Pretarget radiotherapy with an anti-CD25 antibody-streptavidin fusion protein was effective in therapy of leukemia/lymphoma xenografts

Abstract

Although radioimmunotherapy with radiolabeled intact monoclonal antibodies has demonstrated efficacy in the treatment of lymphoma, it provides low tumor-to-normal-tissue radionuclide target ratios and unwanted prolonged radiation exposure to the bone marrow. To overcome these obstacles, the administration of the radionuclide was separated from that of the antibody by using an anti-IL-2 receptor ␣ antibody single chain Fv-streptavidin fusion protein, followed by radiolabeled biotin to treat lymphoma or leukemia xenografted mice. This Pretarget approach provided extremely rapid and effective tumor targeting, permitting the use of short-lived ␣-emitting radionuclides. With the ␤-emitter 90 Y, all of the 10 lymphoma-xenografted mice were cured. With the ␣-emitter 213 Bi, significant efficacy was obtained in treating leukemic mice, and, furthermore, when combined with immunotherapy, 7 of 10 leukemic mice were cured. Thus, Pretarget radioimmunotherapy is very promising and could represent the next generation in the treatment of lymphoma and leukemia.

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

“…In the present study, we demonstrated that 211 At linked to the anti-CD30 monoclonal antibody, HeFi-1, provided effective therapy for the karpas299 leukemia model. A paradigm is emerging in monoclonal antibody-mediated treatment that therapeutic efficacy may be augmented through the use of two agents with different modes of action (30)(31)(32)(33)(34)(35)(36). In this study, we used 211 At-HeFi-1, which causes radiation damage to the tumor cells, followed by the administration of receptor-saturating doses of unmodified HeFi-1.…”

“…Among the ␣-emitters currently under investigation for use in radioimmunotherapy, 211 At is perhaps the most promising candidate for radioimmunotherapeutic applications on the basis of half-life (t 1/2 ϭ 7.2 h) considerations. In contrast, ␤-emitters such as 90 Y that act through crossfire may be preferable in the treatment of large tumor masses (28)(29)(30). In the clinical situation, this latter agent may eliminate nontargeted tumor cells through the crossfire effect emanating from neighboring antigen-bearing cells that have been targeted by the radiolabeled monoclonal antibody.…”

“…A paradigm is also emerging that, for cancer therapy, the addition of two therapeutic agents that function via different mechanisms may be greater than additive in their cytotoxic action, leading to malignant cell death (30)(31)(32)(33)(34)(35)(36). In our previous therapeutic trials, we demonstrated that the therapeutic efficacy of radioimmunotherapy for an adult T cell leukemia model was enhanced by the simultaneous coadministration of an anti-CD25…”

“…E-mail: tawald@helix.nih.gov. monoclonal antibody, daclizumab, at receptor-saturating doses (30,32,36).…”

Human T cell lymphotropic virus-associated leukemia/lymphoma

“…Anti-Tac antibody, which recognizes CD25, the α subunit of the interleukin-2 receptor, has been shown to have therapeutic efficacy for ATLL cells in patients and in a murine xenograft model [56]. A recent study showed that antitumor activity depended on Fc receptor-mediated clearance [57].…”