Preclinical evaluation of 89Zr-labeled anti-CD44 monoclonal antibody RG7356 in mice and cynomolgus monkeys: Prelude to Phase 1 clinical studies.
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.
Department of Otolaryngology-Head and Neck Surgery; VU University Medical Center; Amsterdam, the Netherlands; Department of Radiology and Nuclear Medicine; VU University Medical Center; Amsterdam, the Netherlands.
Danielle J
DJ
Vugts
Department of Otolaryngology-Head and Neck Surgery; VU University Medical Center; Amsterdam, the Netherlands.
Derrek A
DA
Heuveling
Department of Otolaryngology-Head and Neck Surgery; VU University Medical Center; Amsterdam, the Netherlands.
Marijke
M
Stigter-van Walsum
Discovery Oncology; Pharma Research and Early Development; Roche Diagnostics Gmb; Penzberg, Germany.
Stefan
S
Weigand
Oncology Translational Imaging; Pharma Research and Early Development; F Hoffmann-La Roche Ltd; Basel, Switzerland.
Mats
M
Bergstrom
Department of Otolaryngology-Head and Neck Surgery; VU University Medical Center; Amsterdam, the Netherlands; Department of Radiology and Nuclear Medicine; VU University Medical Center; Amsterdam, the Netherlands.
Guus A M S
GA
van Dongen
Oncology Translational Imaging; Pharma Research and Early Development; F Hoffmann-La Roche Ltd; Basel, Switzerland.
Tapan K
TK
Nayak
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007167:Immunotherapy / Q000379:methods*; D008252:Macaca fascicularis; D051379:Mice; D011868:Radioisotopes / Q000737:chemistry*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium / Q000737:chemistry*
D061067:Antibodies, Monoclonal, Humanized; D018960:Hyaluronan Receptors; C576196:RG7356; D011868:Radioisotopes; D015040:Zirconium
89Zr-immuno-PET; CD44; RG7356