A comparative analysis of conventional and pretargeted radioimmunotherapy of B-cell lymphomas by targeting CD20, CD22, and HLA-DR singly and in combinations - PubMed (original) (raw)

Comparative Study

A comparative analysis of conventional and pretargeted radioimmunotherapy of B-cell lymphomas by targeting CD20, CD22, and HLA-DR singly and in combinations

John M Pagel et al. Blood. 2009.

Abstract

Relapsed B-cell lymphomas are currently incurable with conventional chemotherapy and radiation treatments. Radiolabeled antibodies directed against B-cell surface antigens have emerged as effective and safe therapies for relapsed lymphomas. We therefore investigated the potential utility of both directly radiolabeled 1F5 (anti-CD20), HD39 (anti-CD22), and Lym-1 (anti-DR) antibodies (Abs) and of pretargeted radioimmunotherapy (RIT) using Ab-streptavidin (SA) conjugates, followed by an N-acetylgalactosamine dendrimeric clearing agent and radiometal-labeled DOTA-biotin, for treatment of lymphomas in mouse models using Ramos, Raji, and FL-18 human lymphoma xenografts. This study demonstrates the marked superiority of pretargeted RIT for each of the antigenic targets with more complete tumor regressions and longer mouse survival compared with conventional one-step RIT. The Ab-SA conjugate yielding the best tumor regression and progression-free survival after pretargeted RIT varied depending upon the lymphoma cell line used, with 1F5 Ab-SA and Lym-1 Ab-SA conjugates yielding the most promising results overall. Contrary to expectations, the best rates of mouse survival were obtained using optimal single Ab-SA conjugates rather than combinations of conjugates targeting different antigens. We hypothesize that clinical implementation of pretargeted RIT methods will provide a meaningful prolongation of survival for patients with relapsed lymphomas compared with currently available treatment strategies.

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Figures

Figure 1

Figure 1

Therapeutic efficacy of pretargeted RIT (PRIT) compared with conventional RIT in athymic mice bearing Ramos Burkitt lymphoma xenografts. PRIT mice were injected intravenously via tail vein with 300 μg of either (A) anti-CD20 1F5-SA, (B) anti–HLA-DR Lym-1-SA, (C) anti-HD22 HD39-SA, (D) control HB8181-SA, or (F) a combination of the 3 Ab-SA conjugates followed 20 hours later with 50 μg CA, and 4 hours later with 800 μCi (29.6 MBq) 90Y-DOTA-biotin. Mice treated with conventional RIT received either 200 μCi (7.4 MBq) or 300 μCi (11.1 MBq) of either 90Y-labeled (A) 1F5-SA, (B) Lym-1-SA, (C) HD39-SA, (D) HB8181, or (E) a combination of the 3 directly labeled Abs injected intravenously via tail vein. Untreated mice did not receive any therapy. Tumor growth is reported as percentage of initial tumor volume (y-axis) measured over time (x-axis). When mice required killing due to tumor progression or severe toxicity, the final tumor volume was carried through until the last mouse in the group died or 100 days after treatment was reached. Error bars indicate SD.

Figure 2

Figure 2

Kaplan-Meier cumulative survival plots for athymic mice treated with PRIT or conventional RIT following the establishment of palpable Ramos Burkitt lymphoma xenografts. Mice were treated as described in the legend of Figure 1 and analyzed for survival as a function of time. Treatment groups included mice receiving either (A) anti-CD20 1F5, (B) anti–HLA-DR Lym-1, (C) anti-CD22 HD39, (D) control HB8181 Ab conjugates, or (E,F) a combination of all 3 reagents.

Figure 3

Figure 3

Therapeutic efficacy of PRIT in athymic mice bearing Raji Burkitt lymphoma xenografts. PRIT mice were injected intravenously via the tail vein with 300 μg of either (A) anti-CD20 1F5-SA, (B) anti–HLA-DR Lym-1-SA, (C) anti-HD22 HD39-SA, (A-C) control HB8181-SA, or (D) a combination of the 1F5-SA and Lym-1-SA conjugates followed 20 hours later with 50 μg CA, and 4 hours later with 800 μCi (29.6 MBq) 90Y-DOTA-biotin. Untreated mice did not receive any therapy. Tumor growth was measured as described in the legend to Figure 1. Error bars represent SD.

Figure 4

Figure 4

Kaplan-Meier cumulative survival plots for athymic mice treated with PRIT following the establishment of palpable Raji Burkitt lymphoma xenografts. Mice were treated as described in the legend of Figure 3 and analyzed for survival as a function of time. Treatment groups included mice receiving either anti-CD20 1F5, (B) anti–HLA-DR Lym-1, (C) anti-CD22 HD39, (A-C) control HB8181 Ab conjugates, or (D) a combination of 1F5-SA and Lym-1-SA conjugates.

Figure 5

Figure 5

Therapeutic efficacy of PRIT in athymic mice bearing FL-18 transformed follicular lymphoma xenografts. PRIT mice were injected intravenously via tail vein with 300 μg of either (A) anti-CD20 1F5-SA, (B) anti–HLA-DR Lym-1-SA, (C) anti-HD22 HD39-SA, (A-C) control HB8181-SA, or (D) a combination of the 1F5-SA and Lym-1-SA conjugates followed 20 hours later with 50 μg CA, and 4 hours later with 800 μCi (29.6 MBq) 90Y-DOTA-biotin. Untreated mice did not receive any therapy. Tumor growth was measured as described in the legend to Figure 1. Error bars indicate SD.

Figure 6

Figure 6

Kaplan-Meier cumulative survival plots for athymic mice treated with PRIT following the establishment of palpable FL-18 transformed follicular lymphoma xenografts. Mice were treated as described in the legend for Figure 5 and analyzed for survival as a function of time. Treatment groups included mice receiving either anti-CD20 1F5, (B) anti–HLA-DR Lym-1, (C) anti-CD22 HD39, (A-C) control HB8181 Ab conjugates, or (D) a combination of 1F5-SA and Lym-1-SA conjugates.

Comment in

References

    1. Goldenberg DM. Targeted therapy of cancer with radiolabeled antibodies. J Nucl Med. 2002;43:693–713. - PubMed
    1. Sharkey RM, Goldenberg DM. Perspectives on cancer therapy with radiolabeled monoclonal antibodies. J Nucl Med. 2005;46(Suppl 1):115S–127S. - PubMed
    1. Pantelias A, Pagel JM, Hedin N, et al. Comparative biodistributions of pretargeted radioimmunoconjugates targeting CD20, CD22, and DR molecules on human B-cell lymphomas. Blood. 2007;109:4980–4987. - PMC - PubMed
    1. Pagel JM, Pantelias A, Hedin N, et al. Evaluation of CD20, CD22, and HLA-DR targeting for radioimmunotherapy of B-cell lymphomas. Cancer Res. 2007;67:5921–5928. - PubMed
    1. Paganelli G, Chinol M, Maggiolo M, et al. The three-step pretargeting approach reduces the human anti-mouse antibody response in patients submitted to radioimmunoscintigraphy and radioimmunotherapy. Eur J Nucl Med. 1997;24:350–351. - PubMed

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