tumor in vivo, using 2 different syngeneic murine B-cell lymphoma models. Although RIT with (131)I-anti-major histocompatibility complex class II (MHCII) was effective in targeting radiation to tumor, no improvement in survival was seen by escalating the radiation dose alone and there were no long-term survivors. In contrast, using the combination of (131)I anti-MHCII in the presence of unlabeled anti-idiotype (anti-Id), 100% prolonged disease-free survival was seen in both B-cell lymphoma models at the higher radiation dose. Using in vivo tracking we show that treatment with radiation plus anti-Id monoclonal antibody (mAb) results in a substantially greater reduction of splenic tumor cells than with either treatment alone. Prolonged survival could also be achieved using (131)I anti-MHCII plus the signaling anti-CD19 mAb. Furthermore, the ability of these anti-B-cell mAbs to improve survival with targeted radiotherapy appeared to correlate with their ability to initiate intracellular signal transduction. Together these data illustrate that using 1 mAb to target radiation to tumor and a second to induce cell signaling is an effective new strategy in RIT.

Rat Sodium Iodide Symporter for Radioiodide Therapy of Cancer

“…Sodium perchlorate, a specific inhibitor of NIS protein, effectively inhibited radioiodide accumulation in the transduced cells. Varying doses (10,25,50, and 100 MOI) of Ad-rNIS were used for transduction of cancer cells to determine the optimal dose for radioiodide uptake. In all three cell lines, 50 MOI of Ad-rNIS resulted in maximal rNIS expression as revealed by 125 I uptake assay (data not shown).…”

“…Precise delivery of lethal radiation to tumor cells is most desirable for patients. Much scientific effort has been focused on design and development of new approaches for targeted radiotherapy of cancer and improvement of the therapeutic index by more local radiation therapy (3)(4)(5)(6)(7)(8)(9)(10)(11). Targeted delivery of the sodium iodide symporter (NIS) gene to cancer cells could be one approach to concentrate lethal radiation in tumor cells and eradicate tumors with an increased therapeutic index (12,13).…”

Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma

“…mAbs used in this study include Mc10-6A5 (rat anti-BCL 1 idiotype, IgG2a), Mc39-16 (rat anti-A31 idiotype, IgG2a), 1D3 (rat anti-mouse CD19, IgG2a), and TI2-3 (rat anti-mouse MHCII, IgG1). Details of the production and purification of these mAbs have been described previously (14,17 I radioisotopes were supplied by Amersham International (Little Chalfont, United Kingdom), and the mAbs were iodinated using Iodo-Beads (Pierce Chemical, Rockford, IL) as described previously (14). For the cell binding and biodistribution assays, mAbs were labeled with 125 I instead of 131 I.…”

“…High labeling efficiency was consistently achieved (95.5-98.5%), measured by high-performance liquid chromatography. The immunoreactivity of iodinated mAb was monitored by cell binding assay as described (14,18) using kBCL 1 cells.…”

“…We have previously investigated the biodistribution, radiation dosimetry, and therapeutic efficacy of a panel of B-cell-targeting mAbs in the two syngeneic murine lymphoma models: BCL 1 and A31 (14). We found 131 I-labeled anti-MHC class II (MHCII) mAb to be an excellent vector for delivering ''systemic radiotherapy'' as it targets a highly expressed, weakly modulating antigen and thus is able to deliver high doses of radiation to the tumor (14). Long-term clearance of tumor was however found to be dependent on the combination of targeted radiation using 131 I-labeled anti-MHCII mAb plus antibody signaling with unlabeled anti-idiotype.…”