Influence of protein properties and protein modification on biodistribution and tumor uptake of anticancer antibodies, antibody derivatives, and non‐Ig scaffolds

Abstract

Newly developed protein drugs that target tumor-associated antigens are often modified in order to increase their therapeutic effect, tumor exposure, and safety profile. During the development of protein drugs, molecular imaging is increasingly used to provide additional information on their in vivo behavior. As a result, there are increasing numbers of studies that demonstrate the effect of protein modification on whole body distribution and tumor uptake of protein drugs. However, much still remains unclear about how to interpret obtained biodistribution data correctly. Consequently, there is a need for more insight in the correct way of interpreting preclinical and clinical imaging data. Summarizing the knowledge gained to date may facilitate this interpretation. This review therefore provides an overview of specific protein properties and modifications that can affect biodistribution and tumor uptake of anticancer antibodies, antibody fragments, and nonimmunoglobulin scaffolds. Protein properties that are discussed in this review are molecular size, target interaction, FcRn binding, and charge. Protein modifications that are discussed are radiolabeling, fluorescent labeling drug conjugation, glycosylation, humanization, albumin binding, and polyethylene glycolation.

Mesothelin/CD3 Half-Life–Extended Bispecific T-Cell Engager Molecule Shows Specific Tumor Uptake and Distributes to Mesothelin and CD3-Expressing Tissues

“…The effect of increasing tumor affinity on tumor uptake is less straightforward (16). A theoretical peak in maximum uptake seems to exist, where a lower affinity will prevent accumulation, and increasing the affinity will hamper tumor penetration and accumulation (16,43). Therefore, we hypothesize that the extended half-life is mainly responsible for the increase in tumor uptake of the MSLN HLE BiTE compared to canonical BiTE molecules.…”

“…With the extended half-life of HLE BiTE molecules, less frequent Increasing the blood half-life of tumor-targeting antibody constructs raises the tumor uptake in mice (17). The effect of increasing tumor affinity on tumor uptake is less straightforward (16). A theoretical peak in maximum uptake seems to exist, where a lower affinity will prevent accumulation, and increasing the affinity will hamper tumor penetration and accumulation (16,43).…”

“…Currently, eight HLE BiTE molecules are in clinical trials of which four in solid tumors (NCT03319940, NCT03792841, NCT04117958, NCT04260191) (15). Increasing the half-life and molecular weight of a protein might influence the biodistribution and improve tumor targeting (16,17). There is little data regarding the biodistribution and tumor targeting of HLE BiTE molecules.…”

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

“…The major advantages of these radionuclide-based molecular imaging techniques (SPECT and PET) are that they are very sensitive (down to the picomolar level), quantitative, and there is no tissue penetration limit. As a result, new applications of brain molecular imaging in animals are continually being established, which show a correlation between brain uptake of radiolabeled antibodies and brain target levels [ 33 , 34 , 35 , 36 ]. Another advantage is that molecular imaging methods have good spatial resolution (0.35–1.5 mm), allowing differentiation of tracer uptake on the suborgan level.…”

Reaction of [18F]Fluoride at Heteroatoms and Metals for Imaging of Peptides and Proteins by Positron Emission Tomography

“…Additionally, the half-life of the radionuclide must also be adequate for the application and it is often matched to the biological half-life of the molecular probe. For example, larger biomolecules have slower pharmacokinetics and radionuclides with longer half-lives such as [ 68 Ga]gallium (67.7 min), [ 18 F]fluorine (110 min), [ 64 Cu]copper (12.7 h) and [ 124 I]iodine (4.18 days) are more suitable when they are to be used as imaging agents ( Tolmachev and Stone-Elander, 2010 ; Warnders et al, 2018 ). The properties of some radionuclides that decay via β + decay are illustrated in Table 1 ( Brookhaven National Laboratory ; Laboratoire National Henri Becquerel ; Le Loirec and Champion, 2007a ; Le Loirec and Champion, 2007b ; Le Loirec and Champion, 2007c ).…”