Myelotoxicity and RBE of 211At-Conjugated Monoclonal Antibodies Compared with 99mTc-Conjugated Monoclonal Antibodies and 60Co Irradiation in Nude Mice

Journal of Nuclear Medicine

Jörgen Elgqvist¹  Holger Jensen¹  Ragnar Hultborn¹  Börje Karlsson¹  Sture Lindegren¹  Elisabet Warnhammar¹  Peter Bernhardt¹  Lars Jacobsson¹ 

关键词: astatine;    radioimmunotherapy;    radiotoxicity;    bone marrow;    dosimetry;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

The rationale of this study was to determine the myelotoxicity in nude mice of the α-emitter 211At conjugated to monoclonal antibodies (mAbs) and to compare the effect with an electron emitter, 99mTc, and external irradiation from a 60Co source, for estimation of the relative biological effectiveness (RBE). Methods: 211At and 99mTc were conjugated to the IgG1 mAbs MX35 and 88BV59. Nude female BALB/c mice, 8- to 12-wk old, were injected intraperitoneally or intravenously. The biodistribution was determined 3, 6, and 18 h after injection. The bone-to-blood and bone marrow-to-blood activity concentration ratios (BBLR and BMBLR, respectively) were determined for simultaneously injected 211At- and 99mTc-mAbs. Bone marrow samples were taken from the femur. For each mouse, the whole-body retention was measured as well as the blood activity by repeated blood samples from the tail vein (0), 1, 3, 6, 12, and 18 h after injection. External-beam irradiation from a 60Co source was also performed at 3 different dose levels. White blood cell (WBC) counts, red blood cell counts, platelet counts, and hemoglobin were determined for each mouse initially and on days 1, 4, 5, 7, 15, 22, and 27 after injection. The calculations of the absorbed dose to the bone marrow were based on the BBLR, BMBLR, the cumulated activities, and the absorbed fractions. The absorbed fractions, φ, for α-particles and electrons in the bone marrow were calculated using Monte Carlo simulations based on a bone marrow dosimetry model. Results: The BMBLR was 0.58 ± 0.06 and 0.56 ± 0.06 for the 211At- and 99mTc-mAbs, respectively. No significant variation in BMBLR with time was found. The absorbed fractions for α-particles and electrons in the bone marrow were 0.88 and 0.75, respectively. The mean absorbed fractions of the photons from 99mTc were 0.033 and 0.52 for 140 and 18.3 keV, respectively. When different amounts of 211At- and 99mTc-mAbs (0.09–1.3 and 250–1,300 MBq, respectively) were administered intraperitoneally or intravenously, corresponding to absorbed doses to the bone marrow of 0.01–0.60 and 0.39–1.92 Gy, respectively, the WBC counts was suppressed by 1%–90% and 23%–89%, respectively. When external-beam irradiation with a 60Co source was performed to absorbed doses of 1.4, 1.9, and 2.4 Gy, the WBC counts was suppressed by 47%–90%. These results indicate a myelotoxic in vivo RBE of 3.4 ± 0.6 for α-particles compared with 99mTc and 5.0 ± 0.9 compared with 60Co irradiation. Conclusion: The effect on the WBC counts from bone marrow irradiation with 211At-mAbs indicates an in vivo RBE of 3.4 ± 0.6 in comparison with 99mTc-mAbs. The RBE value compared with external irradiation is 5.0 ± 0.9.

【 授权许可】

Unknown