Pretargeted Versus Directly Targeted Radioimmunotherapy Combined with Anti-CD20 Antibody Consolidation Therapy of Non-Hodgkin Lymphoma

Abstract

We determined whether therapeutic responses using a bispecific antibody that pretargeted 90 Y-hapten-peptide radioimmunotherapy or a directly radiolabeled, humanized, 90 Y-anti-CD20 IgG (veltuzumab) could be improved by combining these treatments with unlabeled humanized antibodies against CD22 (epratuzumab), CD74 (milatuzumab), or veltuzumab. Methods: Nude mice bearing established subcutaneous Ramos human Burkitt lymphoma were treated with antibodies alone or in combination with pretargeted radioimmunotherapy (PT-RAIT) or radioimmunotherapy, and tumor growth was monitored. Biodistribution studies examined the effect that predosing with unlabeled veltuzumab had on radioimmunotherapy and PT-RAIT targeting. Results: None of the unconjugated antibodies was effective against established and rapidly growing xenografts, but PT-RAIT, at approximately 30% of its maximum tolerated dose, and radioimmunotherapy alone, at its maximum tolerated dose, were able to arrest growth and even entirely ablate tumors in some animals. Only combinations with veltuzumab improved therapeutic responses, most significantly when a veltuzumab regimen (weekly, 1.0 mg followed by 3 · 0.5 mg) was initiated 1 wk after PT-RAIT or 90 Y-veltuzumab. Biodistribution data indicated that when unlabeled veltuzumab (1.0 or 0.25 mg) was administered in advance of the radiolabeled veltuzumab or bispecific antibody injection, tumor uptake was significantly reduced ( 111 In-veltuzumab, 47% and 25%, respectively; 111 In-hapten-peptide, 74% and 49%, respectively). Despite an approximately 50% decrease in radioactivity uptake in the tumor, antitumor responses were not diminished significantly for 90 Y-veltuzumab, and in the case of PT-RAIT responses were improved. However, higher amounts of predosed veltuzumab reduced the effects of PT-RAIT. Conclusion: These studies suggest that administering unlabeled anti-CD20 IgG therapy after the radioactivity dose provides the best efficacy and that the amount of unlabeled anti-CD20 IgG administered as a predose to anti-CD20-targeted radionuclide therapy should be minimized.

Pretargeted Radioimmunotherapy for Hematologic and Other Malignancies

“…This possibility was suggested by recent experiments with Burkitt lymphoma-bearing nude mice, which showed that unlabeled antibodies against CD20 (veltuzumab) but not against CD22 (epratuzumab) or CD74 (milatuzumab) improved the therapeutic response achieved with 90 Y-hapten-peptide PRIT. 95 Benefits of such an approach may largely depend on exact experimental conditions, as indicated by the observation that tumor uptake was significantly reduced when unlabeled veltuzumab was administered in advance of the radiolabeled veltuzumab or bispecific antibody injection. Likewise, the net effect on PRIT efficacy, that is, improvement or worsening, depended on the amount of predosed unlabeled veltuzumab.…”

“…Additional improvements may also come from the use of other novel strategies, such as the integration of unlabeled antibodies into PRIT-based therapies. 95 Undoubtedly, PRIT will remain an exciting avenue because of constant methodological refinements. With continued research, it holds the potential to establish itself as an important treatment modality for hematologic and other malignancies for smallvolume disease, as radiation boost in combination with other treatments such as stem-cell rescue, or as adjuvant therapy.…”

“…Likewise, the net effect on PRIT efficacy, that is, improvement or worsening, depended on the amount of predosed unlabeled veltuzumab. 95 Leukemia. Early experience of HCT in humans demonstrated the effectiveness of total body irradiation (TBI) as an antileukemic agent when used in the setting of HCT.…”

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

“…26,27 The rationale behind this method was to saturate normal tissue sinks with naked antibody, thereby potentially decreasing off-target toxicity and allowing deeper ADC penetration into tumor tissues. Although there are merits to this approach and it is used for approved radioimmunotherapies, 28,29 only preclinical examples exist in the ADC space. Successful integration of this methodology in clinical ADC dosing will require careful titration of the naked antibody dose to the intact ADC dose; ratios may have to be patient specific to factor in disease burden and may be dependent on tumor type.…”

Treatment with Unlabeled mAb BR96 After Radioimmunotherapy with 177Lu-DOTA-BR96 in a Syngeneic Rat Colon Carcinoma Model

“…The administration of 4 weekly doses of unlabeled anti-CD20 IgG starting 1 week after RIT with the same mAb enhanced the effect of RIT and improved survival compared with RIT alone and starting the administration of unlabeled anti-CD20 IgG before RIT. 24 Biodistribution data showed a lower tumor uptake of the radioimmunoconjugate when unlabeled anti-CD20 IgG was administered before RIT, which might explain the lower therapeutic effect. Hence, consolidation therapy with unlabeled mAbs after RIT might be effective; however, it will probably be less effective in patients given a high predose.…”