**9.1 Size**

Size is a factor that impacts the circulation time of antibodies. IgG antibodies are large proteins with a molecular weight of 150 kDa which limits the diffusion of the antibodies from the blood into the tumor, resulting in a heterogeneous intratumoral distribution. Furthermore, IgG antibodies are characterized by a long circulatory half-life in plasma for three to four days. Due to this slow clearance from the blood, tumor-to-background ratio is usually low. The primary concern for using radionuclide labeled IgG is that it remains in the blood for an extended period of time which continually exposes the highly sensitive red marrow to radiation resulting in dose-limiting myelosuppression. While intact mAbs are primarily catabolized by the liver and spleen, mAb fragments are mainly excreted via the kidneys, thereby increasing uptake in the kidneys and lead to increase consequently the kidney absorbed radiation dose. (Koppe et al., 2005). If radiometals are used as the radiolabel, they will accumulate in the hepatic parenchyma. The large size of an antibody impacts its ability to move through a tumor mass. The smaller forms of antibodies such as F(ab')2 or Fab fragments and more recently, molecularly engineered antibody subfragments with more favorable pharmacokinetic properties, are removed more rapidly from the blood, thereby improving tumor/blood ratio. There have been reports of improved therapeutic responses using smaller-sized antibodies, but these smaller entities frequently are cleared from the blood by renal filtration and as a result many radionuclides (eg, radiometals) become trapped in a higher concentration in the kidneys than in the tumor. Changes in the molecular size/structure of the IgG can also alter the normal tissue distribution, shifting uptake from the liver to the kidneys (Sharkey & Goldenberg, 2009). Reducing the size of antibody below the filtration threshold of kidneys (70 kDa), increases renal excretion and therefore decreases toxicity to this organ. Hence, being smaller molecules, antibodies are more suited to RIT and RIS with short circulation time, lower absolute localisation to the tumor and rapid excretion by the kidneys (Yazaki et al., 2001).
