Radioimmunotherapy Utilizing the Humanized Anti-CD25 Mab Daclizumab Is Highly Effective in Mice Bearing Human Hodgkin’s Lymphoma Xenografts.

Objectives:

CD25 is overexpressed on the cell surface by a variety of malignant diseases including Hodgkin’s lymphoma (HL). It is cleaved from the cell surface releasing a soluble ectodomain (sCD25) which may interfere with a radiolabeled MAb’s ability to reach the target cell. Daclizumab (Zenapax^®), a humanized IgG1 that binds to the alpha subunit of the human interleukin-2 (IL-2) receptor (CD25, Tac), is FDA-approved for the prophylaxis of renal transplant rejection, as part of an immunosuppressive regimen. We performed biodistribution and γ-imaging studies of ¹¹¹In-labeled Zenapax and investigated the therapeutic efficacy of the ⁹⁰Y-labeled version in a human CD25+ human HL xenograft mouse model.

Materials & Methods:

Zenapax was conjugated to the macrocyclic bifunctional chelate DOTA-NHS active ester. For biodistribution studies athymic nude mice bearing s.c. L540 (human HL line) tumors were injected i.v. with ¹¹¹In-DOTA-Zenapax or ¹¹¹In-DOTA-M5A (humanized anti-CEA; 3-5μCi, 2-3μCi/μg) as a control. At various timepoints tumors, blood and major organs were collected, weighed and analyzed for radioactivity. The percent injected dose per gram (%ID/g) was determined. Serum samples were analyzed by HPLC size exclusion chromatography (SEC). For γ-imaging studies L540-tumor-bearing mice received ¹¹¹In-Zenapax (10.5μCi, 1.8μCi/μg) and serial images were acquired at various timepoints. For the evaluation of therapeutic efficacy, groups of 8 L540 tumor bearing nude mice were injected i.v. with a single dose of ⁹⁰Y-labeled-Zenapax (0, 40, 60, 80, 100, or 120μCi). Tumor progression was monitored by physical measurements.

Results:

Maximum tumor accretion for Zenapax was 35 %ID/g at 72h vs. 9 %ID/g for the control MAb. There were no significant differences in normal organ distribution or clearance from the blood between both MAbs. HPLC analysis of serum from Zenapax treated mice showed complexes formation (6–16%; ~210kD), consisting of the MAb and sCD25. γ-imaging studies demonstrated significant tumor retention of ¹¹¹In-Zenapax. Therapeutic efficacy was dose-dependent with complete tumor regression in all mice receiving 100–120 μCi, as well as 5/8 after 80μCi, and 4/8 after 40–60μCi. No severe toxicities were observed. In animals with regrowth of tumors the average delay was 18, 37, and 41 days for mice treated with 40, 60, and 80μCi, respectively. Untreated mice were sacrificed after 21 days due to excessive tumor progression or tumor ulceration.

Conclusions:

Radiolabeled Zenapax demonstrated favorable biodistribution properties and excellent tumor localization. It was highly efficacious in the treatment of mice bearing human HL xenografts with complete tumor regression in the two higher dose groups and high response rates at lower doses. In mice with incomplete regression significant delay of tumor progression was observed. ⁹⁰Y-Zenapax was well tolerated without evidence of toxicity. A clinical therapy trial with ⁹⁰Y-Zenapax in patients with HL is planned.