Improving the treatment of non-Hodgkin lymphoma with antibody-targeted radionuclides

Abstract

Radioimmunotherapy of non-Hodgkin lymphoma comprises a (90)Y- or (131)I-labeled murine anti-CD20 IgG, but both agents also include a substantial dose of unlabeled anti-CD20 IgG given immediately before the radioconjugate to reduce its uptake in the spleen (primary normal B-cell antigen sink); this extends its plasma half-life and improves tumor visualization. Thus, these treatments combine an effective anti-CD20 radioconjugate with an unconjugated anti-CD20 antibody that is also therapeutically active, but the large anti-CD20 IgG predose ( approximately 900 mg) may diminish the tumor localization of the radioimmunoconjugate (eg, 10-35 mg). We have examined alternative approaches that enhance radionuclide targeting and improve antitumor responses. One uses a (90)Y-labeled anti-CD22 IgG (epratuzumab) combined with an antibody therapy regimen of a humanized anti-CD20 IgG (veltuzumab). Pretargeted radionuclide therapy using a trivalent, humanized, recombinant bispecific anti-CD20 antibody with a (90)Y-hapten-peptide is another highly effective method that is also less toxic than directly radiolabeled IgG. Finally, all approaches benefit from the addition of a consolidation-dosing regimen of the anti-CD20 IgG antibody. This article reviews these various options and discusses how some fundamental changes could potentially enhance the response and duration from radionuclide-targeted therapy.

Figure 1

The effect of veltuzumab pre-dosing on the therapeutic response of ⁹⁰Y-veltuzumab. Groups of nude mice (n = 10) bearing s.c. Ramos human B-cell lymphoma xenografts (average 0.65 cm³) were administered 0.115 mCi of ⁹⁰Y-veltuzumab (0.05 mg) alone or they were given 1.0 mg of veltuzumab 1 day prior to ⁹⁰Y-veltuzumab treatment. Survival based on time for tumors to progress to 3.0 cm³.

Figure 2

⁹⁰Y-veltuzumab therapy with consolidation veltuzumab therapy. Nude mice bearing s.c. Ramos tumors were given ⁹⁰Y-veltuzumab alone (0.13 mCi/0.05 mg), or a reduced veltuzumab pre-dose of 0.25 mg was given 1 day before receiving ⁹⁰Y-veltuzumab, and another group received the pre-dose, as well as a veltuzumab consolidation therapy starting 1 week after the radioconjugate using 1.0 mg veltuzumab followed by 3 more weekly injections of 0.5 mg veltuzumab. Survival based on time to progression to 3.0 cm³.

Figure 3

Combination RAIT and antibody therapy using ⁹⁰Y-epratuzumab and unlabeled veltuzumab. Treatment was initiated once the s.c. Ramos xenographs were visible in BALB/c nude mice. Treatment consisted of ⁹⁰Y-epratuzumab (⁹⁰Y-E) alone, veltuzumab (V) alone (1 mg followed 1 week later with 3 more weekly injections of 0.5 mg), or ⁹⁰Y-E combined with V therapy that was started 1 day before the radioconjugate. An irrelevant ⁹⁰Y-anti-CEA IgG was given to assess non-specific radiation effects.

Figure 4

Veltuzumab antibody therapy enhances the response of ⁹⁰Y-epratuzumab even when started 1 week after the radioconjugate treatment. Growth curves of the individual animals with s.c. Ramos xenografts treated with ⁹⁰Y-epratuzumab alone or with veltuzumab therapy initiated either 1 day before (day-1) or 6 days after the radioconjugate dose.

Figure 5

Consolidation veltuzumab therapy improves response of ⁹⁰Y-veltuzumab, but only when given in the absence of a pre-dose, or as in Figure 2, when the pre-dose is minimized. Ramos-bearing nude mice were given 0.13 mCi of ⁹⁰Y-veltuzumab alone or animals received 1.0 mg of veltuzumab prior to the radioconjugate, which was then followed with 3 additional weekly injections of 0.5 mg of veltuzumab (pre & post hA20). Other animals received the same veltuzumab regimen, but it was started 1 week after the radioconjugate was given.

Figure 6

Veltuzumab bsMAb pretargeted ⁹⁰Y-hapten-peptide improves therapeutic response compared to directly radiolabeled ⁹⁰Y-veltuzumab. Nude mice bearing s.c. Ramos tumors were treated with the MTD of ⁹⁰Y-veltuzumab (0.13 mCi/0.05 mg) or a pretargeting procedure using a humanized, recombinant bispecific antibody containing 2 veltuzumab Fab fragments and one anti-hapten Fab fragment capable of binding the ⁹⁰Y-hapten peptide. 0.5 or 0.7 mCi of the pretargeted ⁹⁰Y-hapten-peptide only result in ~50–70% loss in WBC that recovers in several weeks, whereas 0.13 mCi of ⁹⁰Y-veltuzumab causes >90% loss in WBC that requires 7 weeks to recover. Growth curves and the subsequent survival curve shows the improved responses in the pretargeted animals with the ability to completely ablate 9/10 tumors at the 0.7 mCi ⁹⁰Y-hapten-peptide dose.

Figure 7

The effect of veltuzumab pre-dosing and consolidation therapy on a veltuzumab-bsMAb pretargeting procedure. (A) Administering 1.0 mg of veltuzumab 1 day before the injection of the veltuzumab bsMAb reduces efficacy of the pretargeting procedure using 0.25 mCi of the ⁹⁰Y-hapten-peptide, despite the use of additional veltuzumab therapy after the pretargeted ⁹⁰Y-hapten peptide was given. (B) minimizing the veltuzumab pre-dose to 0.25 mg restores the anti-tumor effects of the pretargeting procedure, even improving it in this study. (C) Adding a full veltuzumab consolidation therapy after the pretargeted therapy (i.e., 1.0 mg veltuzumab starting 1 week after the ⁹⁰Y-hapten peptide, followed by 3 weekly doses of 0.5 mg veltuzumab) improves response, even when animals were pre-dosed with 0.25 mg veltuzumab.

Figure 8

Veltuzumab consolidation therapy enhances anti-tumor response in SCID mice bearing RL human lymphoma xenografts. SCID mice received 0.125 mCi of veltuzumab bsMAb pretargeted ⁹⁰Y-hapten-peptide alone, or they were given a 0.25 mg pre-dose of veltuzumab 1 day before the bsMAb injection, as well as receiving a full veltuzumab consolidation therapy (1.0 mg + 3 × 0.5 mg) starting 1 week after the ⁹⁰Y-hapten-peptide. (TRT, treatment-related toxicity in pretargeting alone group).