**8.1 Radionuclides for treatment**

180 12 Chapters on Nuclear Medicine

Positron emission tomography is a nuclear medicine technique that produces high resolution tomographic imaging through the detection of high energy photon pairs emitted during positron decay (Costelloeet al., 2009). This method was initially developed in 1960s, but has largely been used as a research tool. However, PET can provide useful information for clinical practice. The images generated by PET represent the metabolic activity of the underlying tissues and can therefore distinguish benign from malignant lesions on the basis of differences in metabolic activity. Similarly, it can identify recurrent diseases in areas in which conventional scans are difficult to interpret because of prior treatment (Costelloeet al., 2009). PET represents the most advanced imaging technique, because it not only allows a three-dimensional image reconstruction, but also it can quantify the activity uptake (Fass, 2008). It combines the highest degree of sensitivity with a resolution of currently, 5-7 mm. The principal applied radionuclide for PET is Fluor-18 (18F) which is known for its ideal half-life to manage (1.83 h). The development of radiopharmaceutical [2-18F]-2-fluoro-2 deoxyglucose (18FDG) has been so far an important progress for PET imaging in oncology (Berghammer et al., 2001). 18FDG acts as a glucose analogue allowing for the visualization of glucose consumption, a metabolic process being massively enhanced in many malignancies (Einat & Moshe, 2010). PET has several advantages include (1) unlimited depth penetration; (2) whole body imaging possible, (4) quantitative molecular imaging and (5) can be combined with CT or MRI for anatomical information (Pysz et al., 2010). The disadvantage of PET is that it requires a conveniently located and expensive cyclotron and radiochemistry facilities to produce the short-half life isotopes and to incorporate these into

The first theory on the existence of proteins with specific binding capabilities to pathogenic organisms, thus acting as "magic bullet"', was postulated at the end of the 19th century by the german pathologist Paul Ehrlich (Enelich, 1906). He was the first to recognise antibodies for their ability to differentiate between normal cells and transformed malignant cells. He specifically introduced immunotherapy as a potential treatment modality for targeting and treating tumors. After it had been recognized in 1950 that proteins could be labeled with 131I without significantly altering their immunological specificity (Eisen & Keston, 1950), Pressman and Korngold tested the tumor-targeting potential of a 131I-labeled rabbit antiserum in rats bearing osteosarcoma and confirmed preferential antibody uptake in the tumor xenografts (Pressman & Korngold, 1953). The first clinical trial investigated the therapeutic efficacy of radiolabeled antibodies was performed in the 1950s by Beierwaltes, who treated fourteen patients with metastatic melanoma with 131I-labeled rabbit antibodies and reported a pathologically confirmed remission in one patient (Beierwaltes, 1974). In 1965, Gold and Freedman discovered carcinoembryonic antigen (CEA), the first well defined tumor-associated antigen. The purified polyclonal anti-CEA antibodies were shown to localize to CEA expressing tumors in vivo (Gold & Freedman, 1965). In the late 1970s, Goldenberg and colleagues successfully targeted colon cancer in patients using a polyclonal goat anti-CEA antiserum (Goldenberg et al., 1978). Nowadays, CEA has not only become one of the most extensively used tumor markers in clinical oncology, but also due to its pronounced expression in various carcinomas, it is one of the most targeted antigens in RIT. In 1975, Köhler and Milstein reformed the field of radioimmunotargeting as they introduced the hybridoma

**7.2.3 Positron emission tomography (PET)** 

suitable probe molecules (Fass, 2008).

**8. Radioimmunotherapy** 

The selection of a radionuclide for cancer treatments depends on several parameters including:


Three main categories of radionuclides have been investigated for their potential therapeutic characterisation in radioimmunotherapy including β-particle emitters, α-particle emitters and auger electron cascades.

#### **1. β-particle emitters**

So far, the vast majority of preclinical and clinical studies have been made to use β-emitting radionuclides such as 131I, 90Y, 186Re and 188Re. These radionuclides have a tissue range of about several millimeters. This can create a ''cross fire'' effect, so that antigen or receptor negative cells in a tumor can also be treated. High energy B-particles are not efficient for killing of single disseminated cells or small metastases. So, β-particle therapy is preferred for large tumors (Boswell & Brechbiel, 2007).

Breast Cancer: Radioimmunoscintigraphy and Radioimmunotherapy 183

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

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

The antibody affinity is a measure of the strength of binding of an individual antibody binding site to a single antigenic site. This can be considered as the sum of all the non-covalent interactions between antibody and antigen involved in the binding reaction. However, antibody molecules usually have more than one binding site and many antigens contain more than one antigenic site and therefore multivalent binding may be possible. The strength with which a multivalent antibody binds to an antigen, is termed avidity. Although high affinity is a requirement for good tumor localization, there seems to be a point at which further increases in affinity do not increase uptake at the target site (Schlomet al., 1992; Colcher et al., 1988). Indeed, reduced tumor uptake and limitations on penetration of antibody into the tumor

Although this conceptually simple technique has been investigated and refined for almost 50 years, it still has inherent limitations. In the present part, the problems of imaging and therapy of breast cancer by radioimmunoscintigraphy and radioimmnotherapy methods are discussed.

tissue can result from the increasing of antibody affinity (Dearling & Pedley, 2007).

**10. Technical limitations of radioimmunoscintigraphy and** 

tumor and rapid excretion by the kidneys (Yazaki et al., 2001).

**9.2 Immunogenicity** 

multiple doses in all patients (Pagel, 2009).

**9.3 Affinity and avidity** 

**radioimmunotherapy** 
