Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

Abstract

Abstract. Molecular imaging techniques for protein therapeutics rely on reporter labels, especially radionuclides or sometimes near-infrared fluorescent moieties, which must be introduced with minimal perturbation of the protein's function in vivo and are detected non-invasively during whole-body imaging. PET is the most sensitive whole-body imaging technique available, making it possible to perform biodistribution studies in humans with as little as 1 mg of injected antibody carrying 1 mCi (37 MBq) of zirconium-89 radiolabel. Different labeling chemistries facilitate a variety of optical and radionuclide methods that offer complementary information from microscopy and autoradiography and offer some trade-offs in whole-body imaging between cost and logistic difficulty and image quality and sensitivity (how much protein needs to be injected). Interpretation of tissue uptake requires consideration of label that has been catabolized and possibly residualized. Image contrast depends as much on background signal as it does on tissue uptake, and so the choice of injected dose and scan timing guides the selection of a suitable label and helps to optimize image quality. Although only recently developed, zirconium-89 PET techniques allow for the most quantitative tomographic imaging at millimeter resolution in small animals and they translate very well into clinical use as exemplified by studies of radiolabeled antibodies, including trastuzumab in breast cancer patients, in The Netherlands.

Preclinical Development of an anti-5T4 Antibody–Drug Conjugate: Pharmacokinetics in Mice, Rats, and NHP and Tumor/Tissue Distribution in Mice

“…The same can be said for imaging studies which used a variety of probes (e.g., IR800 or 89 Zr). 23,24 A notable exception is the work by Alley et al using both double labeled methods ( 3 H antibody and a 14 C labeled MMAF payload) and more recently Cohen et al ( 89 Zr on the traztuzumab antibody and 131 I on the tubulysin payload) that allows for distinction of the payload-related distribution from that of the antibody. 9,25 Although the dual radiolabeled approach is an important tool, the ability to use LC-MS/MS methodology for payload distribution assessment is flexible and has the potential to be utilized in the discovery and screening side of ADC development as well as any potential clinical applicability.…”

Theranostics Using Antibodies and Antibody-Related Therapeutics

“…Selecting a suitable radionuclide generally starts by matching the serum half-life of the mAb or antibodyrelated therapeutic and the physical half-life of the radionuclide. This step is essential to ensure that radioactivity can be detected long enough for the drug to reach its target while minimizing the duration of exposure to harmful radiation (6). The serum half-life mainly depends on the structure and size of the mAb or antibody-related therapeutic.…”

Superfluorinated PEI Derivative Coupled with 99mTc for ASGPR Targeted 19F MRI/SPECT/PA Tri‐Modality Imaging

“…[25][26][27] 99m Tc is the most widely used radioisotope for SPECT imaging because of its ideal physical properties (Half-life: 6.02 h, γ-Energy: 141 keV (89 %)) and easy availability by a generator system. [28,29] In general, reduced 99m Tc can be combined with a bifunctional chelating agent, such as DTPA (diethylenetriaminepentaacetic acid) and HYNIC (2-hydrazinonicotinic acid), or other chemical groups (such as COO − , OH, NH 2 , and SH). PEI is known for its potential in eliminating metal ions from wastewater by coordination of metal ions with secondary or tertiary amino groups in PEI.…”