Preclinical evaluation of89Zr-labeled anti-CD44 monoclonal antibody RG7356 in mice and cynomolgus monkeys

• DOI: 10.4161/mabs.27415
• Publication Date: 2013-12-09T16:10:36Z
• Authors: Danielle J Vugts; Derrek A Heuveling; Marijke Stigter-v...; Stefan Weigand; Mats Bergstrom; Guus AMS van Dongen; Tapan K Nayak
• Keywords: Radioisotopes; Clinical Trials, Phase I as Topic; Carcinoma; Drug Evaluation, Preclinical; Antibodies, Monoclonal, Humanized; Xenograft Model Antitumor Assays; 3. Good health; Macaca fascicularis; Mice; 03 medical and health sciences; Hyaluronan Receptors; 0302 clinical medicine; Cell Line, Tumor; Animals; Humans; Tissue Distribution; Immunotherapy; Zirconium

RG7356 is a humanized antibody targeting the constant region of CD44. RG7356 was radiolabeled with (89)Zr 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 (89)Zr-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, (89)Zr-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 (89)Zr-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. (89)Zr-RG7356 uptake in these normal organs decreased with increasing dose levels of unlabeled RG7356. (89)Zr-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.