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Antibody-based Radionuclide Imaging
Published in Michael Ljungberg, Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
Steffie M.B. Peters, Erik H. J. G. Aarntzen, Sandra Heskamp
In order to accurately interpret PET/SPECT scans of patients administered with radiolabelled antibodies, it is essential to understand the in vivo behaviour of antibodies. Also, it is important to understand the in vivo fate of the radionuclide in case the antibody is catabolized or the radionuclide becomes detached from the antibody. The latter will be discussed in section 18.4.1. For molecular imaging, radiolabelled antibodies are generally administered intravenously, resulting in rapid systemic distribution via the bloodstream. Circulating radiolabelled antibodies are taken up by different cells followed by degradation or recycling. Radiolabelled antibodies can be rescued from intracellular catabolism through their interaction with the neonatal Fc-receptor (FcRn), which is expressed by endothelial cells lining blood vessels, hepatocytes, and several immune cells such as macrophages, monocytes, and dendritic cells [21, 22]. By binding to FcRn, the antibody is protected from lysosomal degradation, and it is released back in the extracellular space or blood stream. This is the key mechanism responsible for the long serum-half-life of radiolabelled antibodies [21, 23].
Biomolecular Assemblies as Multifunctional Drug Designs
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Albumin is an 66.5 kDa endogenous transport protein facilitated by its multiple ligand binding sites, broad tissue distribution and a long plasma half-life of approximately 19 days [7] due predominately to engagement with the cellular recycling neonatal Fc receptor (FcRn) [8, 9]. Its natural transport and long circulation properties are attractive features for drug delivery applications [10–12]. One approach is to increase the blood circulation of drugs that reversibly bind to the endogenous albumin pool by including natural ligands for albumin, for example fatty acids, into the drug design. Examples include the insulin analog detemir (Levemir®) [13]. As an alternative, the albumin/drug preformulation Abraxane® is an injectable nanoparticle albumin-bound paclitaxel system used in the treatment of cancer [14].
Microscopy Experiments
Published in Raimund J. Ober, E. Sally Ward, Jerry Chao, Quantitative Bioimaging, 2020
Raimund J. Ober, E. Sally Ward, Jerry Chao
In a similar experiment where wild-type IgG molecules were replaced with mutated IgG molecules that no longer bind to FcRn, live cell imaging reveals a very different behavior for IgG. The two sets of images in the bottom row of Fig. 9.8 show that the mutated IgG molecules primarily localize in the vacuoles of the FcRn-positive sorting endosomes. In contrast to the experiment with wild-type IgG, FcRn-positive tubules that leave the endosomes do not contain mutated IgGs. This difference in transport behavior corroborates the understanding that FcRn is indeed responsible for the transport of IgGs in cells. Sorting endosomes, in particular, appear to play a central role in the transport of IgG molecules in FcRn-expressing cells.
Challenges and advancements in the pharmacokinetic enhancement of therapeutic proteins
Published in Preparative Biochemistry & Biotechnology, 2021
Farnaz Khodabakhsh, Morteza Salimian, Mohammad Hossein Hedayati, Reza Ahangari Cohan, Dariush Norouzian
The main mechanisms involved in the rapid clearance of proteins include proteolysis by proteases, glomerular filtration from the kidney, and receptor-mediated clearance in the liver.[4] Proteases play a key role in many physiological and pathological conditions such as blood coagulation, food digestion, complement activation, and chronic inflammation in the body. These proteases are able to digest the administered therapeutic proteins, and therefore, influence theirs in vivo half-life. Detrimental effects of proteases are not limited to the circulation, but they could exert deleterious effects at the site of injection. This is because many therapeutic proteins are administrated via subcutaneous (s.c.) injections in addition to intravenous (i.v.) route. Other instabilities like the formation of aggregates at the site of injection reduce the bioavailability of the administrated protein. Many studies have been performed to decrease the deleterious effect of such proteases on the protein structure.[5] One approach is amino acid changes in the recognition site of proteases in the protein sequence such that these changes do not have any influence on the structure or function of the desired protein. However, this approach does not apply to all proteins because the introduction of mutations usually does not give predictable results.[6] However, when the protein reaches circulation, glomerular filtration and receptor-mediated hepatocyte uptake play significant roles in reducing the plasma level of administrated protein. It is known that the glomerulus pores are about 60 angstroms in diameter (∼70 kDa) and also have a negative charge due to the presence of anionic proteoglycans in the extracellular matrix of the base membrane. Since many therapeutic proteins, except monoclonal antibodies, have a small size, often less than 6 nanometers, they can easily pass from the glomerular capsule and subsequently released to the urine.[7] In contrast, larger proteins with a negative charge on the surface, like human serum albumin (HSA), are resistant to pass through kidney filtration. Besides the glomerular filtration, protein degradation also occurs in the liver. Hepatic clearance happens by the interaction between the sialoglycoprotein receptor existed on the hepatocyte cell membranes, which is followed by endocytosis and protein degradation.[8] In addition to the mentioned mechanisms, it has been demonstrated that an endosomal recycling process, called neonatal Fc receptor-mediated recycling, increases the plasma half-life of albumin and immunoglobulins in the circulation. In this mechanism, the protein strongly binds to neonatal Fc receptor (FcRn) at acidic conditions and is protected from the availability of lysosomes in the endosomal space. But when the pH increases to 7.4, the binding becomes weak and the bonded protein returns to the blood circulation.[9] In the next section, we will describe the strategies currently used for in vivo half-life extension of therapeutic proteins.