Preclinical evaluation of 89Zr-labeled anti-CD44 monoclonal antibody RG7356 in mice and cynomolgus monkeys: Prelude to Phase 1 clinical studies |
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Authors: | Danielle J Vugts Derrek A Heuveling Marijke Stigter-van Walsum Stefan Weigand Mats Bergstrom Guus AMS van Dongen Tapan K Nayak |
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Institution: | 1.Department of Otolaryngology-Head and Neck Surgery; VU University Medical Center; Amsterdam, the Netherlands;2.Department of Radiology and Nuclear Medicine; VU University Medical Center; Amsterdam, the Netherlands;3.Discovery Oncology; Pharma Research and Early Development; Roche Diagnostics Gmb; Penzberg, Germany;4.Oncology Translational Imaging; Pharma Research and Early Development; F Hoffmann-La Roche Ltd; Basel, Switzerland |
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Abstract: | RG7356 is a humanized antibody targeting the constant region of CD44. RG7356 was radiolabeled with 89Zr for preclinical evaluations in tumor xenograft-bearing mice and normal cynomolgus monkeys to enable study of its biodistribution and the role of CD44 expression on RG7356 uptake.
Studies with 89Zr-RG7356 were performed in mice bearing tumor xenografts that differ in the level of CD44 expression (CD44+ or CD44-) and RG7356 responsiveness (resp or non-resp): MDA-MB-231 (CD44+, resp), PL45 (CD44+, non-resp) and HepG2 (CD44–, non-resp). Immuno-PET whole body biodistribution studies were performed in normal cynomolgus monkeys to determine normal organ uptake after administration of a single dose.
At 1, 2, 3, and 6 days after injection, 89Zr-RG7356 uptake in MDA-MB-231 (CD44+, resp) xenografts was nearly constant and about 9 times higher than in HepG2 (CD44–, non-resp) xenografts (range 27.44 ± 12.93 to 33.13 ± 7.42% ID/g vs. 3.25 ± 0.38 to 3.90 ± 0.58% ID/g). Uptake of 89Zr-RG7356 was similar in MDA-MB-231 (CD44+, resp) and PL45 (CD44+, non-resp) xenografts. Studies in monkeys revealed antibody uptake in spleen, salivary glands and bone marrow, which might be related to the level of CD44 expression. 89Zr-RG7356 uptake in these normal organs decreased with increasing dose levels of unlabeled RG7356.89Zr-RG7356 selectively targets CD44+ responsive and non-responsive tumors in mice and CD44+ tissues in monkeys. These studies indicate the importance of accurate antibody dosing in humans to obtain optimal tumor targeting. Moreover, efficient binding of RG7356 to CD44+ tumors may not be sufficient in itself to drive an anti-tumor response. |
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Keywords: | CD44 89Zr-immuno-PET RG7356 |
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