**9.2 Immunogenicity**

182 12 Chapters on Nuclear Medicine

Radionuclides emitting α-particles such as 225Ac (half-life 10 days), 211At (half-life 7.2 h), 212Bi (half-life 60.55 min) and 213Bi (half-life 45.6 min) are options for treatment of small tumor nests or single disseminated tumor cells. Alfa particle emitting radionuclides are short ranged, high-energy helium nuclei with a high linear energy transfer (LET). As a consequence, α-emitters have a high relative biological effectiveness (RBE) which means, if

Auger-electrons, discovered by Lise Meitner in 1922 and by Pierre Auger in 1923, are formed when the vacancy created in an inner shell is filled with an electron from a higher energy level after electron capture. Auger-electrons have high LET Like α-particles (Cornelissen & Vallis, 2010). Auger-electron emitters, like 125I, deposit a concentrated amount of energy in even shorter distances than α-emitters. This means that these radionuclides need to be located in the vicinity of the tumor cell nucleus to be effective. For this reason, antibodies labeled with auger-emitting radionuclides need to target the entire

nuclear localisation is possible, fewer radionuclides per cell are needed (Fass, 2009).

**9. Improving the properties of antibody in radioimmunoscintigraphy and** 

Several investigations using different radionuclides, engineered antibodies and methods to increase antibody accumulation and penetration are currently being evaluated and have so far shown promising results. The main properties of antibodies that have been manipulated

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

tumor cell population for efficient therapy (Cornelissen & Vallis, 2010).

to optimize efficacy are size, immunogenicity, affinity and avidity.

**2. α-particle emitters** 

**3. Auger electron cascades** 

**radioimmunotherapy** 

**9.1 Size** 

The first mAbs being investigated for RIS and RIT were murine antibodies which can provoke an immune response in human beings. HAMA inactivate and eliminate murine antibodies after repeated administration. The formation of antibody-HAMA complexes also leads to the allergic-like HAMA response. In this way, therapeutic benefit of murine mAbs is limited by their side effect profile, short serum half-life and inability to trigger human immune effector functions. In order to reduce the immunogenicity of antibodies, chimeric antibodies were designed by combining constant domains of human antibodies with variable regions of murine antibodies (Carlssona et al., 2003). However, chimeric mAbs minimize the immunogenic content, trigger the immunologic efficiency and allow a prolonged serum half-life in comparison with murine mAbs. As a further advancement of chimeric mAbs, in 1986, Jones first reported the production of humanized monoclonal antibodies (Jones et al., 1986). Humanized antibodies are almost completely of human origin with only the complementarity determining regions (CDRs) being murine. To completely avoid the risk of immunogenicity, further developments have led to the production of fully human antibodies that contain 100% human proteins. For the development of fully human mAbs, phage display technology and genetically engineered mice are the key techniques that have been widely used to link genotype and phenotype. Immunosuppressive agents have been investigated to reduce HAMA. Low-dose cyclosporin, as used with a highly immunogenic antibody, was unable to significantly reduce HAMA following murine CC49 delivery. Thus, cyclosporin may have some efficacy in reducing immunogenicity of murine antibodies in patients, but does not appear to be sufficient to permit administration of multiple doses in all patients (Pagel, 2009).
