Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2

O Vilhelmsson Timmermand, E Larsson, D Ulmert, T A Tran, Se Strand, O Vilhelmsson Timmermand, E Larsson, D Ulmert, T A Tran, Se Strand

Abstract

Background: Prostate cancer ranks as the second most lethal malignancy in the Western world. Previous targeting of prostate-specific antigen and human kallikrein-related peptidase 2, two related enzymes abundantly expressed in prostatic malignancies, with radioimmunoconjugates intended for diagnostic purposes, have proven successful in rodent prostate cancer (PCa) models. In this study, we investigated the uptake and therapeutic efficacy of (177)Lu-m11B6, a human kallikrein-related peptidase 2 (hK2)-targeting radioimmunoconjugate in a pre-clinical setting.

Methods: The murine 11B6 antibody, m11B6, with high affinity for hK2, was labeled with (177)Lu. Therapy planning was done from a biokinetic study in LNCaP xenografts, and therapeutic activities of (177)Lu-m11B6 were administered to groups of mice. Body weight and general conditions of the mice were followed over a period of 120 days.

Results: The tumor uptake in LNCaP xenografts was 30 ± 8.2 % injected activity per gram 1 week post-injection. In vivo targeting was hK2-specific as verified by a 2.5-fold decrease in tumor uptake in pre-dosed xenografts or by a fourfold lower tumor accumulation in hK2-negative DU 145 xenografts. Therapy showed a dose-dependent efficacy in LNCaP xenografts treated with (177)Lu-m11B6. No therapeutic effect was seen in the control groups. The median survival for the lowest given activity of (177)Lu-m11B6 was 88 days compared to that of 38 days in mice given labeled non-specific IgG. For the higher administrated activities, total tumor regression was seen with minimal normal organ toxicity.

Conclusions: We have proven the possibility of radioimmunotherapy targeting hK2 in subcutaneous prostate cancer xenografts. (177)Lu-m11B6 exhibited high therapeutic efficacy, with low observed toxicity. Additionally, an evaluation of the concept of pre-therapy planning using a dosimetry model was included in this radioimmunotherapy study.

Keywords: 11B6; 177Lu; 177Lu-m11B6; Dosimetry; Human kallikrein-related peptidase 2; Prostate cancer; Radioimmunotherapy; hK2.

Figures

Fig. 1
Fig. 1
SPECT/CT imaging with two projections per mouse, frontal and sagittal view, arrows indicating xenografts. a From left to right, a mouse with LNCaP xenograft (right side) imaged at 24, 48, 72, and 1 week p.i. of 8 MBq 177Lu-m11B6. b Mouse with LNCaP xenograft (right side) imaged at 48 and 72 h p.i. of 8 MBq 177Lu-m11B6 and m11B6. 1 mg cold m11B6 was injected 24 h prior to injection with 177Lu-m11B6
Fig. 2
Fig. 2
SPECT quantification and biodistribution of 177Lu-m11B6. a SPECT quantification of 7.9 ± 0.69 MBq, 30 μg 177Lu-m11B6 in s.c. LNCaP-xenografted NMRI nude mice at 24, 48, 72, and 168 h. b. Biodistribution of 7.9 ± 0.69 MBq, 30 μg 177Lu-m11B6 in s.c. LNCaP at 72 and 168 h p.i. c In vivo specificity, 7.9 ± 0.69 MBq q, 30 μg 177Lu-m11B6 in s.c. LNCaP- and DU 145-xenografted NMRI nude mice at 72 h with a group of pre-dosed mice (1 mg cold m11B6 24 h pre-injection of labeled antibody)
Fig. 3
Fig. 3
Representation of LNCaP tumor volumes measured with caliper over 120 days after injection of a 10.1.2 MBq of 177Lu-m11B6, b 19.1.4 MBq 177Lu-m11B6, c 36 ± 0.68 MBq 177Lu-m11B6, d NaCl, e non-specific IgG 18 ± 1.3 MBq and f 30 μg m11B6
Fig. 4
Fig. 4
Percent change in xenograft volume over time. a Percent change over time 177Lu-m11B6 and controls. b. Zoomed in, the change during the first 60 days of 177Lu-m11B6 treatment. c Tumor growth development in percent for DU 145 xenografts for mice given 24 ± 0.45 MBq 177Lu-m11B6 and NaCl, respectively
Fig. 5
Fig. 5
Survival and weight. a Kaplan-Meier. Survival over time, median survival was 45 days for NaCl, 38 days for non-specific IgG, 35 days for 30 μg m11B6, and 88 days for 10 MBq of 177Lu-m11B6. For the two remaining groups there is no median survival available since only one mouse where sacrificed within 120 days due to too large tumor volume. b Animal weight after treatment with 177Lu-m11B6, no change is seen. c Animal weight in control groups, a drop in the weights of some animals were seen, especially in the group given non-specific IgG

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