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

¹ Department of Radiation Physics, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden
² Department of Oncology, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden
³ Positron Emission Tomography and Cyclotron Unit, Köpenhamn, Denmark

View larger version (14K): [in a new window]   FIGURE 1. Experimental flow chart indicates times at which the different experiments in studies A, B, and C were performed.

View larger version (26K): [in a new window]   FIGURE 2. WBC counts, RBC counts, PLT counts, and HGB as function of time after injection during the long-term study, when animals were injected intraperitoneally with 211At-conjugated () and 99mTc-conjugated () mAb 88BV59 (n = 17 and 30, respectively), giving an absorbed dose to bone marrow of approximately 0.3 and 1.3 Gy, respectively. The nadir of WBC counts was reached at days 4–7. Results from control animals (unlabeled antibody 88BV59 [n = 20] and PBS [n = 30]) are also plotted (•). Since no significant (P > 0.05) difference between unlabeled antibody and PBS was observed, the 2 control groups were put together. Day 5 was chosen as the reference point when comparing myelotoxicity of different combinations of nuclide and antibody (Fig. 5). Values are means ± SEM.

View larger version (18K): [in a new window]   FIGURE 3. Whole-body retention for intraperitoneally (i.p.) or intravenously (i.v.) injected 211At-MX35 (, n = 14 [i.p.] and n = 4 [i.v.]), 211At-88BV59 (, n = 16 [i.p.] and n =4 [i.v.]), 99mTc-MX35 (, n = 16 [i.p.] and n = 4 [i.v.]), and 99mTc-88BV59 (, n = 10 [i.p.]) at 0, 1, 3, 6, 12, and 18 h after injection. Whole-body retention curves were used to estimate cumulated activity (i.e., AUC) and, hence, the photon contribution to absorbed dose from 99mTc for each individual animal. Values are means ± SEM.

View larger version (25K): [in a new window]   FIGURE 4. Blood activity kinetics for intraperitoneally injected 211At-MX35 (, n = 14), 211At-88BV59 (, n = 16), 99mTc-MX35 (, n = 16), and 99mTc-88BV59 (–, n = 10) as well as for intravenously injected 211At-MX35 (, n = 4), 211At-88BV59 (x, n = 4), and 99mTc-MX35 (, n = 4) at 1, 3, 6, 12, and 18 h after injection. Individual curves for each animal were used to estimate cumulated activity (i.e., AUC) and, hence, the contribution from -particles or electrons, originating from decays of 211At and 99mTc, respectively, to absorbed dose to bone marrow for each individual animal. Values are means ± SEM.

View larger version (24K): [in a new window]   FIGURE 5. Relative suppression of WBC counts as function of absorbed dose to bone marrow in nude mice when injected with 211At-conjugated (, n = 38) and 99mTc-conjugated (, n = 20) mAbs or when irradiated externally with a 60Co source (, n = 19). The y-axis is logarithmic, where 1 represents no suppression and 0.1 represents 90% suppression of WBC counts. Solid lines represent exponential fits to 211At and 99mTc data. Dashed lines flanking each full line represent 95% confidence interval. In vivo RBE is defined as quotient of absorbed dose from 99mTc and that from 211At for equal toxic effect—that is, for equal degrees of suppression of WBC counts. The 2 data points with error bars originate from preliminary experiments with 99mTc-88BV59, where cumulated blood activity concentrations and suppression of WBC counts were investigated in separate animals (, n = 10).