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

Robert M. Sharkey; Habibe Karacay; Christine R. Johnson; Samuel Litwin; Edmund A. Rossi; William J. McBride; Chien-Hsing Chang; David M. Goldenberg

doi:10.2967/jnumed.108.058602

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FIGURE 1.
Survival curves for PT-RAIT combined with unconjugated antibodies with PT-RAIT. BALB/c nude mice bearing subcutaneous Ramos tumors underwent PT-RAIT with or without unconjugated antibody. Tumor size was monitored for 16 wk. Animals were removed from study when tumor progressed to greater than or equal to 2.5 cm. Growth curves for individual groups and animals are shown in Supplemental Figure 1 (hLL1, milatuzumab; hA20, veltuzumab; hLL2, epratuzumab).
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FIGURE 2.
Combining PT-RAIT with veltuzumab treatment regimen starting 1 d in advance of TF4 injection: Untreated (A), percentage of animals remaining with tumors less than or equal to 2.5 cm³ (B), PT-RAIT alone (2.25 nmol/355 μg of TF4, followed 29 h later with 9.25 MBq/0.09 nmol of ⁹⁰Y-IMP-288) (C), and PT-RAIT plus hA20 before and after PT-RAIT (same as treatment C, but 1 mg of veltuzumab was administered 1 d before TF4 and then followed by 3 weekly injections of 0.5 mg of veltuzumab) (D). T₀ is time ⁹⁰Y-IMP-288 was administered. Arrows show times when veltuzumab was administered.
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FIGURE 3.
Effect of single predose of veltuzumab (0.25 mg) on PT-RAIT: untreated (A), percentage of animals remaining with tumors less than or equal to 2.5 cm³ (B), PT-RAIT alone (2.25 nmol/355 μg of TF4, followed 29 h later with 9.25 MBq/0.09 nmol of ⁹⁰Y-IMP-288) (C), and PT-RAIT plus hA20 before and after PT-RAIT (same as treatment C, but 0.25 mg of veltuzumab [hA20] was administered 1 d before TF4 [1 animal was removed at 8.7 wk for NTRT]) (D). T₀ is time ⁹⁰Y-IMP-288 was administered.
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FIGURE 4.
Effect of pre- and postdosing with unconjugated veltuzumab on therapeutic activity of ⁹⁰Y-veltuzumab and PT-RAIT: Untreated (A), PT-RAIT alone (2.25 nmol/355 μg of TF4, followed 29 h later with 9.25 MBq/0.09 nmol of ⁹⁰Y-IMP-288) (B), PT-RAIT followed 7 d later with veltuzumab, starting with 1 mg and then with 3 weekly doses of 0.5 mg of veltuzumab (C), 4.81 MBq (0.13 mCi; 50 μg) of ⁹⁰Y-veltuzumab alone (D), treatment D coinjected with 1 mg of epratuzumab (hLL2) at T₀, followed by weekly injections × 3 of 0.5 mg of epratuzumab (E), 1 mg of veltuzumab administered 1 d before ⁹⁰Y-veltuzumab (4.81 MBq/50 μg) and then followed weekly with 3 × 0.5 mg of veltuzumab (F), treatment D followed 1 wk later with 1 mg of veltuzumab, with 3 × 0.5 mg of veltuzumab administered weekly thereafter (G), and percentage of animals remaining with tumors smaller than 2.5 cm³ (H). Ramos tumors were administered ⁹⁰Y-veltuzumab or PT-RAIT with or without unconjugated antibody. For PT-RAIT, T₀ is time ⁹⁰Y-IMP-288 was administered. Each growth curve shows fraction of animals cured (S) and median time to 2.5 cm³ (MS). Arrows indicate animals removed from study because of TRT or NTRT event.
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FIGURE 5.
Effect of single predose of veltuzumab (1 mg) on ⁹⁰Y-veltuzumab treatment: untreated (A), percentage of animals remaining with tumors smaller than 2.5 cm³ (B), 4.255 MBq (0.115 mCi; 50 μg) of ⁹⁰Y-veltuzumab alone (C), treatment C, first administered 1 mg of veltuzumab (arrowhead) 1 d in advance of ⁹⁰Y-veltuzumab injection (D).

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TABLE 1

Effect of Veltuzumab Advanced Dose on Biodistribution of ¹¹¹In-Veltuzumab IgG or TF4-Pretargeted ¹¹¹In-IMP-288

	Set A		Set B		Set C
Antibody and target	No predose	1.0 mg/1 d	No predose	0.25 mg/1 d	No predose	0.25 mg/1 h	1.0 mg/1 h
¹¹¹In-veltuzumab IgG
Tumor	16.9 ± 4.1	9.0 ± 1.4	22.5 ± 3.8	16.8 ± 2.0	22.1 ± 2.7	18.1 ± 2.5	13.2 ± 4.5
Tumor weight	0.532 ± 0.124	0.677 ± 0.302	0.264 ± 0.081	0.255 ± 0.047	0.307 ± 0.150	0.323 ± 0.144	0.352 ± 0.258
Liver	3.5 ± 0.6	4.0 ± 0.5	4.7 ± 1.7	5.6 ± 0.4	4.1 ± 0.4	4.7 ± 1.3	4.7 ± 0.3
Spleen	4.3 ± 1.8	4.3 ± 0.5	5.4 ± 4.0	5.6 ± 0.8	3.6 ± 0.8	4.1 ± 1.0	4.3 ± 0.5
Kidneys	5.0 ± 0.7	7.1 ± 1.0	4.8 ± 0.5	5.40 ± 0.8	5.2 ± 0.6	6.7 ± 1.2	6.6 ± 0.3
Lungs	6.9 ± 1.5	7.8 ± 1.0	5.9 ± 1.0	7.2 ± 1.5	6.0 ± 2.4	6.0 ± 1.0	7.7 ± 2.9
Blood	14.8 ± 2.0	20.3 ± 2.6	16.1 ± 2.3	22.6 ± 2.3	15.2 ± 1.9	18.2 ± 2.8	19.8 ± 2.2
TF4-pretargeted ¹¹¹In-IMP-288
Tumor	11.28 ± 0.21*	2.96 ± 0.75*	13.40 ± 0.60	6.82 ± 0.75*	13.23 ± 1.81	6.74 ± 1.51	2.40 ± 0.61
Tumor weight	0.559 ± 0.209	0.754 ± 0.253	0.303 ± 0.061	0.469 ± 0.180	0.228 ± 0.067	0.329 ± 0.131	0.195 ± 0.063
Liver	0.43 ± 0.12	0.68 ± 0.17	0.63 ± 0.10	0.71 ± 0.17	0.66 ± 0.30	0.81 ± 0.14	0.77 ± 0.25
Spleen	0.63 ± 0.23	1.38 ± 0.52	1.40 ± 0.71	1.40 ± 0.56	1.32 ± 0.98	1.29 ± 0.69	1.23 ± 0.51
Kidneys	1.14 ± 0.14	1.50 ± 0.09	1.38 ± 0.18	1.31 ± 0.26	1.53 ± 0.27	1.46 ± 0.24	1.27 ± 0.15
Lungs	0.37 ± 0.03	0.68 ± 0.39	0.34 ± 0.06	0.42 ± 0.09	0.48 ± 0.14	0.38 ± 0.04	0.50 ± 0.22
Blood	0.01 ± 0.00	0.02 ± 0.01	0.02 ± 0.00	0.02 ± 0.01	0.02 ± 0.01	0.02 ± 0.00	0.02 ± 0.01

Animals were necropsied either 3 d after ¹¹¹In-veltuzumab injection or 24 h after ¹¹¹In-IMP-288 injection (¹¹¹In-IMP-288 was administered 29.5 h after TF4). %ID/g for each groups is shown (mean ± SD; n = 5/group, except where indicated by *, where n = 4).