Introduction Radiolabeling of a monoclonal antibody (mAb) with a metallic radionuclide requires the conjugation of a bifunctional chelator to the mAb. The conjugation, however, can alter the physical and immunological properties of the mAb, consequently affecting its tumor targeting pharmacokinetics. In this study, we investigated the effect of the amount of 2-(p-isothiocyanatobenzyl)-cyclohexyl-diethylenetriamine-pentaacetic acid (CHX-A″) conjugated to MORAb-009, a mAb directed against mesothelin and the effect of MORAb dose on the biodistribution of 111In labeled MORAb-009. Methods We used nude mice bearing A431/K5 tumor as a mesothelin-positive tumor model and A431 tumor as a mesothelin-negative control. To find the optimal level of CHX-A″ conjugation, CHX-A″-MORAb-009 conjugates with 2.4, 3.5, and 5.5 CHX-A″ molecules were investigated. To investigate the effect of injected MORAb-009 dose on neutralizing the shed-mesothelin in the circulation, the biodistribution studies were performed after the i.v. co-injection of the 111In labeled MORAb-009 (2.4 CHX-A″/MORAb-009) with three different doses, 0.2, 2, and 30 μg of MORAb-009. Results The tumor uptake in A431/K5 tumor was 4 times higher than that in A431 tumor, indicating that the tumor uptake in A431/K5 was mesothelin-mediated. The conjugate with 5.5 CHX-A″ showed a lower isoelectric point (pI) and lower immunoreactivity (IR) than the 2.4 CHX-A″ conjugate. These differences were reflected in biodistribution of the 111In label. The 111In labeled MORAb-009 conjugated with 2.4 CHX-A″ produced higher tumor uptake, and lower liver and spleen uptakes than the 5.5 CHX-A″ conjugate. The biodistribution studies also revealed that the tumor uptake was significantly affected by the injected MORAb-009 dose and tumor size. The 30 μg dose produced higher tumor uptake than the 0.2 and 2 μg doses whereas the 30 μg dose produced lower liver and spleen uptakes than the 0.2 μg dose. Conclusion This study demonstrates that the number of chelate conjugation and the injected dose are two important parameters to achieve high tumor and low non-target organ uptake of 111In labeled MORAb-009. This study also suggests that the injected dose of mAb could be individualized based on the tumor size or the blood level of shed-antigen in a patient to achieve the ideal tumor-to-organ radioactivity ratios.
Introduction This study was undertaken to investigate the effect of Paclitaxel and Bevacizumab on the therapeutic efficacy of 90Y-labeled B3 mAb, directed against Ley antigen, for the treatment of Ley-positive A431 tumors implanted s.c. in the right hind flank of nude mice. Methods When the tumor size reached ~200 mm3, the mice received a single dose of i.v. 90Y-labeled B3 (60 μCi/150 μg or 100 μCi/150 μg B3), i.p. Paclitaxel (40 mg/kg), or i.v. Bevacizumab (5 mg/kg) for monotherapy. To investigate the effect of combined therapies on survival, the mice were treated with two or three agents in the following combinations: 90Y-B3 on day 0 and Paclitaxel on day 1; Bevacizumab on −1 day and 90Y-B3 on day 0; Bevacizumab on −1 day and Paclitaxel on day 1; Bevacizumab, 90Y-B3, and Paclitaxel each at 1-day intervals. The mice with no treatment were used as a control. The tumor volume at 1,000 mm3 was used as a surrogate endpoint of survival. Results Compared to control animals, Paclitaxel delayed tumor growth with a significantly longer median survival time (P < 0.001) whereas Bevacizumab alone showed a less pronounced effect on a median survival time (P = 0.18). 90Y-B3 increased the median survival time in a dose dependent manner (P < 0.05). The combined therapy of Bevacizumab with Paclitaxel produced a trend toward an increase of the median survival time compared to Paclitaxel alone (P = 0.06), whereas Bevacizumab combined with 90Y-B3 showed a statistically insignificant increase in the median survival time compared to 90Y-B3 alone (P = 0.25). The tumor sizes of all animals in these groups reached the surrogate end point of survival by day 35. In contrast, the combined therapy involving 90Y-B3 with Paclitaxel showed a striking synergistic effect in shrinking tumors and prolonging the survival time (P < 0.001); on day 120, 3 of 9 mice (33%) and 6 of 6 mice (100%) were alive without tumor when treated with 60 μCi 90Y-B3 and 100 μCi 90Y-B3, respectively. The addition of Bevacizumab treatment one day before the combined therapy of 60 μCi 90Y-B3 with Paclitaxel did not produce a statistically significant increase in survival when compared to the 90Y-B3 with Paclitaxel (P > 0.10). Fluorescence microscopy analysis indicated that Paclitaxel increased, whereas Bevacizumab decreased the accumulation and penetration of Alexa Fluor 647-B3 into tumor microenvironment compared to the control (P < 0.05). Conclusion Our findings on the Paclitaxel effect support a hypothesis that the increased tumor accumulation and penetration of 90Y-B3 as well as the high radio-sensitization of tumor cells by Paclitaxel may be the major factors responsible for the synergistic effect of the combined therapy involving 90Y-B3 with Paclitaxel.
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