The Role of ⁸⁹Zr-Immuno-PET in Navigating and Derisking the Development of Biopharmaceuticals

Abstract

The identification of molecular drivers of disease and the compelling rise of biotherapeutics have impacted clinical care but have also come with challenges. Such therapeutics include peptides, monoclonal antibodies, antibody fragments and nontraditional binding scaffolds, activatable antibodies, bispecific antibodies, immunocytokines, antibody-drug conjugates, enzymes, polynucleotides, and therapeutic cells, as well as alternative drug carriers such as nanoparticles. Drug development is expensive, attrition rates are high, and efficacy rates are lower than desired. Almost all these drugs, which in general have a long residence time in the body, can stably be labeled with 89 Zr for whole-body PET imaging and quantification.Although not restricted to monoclonal antibodies, this approach is called 89 Zr-immuno-PET. This review summarizes the state of the art of the technical aspects of 89 Zr-immuno-PET and illustrates why it has potential for steering the design, development, and application of biologic drugs. Appealing showcases are discussed to illustrate what can be learned with this emerging technology during preclinical and especially clinical studies about biologic drug formats and disease targets. In addition, an overview of ongoing and completed clinical trials is provided. Although 89 Zr-immuno-PET is a young tool in drug development, its application is rapidly expanding, with first clinical experiences giving insight on why certain drugtarget combinations might have better perspectives than others.

Hydroxypyridinones as a Very Promising Platform for Targeted Diagnostic and Therapeutic Radiopharmaceuticals

“…As a result, 67 Ga was once widely used in nuclear medicine, but it is not an ideal radionuclide for diagnostic imaging. The reason is that its γ photons abundance, suitable for imaging, is quite low compared to 111 In, i.e., to achieve the same γ photon detection efficiency, the amount of 67 Ga used must be three times that of 111 In.…”

“…Radiopharmaceuticals can be small molecule compounds or radiolabeled biological macromolecules, such as antibodies. Zevalin ( 111 In-and 90 Y-ibritumomab tiuxetan) is a monoclonal antibody drug that has been approved by the FDA for the diagnosis and treatment of non-Hodgkin's lymphoma (NHL) [3]. Because monoclonal antibodies have high specificity for certain antigens, they can be used as therapeutic drugs for tumors and other diseases, such as the serious COVID-19 epidemic (coronavirus disease 2019).…”

Specific and Nonspecific Uptake in Quantitative 89Zr-Immuno-PET

“…In a recent review, Van Dongen et al illustrated why 89 Zr-immuno-PET has become an important tool for the in vivo characterization of novel biological drugs and their targets (1). A technical State of the Art summarized PET quantification of 89 Zr-tracer uptake, stressing that total-tissue uptake results from a target-specific and a non-specific contribution.…”

“…This description is fully in line with a previous study co-authored by van Dongen, using Patlak analysis in normal tissues (kidneyliver-lung-spleen) without known target expression for four 89 Zr-labeled mAbs, respectively (2). Van Dongen et al thus suggested that future quantitative 89 Zr-immuno-PET studies should consider multiple-time-point acquisitions to assess non-specific-uptake versus time, with at least three late time-points, and that sophisticated modelling strategies should be developed (1,2).…”

“…We believe that this suggestion warrants further comments that might be helpful for anticipating quantitative 89 Zr-immuno-PET studies in tumors, designed for assessing in-vivo target engagement. First, the non-specific-irreversible uptake should be quantitatively compared to the total-tumor uptake, in order to actually determine whether it might be significant or negligible (1,2). To justify this proposal, let us consider recent results about -3B, respectively), Patlak analysis provides a total-tumor K i of 0.0289 mL⋅g -1 ⋅h -1 (R 2 =0.9993).…”