Effect of chelator conjugation level and injection dose on tumor and organ uptake of 111In-labeled MORAb-009, an anti-mesothelin antibody

초록

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 In-111-labeled MORAb-009. Methods: We used nude mice bearing the A431/K5 tumor as a mesothelin-positive tumor model and the 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, biodistribution studies were performed after the intravenous co-injection of In-111-labeled MORAb-009 (2.4 CHX-A ''/MORAb-009) with three different doses: 0.2, 2 and 30 mu g of MORAb-009. Results: The tumor uptake in A431/K5 tumor was four 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 the biodistribution of the In-111 label. The In-111-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-mu g dose produced higher tumor uptake than the 0.2- and 2-mu g doses, whereas the 30-mu g dose produced lower liver and spleen uptakes than the 0.2-mu g 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 In-111-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. Published by Elsevier Inc.

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