Immuno-Positron Emission Tomography with Zirconium-89-Labeled Monoclonal Antibodies in Oncology: What Can We Learn from Initial Clinical Trials?

Abstract

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.

Keywords: 89zirconium; clinical oncology; imaging biomarker; molecular imaging; monoclonal antibodies; positron emission tomography.

Figure 1

Dose-dependent biodistribution and clearance of ⁸⁹Zr-trastuzumab. Radioactivity in the blood pool and intestinal excretion are indicated by arrows. (A) Trastuzumab-naïve patient, imaging dose = 10 mg. (B) Trastuzumab-naïve patient, imaging dose = 50 mg. (C) Patient on trastuzumab treatment, imaging dose = 10 mg. Reprinted with permission from Dijkers et al. (2010).

Figure 2

Patterns of HER2-PET/CT confronted with FDG-PET/CT, maximum intensity projection. Lesion uptake was considered pertinent when visually higher than blood pool. (A) Entire tumor load showed pertinent tracer uptake. (B) Dominant part of tumor load showed tracer uptake. (C) Minor part of tumor load showed tracer uptake. (D) Entire tumor load lacked tracer uptake. Reprinted with permission from Gebhart et al. (2016).

Figure 3

⁸⁹Zr-huJ591-PET and conventional imaging modalities of a patient with rising prostate specific antigen. ^99mTc-MDP bone scan shows only a few lesions. FDG-PET shows nodal disease in the thorax, retroperitoneum, and pelvic region and a few bone lesions in the spine. Overall more bone lesions were seen on ⁸⁹Zr-huJ591-PET than on FDG-PET, including multiple lesions in vertebrae, pelvic bones, ribs, and humerus. Targeting was also seen to the retroperitoneal and pelvic lymph nodes by ⁸⁹Zr-huJ59-PET. (A) Anterior and posterior ^99mTc-MDP bone scan. (B) FDG-PET maximum intensity projection. (C)⁸⁹Zr-huJ591 PET. (D) FDG-PET sagittal fused image. (E) ⁸⁹Zr-hu J591 PET sagittal fused image. Reprinted with permission from Pandit-Taskar et al. (2014).

Figure 4

⁸⁹Zr-rituximab-PET images obtained 6 days after injection. (A) Patient 2 without B cell depletion, anterior view. (B) Patient 3 with B cell depletion, posterior view. Reprinted with permission from Muylle et al. (2015).