Halperin7e_CH29

651

C H A P T E R 2 9  Radioimmunotherapy and Unsealed Radionuclide Therapy

The ideal target for RIT-targeting constructs would be one that is overexpressed on cancer cells, is uniformly expressed, is not found to any significant level in normal tissue, is not shed into the circulation, and exhibits an important role in tumor growth and progression. 10 TAAs, as the name implies, are antigens “associated” with tumors but are also present in normal tissue. True tumor-specific antigens have not yet been identified and utilized. Overexpression is necessary because typical targeting constructs require antigen densities ≥10 5 receptors on each cell for adequate targeting. A homogenous antigen expression is desired so that a uniform activity dis- tribution of the radionuclide will result. Nonuniform activity distributions (heterogeneity of antigen in target tissue being one potential cause) will significantly lower the effectiveness of RIT by subsequently resulting in nonuniform or heteroge- neous dose distributions. 11 This is particularly important for radionuclides with short path lengths of the emitted particles (i.e.,Auger and α -particle emitters). Radionuclides with longer path lengths, such as high-energy β -emitters, can partly over- come the problem of nonuniform dose distributions through the crossfire effect. If the target antigen is significantly shed into the circulation, the targeting construct may bind and “complex” with the antigen. This will result in a more rapid clearance of the RIT agent and a much less effective treat- ment. If the TAA has an important signaling role, then subse- quent binding of the targeting construct will most likely add to the cytotoxicity of the radionuclide because of the blockade or promotion of intracellular signaling, potentially resulting in disruption of growth pathways important for tumor growth. Some TAAs (receptors) will internalize when bound by the tar- geting construct. In truth, most receptors internalize, although they do so at different rates. A rapid internalization process will have an impact on the type of radionuclide that is selected and potentially on the delivery strategy of the RIT agent. A multitude of agents have been used as carriers (target- ing constructs) for the targeted delivery of radiation to can- cer. These consist of antibodies, antibody fragments, peptides, affibodies, aptamers, and nanostructures (i.e., liposomes, nanoparticles, microparticles, nanoshells, and minicells). By an exceedingly large margin, intact monoclonal anti- bodies (mAbs) have dominated the field of RIT as targeting constructs 12 (Fig. 29.1). In humans, there are five classes or isotypes of antibodies (IgA, IgD, IgE, IgG, and IgM). IgG is the most commonly used mAb for RIT because it is the most prev- alent antibody in serum and has the longest serum half-life, typically measured in weeks (~23 days). IgG is further divided into four subtypes, IgG 1–4 . IgG antibodies are large glycopro- tein macromolecules, with an atomic mass of approximately 150,000 dalton (Da) or 150 kDa. The “y-shaped structure” (Fig. 29.1A) consists of two Fab fragments (antigen-binding fragment; ~50,000 Da each) and an Fc fragment (crystalliz- able fragment; ~50,000 Da). The “tip” of each Fab fragment has a variable amino acid sequence, from one mAb to another. Accordingly, each tip is an antigen-binding site (ABS) and is responsible for antigen recognition. Each ABS forms a noncovalent bond (electro- static forces, van der Waals forces, hydrophobic interactions, and hydrogen bonds) with the target or antigen. The specific region of an antigen, which binds to the ABS, is referred to as an epitope. It has been proposed that a million or more different antibodies exist in various individuals. Theoretically, >10 9 different antibodies can be produced. The outer core of the mAb consists of two identical light chains (outer por- tion of the Fab fragment) designated with an “L.” The inner core, consisting of the Fc region and the inner Fab region, is designated as heavy or “H.” Both the light and heavy chains contain homologous, 110 amino acid sequences that fold on one another and are connected by a disulfide bridge, result- ing in “globular” motif or loop, called an Ig domain. There are three constant heavy domains (C H 1-3) and only one constant

libraries). SEREX involves a bacteriophage recombinant cDNA expression library, prepared from various malignancies (iso- lated tumors or malignant cell lines) or testis tissue. 9 This cDNA expression library is transduced in Escherichia coli to produce a recombinant protein library.These various proteins (clones) are then tested against the serum from autologous cancer patients. Clones that react to IgG antibodies are identified and are then further characterized as TAAs. Many of these SEREX-identified TAAs have been elucidated by other processes and laboratories. This has led to the concept of a finite number of TAAs that are produced in cancer patients and are potentially identified by the immune system.These finite TAAs are collectively referred to as the cancer immunome. SEREX-defined antigens, representing broad categories, may be organized as follows: mutational anti- gens, amplified or overexpressed antigens, differentiation anti- gens, and cancer/testis antigens.Within these categories, only a limited number of solid tumor TAAs have been used as targets for RIT (Table 29.1). TABLE 29.1  SELECT TUMOR ANTIGEN TARGETS AND MONOCLONAL ANTIBODIES EVALUATED FOR SOLID TUMOR RADIOIMMUNOTHERAPY Malignancy Antigen Antibody Colorectal cancer CEA

Section II

cT84.66, hMN-14, A5B7, TFT, IMP-288, CC49 B72.3, CC49, A33 huA33 NR-LU-10, NR-LU-13 chTNT-1/B F19

TAG-72 A33 EpCAM DNA histone H1 FAP

Breast cancer

MUC1 L6 TAG-72 CEA Lewis

huBrE3, M170 chL6 CC49 cT84.66 B3 HMFG-1 cMov18 B72.3, CC49 Hu3S193 chTNT-1/B CC49 cT84.66 U36, BIWA4 425 81C6, BC4 chTNT-1/B

Ovarian cancer

MUC1 Folate receptor TAG-72 Lewis

Prostate cancer

PSMA TAG-72 MUC1

huJ591, 7E11-C5.3, PSMA-617 CC49 M170

Lung cancer

DNA histone H1 TAG-72 CEA EGFR Tenascin-C DNA histone H1 p97 Ganglioside GD2 Melanin CD44v6 Ganglioside GD2 NCAM Tenascin-C Ganglioside GD2 4Ig-B7-H3 DNA/histone Ganglioside GD2 A33 CAIX/MN

Head and neck cancer

Glioblastoma

Melanoma

96.5 3F8 PTI-6D2 cG250

Renal cancer

Medullary thyroid cancer CEA

cT84.66, hMN-14, NP-4, F6-734, Labetuzumab

Neuroblastoma

3F8 UJ13 A, ERIC-1 81C6

Gastric

huA33

Brain tumors

3F8 8H9 chTNT-1/B

Medulloblastoma

3F8

CEA-producing tumors

CEA

M5A

Pancreatic cancer

MUC1

hPAM4

Leptomeningeal cancer

Ganglioside GD2

3F8

Gastrointestinal CC49 CAIX/MN, carbonic anhydrase IX; CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; FAP, fibroblast-activating protein; MUC1, mucin 1; NCAM, neural cell adhesion molecule; PSMA, prostate-specific membrane antigen; TAG-72, tumor-associated glycoprotein. Modified from Wong YC, Williams LE, Yazaki PJ. Radioimmunotherapy of colorectal cancer. In: Speer TW, ed. Targeted radionuclide therapy . Philadelphia: Lippincott Williams & Wilkins, 2011:325. With permission. TAG-72