PET imaging of HER1-expressing xenografts in mice with 86Y-CHX-A''-DTPA-cetuximab.
OBJECTIVE
Cetuximab is a recombinant, human/mouse chimeric IgG(1) monoclonal antibody that binds to the epidermal growth factor receptor (EGFR/HER1). Cetuximab is approved for the treatment of patients with HER1-expressing metastatic colorectal cancer. Limitations in currently reported radiolabeled cetuximab for PET applications prompted the development of (86)Y-CHX-A''-DTPA-cetuximab as an alternative for imaging HER1-expressing cancer. (86)Y-CHX-A''-DTPA-cetuximab can also serve as a surrogate marker for (90)Y therapy.


METHODS
Bifunctional chelate, CHX-A''-DTPA was conjugated to cetuximab and radiolabeled with (86)Y. In vitro immunoreactivity was assessed in HER1-expressing A431 cells. In vivo biodistribution, PET imaging and noncompartmental pharmacokinetics were performed in mice bearing HER1-expressing human colorectal (LS-174T and HT29), prostate (PC-3 and DU145), ovarian (SKOV3) and pancreatic (SHAW) tumor xenografts. Receptor blockage was demonstrated by coinjection of either 0.1 or 0.2 mg cetuximab.


RESULTS
(86)Y-CHX-A''-DTPA-cetuximab was routinely prepared with a specific activity of 1.5-2 GBq/mg and in vitro cell-binding in the range 65-75%. Biodistribution and PET imaging studies demonstrated high HER1-specific tumor uptake of the radiotracer and clearance from nonspecific organs. In LS-174T tumor-bearing mice injected with (86)Y-CHX-A''-DTPA-cetuximab alone, (86)Y-CHX-A''-DTPA-cetuximab plus 0.1 mg cetuximab or 0.2 mg cetuximab, the tumor uptake values at 3 days were 29.3 +/- 4.2, 10.4 +/- 0.5 and 6.4 +/- 0.3%ID/g, respectively, demonstrating dose-dependent blockage of the target. Tumors were clearly visualized 1 day after injecting 3.8-4.0 MBq (86)Y-CHX-A''-DTPA-cetuximab. Quantitative PET revealed the highest tumor uptake in LS-174T (29.55 +/- 2.67%ID/cm(3)) and the lowest tumor uptake in PC-3 (15.92 +/- 1.55%ID/cm(3)) xenografts at 3 days after injection. Tumor uptake values quantified by PET were closely correlated (r (2) = 0.9, n = 18) with values determined by biodistribution studies.


CONCLUSIONS
This study demonstrated the feasibility of preparation of high specific activity (86)Y-CHX-A''-DTPA-cetuximab and its application for quantitative noninvasive PET imaging of HER1-expressing tumors. (86)Y-CHX-A''-DTPA-cetuximab offers an attractive alternative to previously labeled cetuximab for PET and further investigation for clinical translation is warranted.
Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. tapann@gmail.com
Tapan K
TK
Nayak
Celeste A S
CA
Regino
Karen J
KJ
Wong
Diane E
DE
Milenic
Kayhan
K
Garmestani
Kwamena E
KE
Baidoo
Lawrence P
LP
Szajek
Martin W
MW
Brechbiel
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D000068818:Cetuximab; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017879:Isothiocyanates / Q000737:chemistry*; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D015021:Yttrium Radioisotopes
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017879:Isothiocyanates; D015021:Yttrium Radioisotopes; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D004369:Pentetic Acid; D066246:ErbB Receptors; D000068818:Cetuximab