Astatine-211 radioimmunotherapy of ovarian cancer. Therapeutic efficacy, myelotoxicity, andradiation dosimetry in an animal model

Abstract

Alpha-particle emitting radionuclides have recently obtained an increased attention whenconsidering new strategies for treating disseminated cancer. Astatine (211At), that emits alphaparticleswith a mean path length of 62 μm, a mean linear energy transfer (LET) of 111keV/Mum, and a half-life of 7.2 hours, is one among the most promising nuclides in thisrespect. We have used 211At for evaluating the therapeutic efficacy, myelotoxicity, andradiation dosimetry in the treatment of intraperitoneally disseminated micrometastatic ovariancancer in nude mice. In order to specifically irradiate the tumor cells 211At was labeled tomonoclonal antibodies (mAbs), targeting certain cell surface epitopes.The myelotoxicity for alpha-particles was studied in non-tumor bearing mice and comparedwith low-LET irradiation for relative biological effectiveness (RBE) determination. Animalswere injected intraperitoneally or intravenously with 211At- or 99mTc-mAbs. Myelotoxicitywas measured as suppression of white blood cell (WBC) counts. A nadir of the WBC countsat 4 7 days after injection was observed. Normal tissue activity concentration and wholebodyretention were measured with a NaI(Tl) detector and the absorbed dose was calculatedfor alpha-particles, electrons, and gammas. A mean value for the bone marrow-to-blood ratioof 0.58 was observed for the 211At-mAbs. The in vivo RBE for alpha-particles was 3.4 ± 0.6when compared to electrons from 99mTc and 5.0 ± 0.9 when compared to external 60Coirradiation.The in vivo therapeutic efficacy as well as the mean absorbed dose to tumors was studied indifferent settings for both intact and fragmented mAbs (MX35, MX35 F(ab´)2, or MOv18).Animals were inoculated with ~1 × 107 OVCAR-3 cells. At 1, 3, 4, 5, or 7 weeks afterinoculation, the animals were intraperitoneally treated with 400 1,200 kBq 211At-MX35 orwith 25 400 kBq 211At-MX35 F(ab´)2. Eight weeks after treatment the animals weresacrificed and the tumor-free fraction (TFF), defined as percent of animals with no macroandmicroscopic tumors and no ascites, was determined. The mean TFF was 64% aftertreatment with 400 1,200 kBq 211At-MX35. The mean absorbed dose was >6 Gy for tumorradii (rtumor) <71 Mum. A significant increase in the TFF was observed between 50 (TFF =22%) and 100 kBq (TFF = 50%) 211At-MX35 F(ab´)2. This was in agreement with a model ofthe metastatic cure probability. The TFF was 95% for rtumor H 30 Mum when 400 kBq 211At-MX35 F(ab´)2 was intraperitoneally injected. The TFF was significantly higher for 211At-MX35 F(ab´)2 compared to 211At-Rituximab F(ab´)2 (non-specific mAb) (with odds ratiosincreasing exponentially) at later time points, i.e. at 4, 5, or 7 weeks after inoculation.The therapeutic efficacy and myelotoxicity was also studied for fractionated treatmentcompared to single treatment. A total of 50, 400, or 800 kBq intraperitoneally injected 211At-MX35 F(ab´)2 was administered as single or fractionated treatments. The TFF was 17%, 39%,and 56% for single treatments with 50, 400, and 800 kBq, recpectively. The TFF was 22%,28%, and 41% for 3 × 17, 3 × 133, and 3 × 267 kBq (4 days between each injection),respectively. No significant difference between single and fractionated treatment was noticed(P > 0.5). Alleviation in the myelotoxicity was noticed for the fractionated treatmentcompared to the single treatment in terms of a decreased suppression (from 46% to 19%) anddelayed nadir (from day 4 to day 11) of the WBC counts.