Page 162 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer
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Chapter 8
tumors as well as cancer stem cells and has a role in cell proliferation, migration and angiogenesis. This target antigen has been considered attractive for immunotherapy (6), as blocking inhibits tumor growth and metastatic potential (7,8). A preclinical dose-escalation study with 89Zr-labeled RG7356 confirmed tumor targeting of CD44+ tumors in xenografts bearing mice. Since RG7356 is not cross-reactive with murine CD44, studies in mice do not provide any information regarding accessible binding sites in physiologically normal organs. Assessment of biodistribution in cynomolgus monkeys showed uptake in normal CD44+ tissues, for example spleen and bone marrow (9). Subsequently, a first-in-human phase I dose-escalation trial was performed in patients with advanced, CD44-expressing solid tumors, showing that RG7356 was well tolerated with modest clinical efficacy (10). PET imaging with 89Zr-labeled RG7356 was performed to assess biodistribution and tumor uptake of RG7356 in a subgroup (13 of 65 patients) of this phase I trial. The previous publication on the main trial (10) included the background of the antigen and antibody as well as a brief summary of visual assessment of the imaging subgroup. 89Zr-RG7356 was localized to spleen, bone marrow and liver, while tumor accumulation of 89Zr-RG7356 with co- administration of unlabeled antibody (≥ 199mg), suggesting that the modest efficacy was not related to poor drug delivery to the tumor perse (10). In the current study, we separately report on the exploratory imaging sub-study with 89Zr-labeled RG7356 by performing quantitative analysis of the imaging data.
The aim of this study was to quantify biodistribution and tumor uptake of 89Zr-RG7356, and to evaluate whether uptake of 89Zr-RG7356 in normal tissues was dose-dependent as indication of target-mediated specific uptake. With this example, we aim to provide a general approach for application of immuno-PET to evaluate new drug-target-combinations in first-in-human studies.
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