K Nakamura1, A Kubo. 1. Department of Radiology, Keio University School of Medicine, Tokyo, Japan.
Abstract
BACKGROUND: Some vasoactive drugs have been studied in the hope of altering the vascular permeability and/or blood of tumors to enhance monoclonal antibody (MoAb) uptake. The pretreatment of interleukin-2 (IL-2), one of the vasoactive reagents, produced a generalized vascular permeability, but its function was not tumor specific. Conversely, MoAb/IL-2 immunoconjugates were developed that selectively alter the vasopermeability of tumors. In the current study the authors evaluated whether radiolabeled anti-carcinoembryonic antigen (CEA) MoAb, ZCE025/IL-2 immunoconjugate, specifically can enhance delivery of iodine-125 (I-125) to tumor sites. METHODS: ZCE025 was conjugated with IL-2, and the conjugate then labeled with I-125. Biodistribution studies were performed in athymic mice bearing CEA-producing human tumor (MKN45) xenografts. Mice were injected with I-125-ZCE025/IL-2 conjugate, and I-125 activities in the organs, including blood and tumor, were investigated at 1, 3, and 5 days after injection. Vascular permeability of the organs, including tumors, also was studied by using I-131 labeled mouse serum albumin in three groups. RESULTS: I-125 labeled ZCE025/IL-2 conjugate destroyed its lymphokine-activated killer cell (LAK) activation, but retained a minimum of 75% of the antibody binding reactivity. Biodistribution of I-125-ZCE025/IL-2 conjugate showed increased uptake of I-125 in tumor by a factor of 1.5, 4.2, and 4.1 compared with I-125-ZCE025 on Days 1, 3, and 5, respectively. In contrast, I-125 distribution was not enhanced in any organs except the tumor. Vascular permeability studies demonstrated that the physiologic effect of IL-2 was tumor specific in the mice that received the I-125-ZCE025/IL-2 conjugate. CONCLUSIONS: These studies indicate that the administration of radiolabeled MoAb/IL-2 double conjugate may enhance the therapeutic potential of radiolabeled MoAb without any pretreatment with IL-2 or repeated injection of MoAb.
BACKGROUND: Some vasoactive drugs have been studied in the hope of altering the vascular permeability and/or blood of tumors to enhance monoclonal antibody (MoAb) uptake. The pretreatment of interleukin-2 (IL-2), one of the vasoactive reagents, produced a generalized vascular permeability, but its function was not tumor specific. Conversely, MoAb/IL-2 immunoconjugates were developed that selectively alter the vasopermeability of tumors. In the current study the authors evaluated whether radiolabeled anti-carcinoembryonic antigen (CEA) MoAb, ZCE025/IL-2 immunoconjugate, specifically can enhance delivery of iodine-125 (I-125) to tumor sites. METHODS:ZCE025 was conjugated with IL-2, and the conjugate then labeled with I-125. Biodistribution studies were performed in athymic mice bearing CEA-producing humantumor (MKN45) xenografts. Mice were injected with I-125-ZCE025/IL-2 conjugate, and I-125 activities in the organs, including blood and tumor, were investigated at 1, 3, and 5 days after injection. Vascular permeability of the organs, including tumors, also was studied by using I-131 labeled mouse serum albumin in three groups. RESULTS:I-125 labeled ZCE025/IL-2 conjugate destroyed its lymphokine-activated killer cell (LAK) activation, but retained a minimum of 75% of the antibody binding reactivity. Biodistribution of I-125-ZCE025/IL-2 conjugate showed increased uptake of I-125 in tumor by a factor of 1.5, 4.2, and 4.1 compared with I-125-ZCE025 on Days 1, 3, and 5, respectively. In contrast, I-125 distribution was not enhanced in any organs except the tumor. Vascular permeability studies demonstrated that the physiologic effect of IL-2 was tumor specific in the mice that received the I-125-ZCE025/IL-2 conjugate. CONCLUSIONS: These studies indicate that the administration of radiolabeled MoAb/IL-2 double conjugate may enhance the therapeutic potential of radiolabeled MoAb without any pretreatment with IL-2 or repeated injection of MoAb.
Authors: Julie K Jang; Leslie A Khawli; Ryan Park; Brian W Wu; Zibo Li; David Canter; Peter S Conti; Alan L Epstein Journal: Mol Cancer Ther Date: 2013-10-15 Impact factor: 6.261