Zirconium-89 labeled panitumumab: a potential immuno-PET probe for HER1-expressing carcinomas

Introduction: Anti-HER1 monoclonal antibody (mAb), panitumumab (Vectibix) is a fully human mAb approved by the FDA for the treatment of epidermal growth factor receptor (EGFR, HER1)-expressing colorectal cancers. By combining the targeted specificity of panitumumab with the quantitative in vivo imaging capabilities of PET, we evaluated the potential of Zr-89-DFO-panitumumab PET/CT imaging and performed non-invasive, in vivo imaging of HER1 expression and estimated human dosimetry. Methods: Panitumumab was radiolabeled with Zr-89 using a derivative of desferrioxamine (DFO-Bz-NCS) and with In-111 using CHX-A" DTPA as bifunctional chelators. Comparative biodistribution/dosimetry of both radiotracers was performed in non-tumor bearing athymic nude mice (n=2 females and n=2 males) over 1-week following i.v. injection of either using Zr-89-DFO-panitumumab or In-111-CHX-A"-DTPA-panitumumab. Micro-PET/CT imaging of female athymic nude mice bearing human breast cancer tumors (n=5 per tumor group) with variable HER1-expression very low (BT-474), moderate (MDA-MB-231), and very high (MDA-MB-468) was performed at over 1 week following i.v. injection of Zr-89-DFO-panitumumab. Results: Radiochemical yield and purity of Zr-89-Panitumumab was >70% and >98% respectively with specific activity 150 +/- 10 MBq/mg of panitumumab in a similar to 4 hr synthesis time. Biodistribution of In-111-CHX-A" DTPA-panitumumab and Zr-89-DFO-panitumumab in athymic non-tumor bearing nude mice displayed similar percent injected dose per gram of tissue with prominent accumulation of both tracers in the lymph nodes, a known clearance mechanism of panitumumab. Also exhibited was prolonged blood pool with no evidence of targeted accumulation in any organ. Human radiation dose estimates showed similar biodistributions with estimated human effective doses of 0.578 and 0.183 mSv/MBq for Zr-89-DFO-panitumumab and In-111-CHX-A"DTPA-panitumumab, respectively. Given the potential quantitative and image quality advantages of PET, imaging of tumor bearing mice was only performed using Zr-89-DFO-panitumumab. Immuno-PET imaging of Zr-89-DFO-panitumumab in mice bearing breast cancer xenograft tumors with variable HER1 expression showed high tumor uptake (SUV >7) in the MDA-MB-468 high HER1-expressing mice and a strong correlation between HER1-expression level and tumor uptake (R-2 = 0.857, P < .001). Conclusions: Zr-89-DFO-panitumumab can prepared with high radiochemical purity and specific activity. Zr-89-DFO-panitumumab microPET/CT showed uptake corresponding to HER-1 expression. Due to poor clearance, initial dosimetry estimates suggest that only a low dose Zr-89-DFO-panitumumab shows favorable human dosimetry; however due to high tumor uptake, the use of Zr-89-DFO-panitumumab is expected to be clinically feasible. Published by Elsevier Inc.