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Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®.

ABSTRACT: PURPOSE:The chimeric monoclonal antibody (mAb) chDAB4 (APOMAB®) targets the Lupus associated (La)/Sjögren Syndrome-B (SSB) antigen, which is over-expressed in tumors but only becomes available for antibody binding in dead tumor cells. Hence, chDAB4 may be used as a novel theranostic tool to distinguish between responders and nonresponders early after chemotherapy. Here, we aimed to ascertain which positron emitter, Zirconium-89 ([89Zr]ZrIV) or Iodine-124 ([124I]I), was best suited to label chDAB4 for post-chemotherapy PET imaging of tumor-bearing mice and to determine which of two different bifunctional chelators provided optimal tumor imaging by PET using [89Zr]ZrIV-labeled chDAB4. METHODS:C57BL/6?J mice bearing subcutaneous syngeneic tumors of EL4 lymphoma were either untreated or given chemotherapy, then administered radiolabeled chDAB4 after 24?h with its biodistribution examined using PET and organ assay. We compared chDAB4 radiolabeled with [89Zr] ZrIV or [124I] I, or [89Zr]Zr-chDAB4 using either DFO-NCS or DFOSq as a chelator. RESULTS:After chemotherapy, [89Zr]Zr-chDAB4 showed higher and prolonged mean (± SD) tumor uptake of 29.5?±?5.9 compared to 7.8?±?1.2 for [124I] I -chDAB4. In contrast, antibody uptake in healthy tissues was not affected. Compared to DFO-NCS, DFOSq did not result in significant differences in tumor uptake of [89Zr]Zr-chDAB4 but did alter the tumor:liver ratio in treated mice 3?days after injection in favour of DFOSq (8.0?±?1.1) compared to DFO-NCS (4.2?±?0.7). CONCLUSION:ImmunoPET using chDAB4 radiolabeled with residualizing [89Zr] ZrIV rather than [124I] I optimized post-chemotherapy tumor uptake. Further, PET imaging characteristics were improved by DFOSq rather than DFO-NCS. Therefore, the radionuclide/chelator combination of [89Zr] ZrIV and DFOSq is preferred for the imminent clinical evaluation of chDAB4 as a selective tumor cell death radioligand.

SUBMITTER: Liapis V

PROVIDER: S-EPMC7672150 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®.

Liapis Vasilios V Tieu William W Rudd Stacey E SE Donnelly Paul S PS Wittwer Nicole L NL Brown Michael P MP Staudacher Alexander H AH

EJNMMI radiopharmacy and chemistry 20201117 1

<h4>Purpose</h4>The chimeric monoclonal antibody (mAb) chDAB4 (APOMAB®) targets the Lupus associated (La)/Sjögren Syndrome-B (SSB) antigen, which is over-expressed in tumors but only becomes available for antibody binding in dead tumor cells. Hence, chDAB4 may be used as a novel theranostic tool to distinguish between responders and nonresponders early after chemotherapy. Here, we aimed to ascertain which positron emitter, Zirconium-89 ([<sup>89</sup>Zr]Zr<sup>IV</sup>) or Iodine-124 ([<sup>124< ...[more]

PMID: 33205364

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Project description:Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using zirconium-89 ((89)Zr)-labeled monoclonal antibodies also known as (89)Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs. This technique provides a potential imaging biomarker to assess target expression, as well as tumor targeting of mAbs. In this review we summarize results from initial clinical trials with (89)Zr-immuno-PET in oncology and discuss technical aspects of trial design. In clinical trials with (89)Zr-immuno-PET two requirements should be met for each (89)Zr-labeled mAb to realize its full potential. One requirement is that the biodistribution of the (89)Zr-labeled mAb (imaging dose) reflects the biodistribution of the drug during treatment (therapeutic dose). Another requirement is that tumor uptake of (89)Zr-mAb on PET is primarily driven by specific, antigen-mediated, tumor targeting. Initial trials have contributed toward the development of (89)Zr-immuno-PET as an imaging biomarker by showing correlation between uptake of (89)Zr-labeled mAbs on PET and target expression levels in biopsies. These results indicate that (89)Zr-immuno-PET reflects specific, antigen-mediated binding. (89)Zr-immuno-PET was shown to predict toxicity of RIT, but thus far results indicating that toxicity of mAbs or mAb-drug conjugate treatment can be predicted are lacking. So far, one study has shown that molecular imaging combined with early response assessment is able to predict response to treatment with the antibody-drug conjugate trastuzumab-emtansine, in patients with human epithelial growth factor-2 (HER2)-positive breast cancer. Future studies would benefit from a standardized criterion to define positive tumor uptake, possibly supported by quantitative analysis, and validated by linking imaging data with corresponding clinical outcome. Taken together, these results encourage further studies to develop (89)Zr-immuno-PET as a predictive imaging biomarker to guide individualized treatment, as well as for potential application in drug development.

Project description:IntroductionAnti-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 (89)Zr-DFO-panitumumab PET/CT imaging and performed non-invasive, in vivo imaging of HER1 expression and estimated human dosimetry.MethodsPanitumumab was radiolabeled with (89)Zr using a derivative of desferrioxamine (DFO-Bz-NCS) and with (111)In 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 (89)Zr-DFO-panitumumab or (111)In-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 (89)Zr-DFO-panitumumab.ResultsRadiochemical yield and purity of (89)Zr-Panitumumab was >70% and >98% respectively with specific activity 150 ± 10 MBq/mg of panitumumab in a ~4 hr synthesis time. Biodistribution of (111)In-CHX-A" DTPA -panitumumab and (89)Zr-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 (89)Zr-DFO-panitumumab and (111)In-CHX-A"-DTPA-panitumumab, respectively. Given the potential quantitative and image quality advantages of PET, imaging of tumor bearing mice was only performed using (89)Zr-DFO-panitumumab. Immuno-PET imaging of (89)Zr-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(89)Zr-DFO-panitumumab can prepared with high radiochemical purity and specific activity. (89)Zr-DFO-panitumumab microPET/CT showed uptake corresponding to HER-1 expression. Due to poor clearance, initial dosimetry estimates suggest that only a low dose (89)Zr-DFO-panitumumab shows favorable human dosimetry; however due to high tumor uptake, the use of (89)Zr-DFO-panitumumab is expected to be clinically feasible.

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Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®.

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Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®.

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