Effective therapy of murine models of human leukemia and lymphoma with radiolabeled anti-CD30 antibody, HeFi-1

Abstract

CD30 is a member of the TNF receptor superfamily. Overexpression of CD30 on some neoplasms versus limited expression on normal tissues makes this receptor a promising target for antibody-based therapy. Radioimmunotherapy of cancer with radiolabeled antibodies has shown promise. In this study, we evaluated the therapeutic efficacy of an anti-CD30 antibody, HeFi-1, armed with (211)At in a leukemia (karpas299) model and with (90)Y in a lymphoma (SUDHL-1) model. Furthermore, we investigated the combination therapy of (211)At-HeFi-1 with unmodified HeFi-1 in the leukemia model. Treatment with unmodified HeFi-1 significantly prolonged the survival of the karpas299-bearing mice compared with the controls (P < 0.001). Treatment with (211)At-HeFi-1 showed greater therapeutic efficacy than that with unmodified HeFi-1 as shown by survival of the mice (P < 0.001). Combining these two agents further improved the survival of the mice compared with the groups treated with either (211)At-HeFi-1 (P < 0.05) or unmodified HeFi-1 (P < 0.001) alone. In the lymphoma model, the survival of the SUDHL-1-bearing mice was significantly prolonged by the treatment with (90)Y-HeFi-1 compared with the controls (P < 0.001). In summary, radiolabeled HeFi-1 is very promising for the treatment of CD30-expressing leukemias and lymphomas, and the combination regimen of (211)At-HeFi-1 with unmodified HeFi-1 enhanced the therapeutic efficacy.

Fig. 1.

Immunoreactivity of radiolabeled HeFi-1. (A) ²¹¹At-HeFi-1 with karpas299 cells. (B) ¹¹¹In-HeFi-1 with SUDHL-1 cells. The cell-binding assay was performed as described in Materials and Methods. Both ²¹¹At-HeFi-1 and ¹¹¹In-HeFi-1 bound to the CD30-positive cells specifically with the maximum bindings of >90% of added radioactivity. The binding was inhibited by the addition of a 1,000-fold greater concentration of unmodified HeFi-1. Radiolabeled B3 did not bind to the cells.

Fig. 2.

The effect of ²¹¹At-HeFi-1 or unmodified HeFi-1 or their combination on the proliferation of karpas299 cells in vitro. Karpas299 cells were treated as described in Materials and Methods. The data represent means ± SD of six samples and are representative of three experiments. Unmodified HeFi-1 and ²¹¹At-HeFi-1 inhibited the proliferation of karpas299 cells by 40% and 60%, respectively, compared with cells treated with medium alone. The combination of ²¹¹At-HeFi-1 with unmodified HeFi-1 enhanced the antitumor efficacy with >80% of proliferation of the cells being inhibited.

Fig. 3.

Therapeutic study of ²¹¹At-HeFi-1 or unmodified HeFi-1 or their combination in the karpas299 leukemia model. (A) Kaplan–Meier survival plot of the karpas299 leukemia-bearing SCID/NOD mice. (B) Serum sIL-2Rα levels of the karpas299 leukemia-bearing SCID/NOD mice at day 26 after therapy. The treatment with unmodified HeFi-1 or ²¹¹At-HeFi-1 inhibited the tumor growth significantly as seen by the reduced concentrations of serum sIL-2Rα at day 26, compared with those in the control and ²¹¹At-B3 groups. The combination of these two therapeutic agents further improved the efficacy as shown by the undetectable sIL-2Rα levels in this group at day 26. Survival of the karpas299-bearing mice was significantly prolonged in the unmodified HeFi-1 group compared with those in the control and ²¹¹At-B3 groups (P < 0.001). Treatment with a single dose of 12 μCi of ²¹¹At-HeFi-1 showed more effective therapeutic results in the karpas299 model compared with unmodified HeFi-1 (P < 0.001). The combination of these two therapeutic agents provided further improvement in survival of the mice, compared with the groups treated either with ²¹¹At-HeFi-1 (P < 0.05) or with unmodified HeFi-1 (P < 0.001) alone.

Fig. 4.

Therapeutic study of ⁹⁰Y-HeFi-1 in the SUDHL-1 model. (A) Tumor volume. (B) Kaplan–Meier survival plot of the SUDHL-1-bearing nude mice. Treatment with ⁹⁰Y-HeFi-1 inhibited the SUDHL-1 lymphoma growth significantly as seen by tumor size and prolonged survival of the SUDHL-1-bearing mice compared with the control and ⁹⁰Y-B3 groups. ∗, P < 0.001; †, P < 0.05, compared with the control group.