Introduction and Background

The advent of the hybridoma, described by Kohler and Milstein, resurrected the concept put forth by Ehrlich a century ago: antibodies might serve as "magic bullets" (Ehrlich et al. 1904). Their seminal publication described the fusion of a plasmacytoma with spleen cells and the subsequent isolation of hybrids that secreted monoclonal antibodies of a pre-defined specificity. Such work was a clear step towards the development of targeted antibody therapy (Kohler and Milstein 1975).

In the 1980s much interest was focused on the generation of murine mAbs against tumor-associated antigens (TAAs). Multitudes of pre-clinical studies followed, which provided proof-of-concept for the potential application of mAbs in chemotherapeutics. However, inherent limitations of these models also demonstrated discordance in predictability of therapeutic efficacy. Preclinical and clinical investigations with murine mAbs illustrated several constraints that required attention before any degree of success could be achieved in cancer therapy. Foremost of these was the seemingly inevitable production of human anti-murine immunoglobulin antibodies (HAMAs) after one to three treatments (Schlom 1990). Other factors limiting treatment included: (1) insufficient tumor penetration with resulting inadequate therapeutic dose delivered to tumor lesions; (2) insufficient activation of effector function(s); (3) slow blood compartment clearance; (4) low mAb affinity and avidity; and (5) trafficking to or targeting of normal organs (Schlom 1990). Some of these limitations were addressed by chemical modification of the mAb, but most of these challenges have been addressed with genetic engineering techniques (Milenic 2000). This effort has primarily been applied to eliminating HAMAs by the production of chimeric mAbs, complementarity-determining region (CDR) grafting, or complete humanization of the protein (Milenic 2000).

Current advances have reached the stage where investigators are finally able to fully explore the real therapeutic potential of radiolabeled mAbs (Fig. 6.1). With the elimination of many obstacles and a better understanding of the inherent limitations of mAbs, coupled with interest and support from industry, several radiolabeled mAbs have been and are currently being evaluated in Phase III clinical trials (Table 6.1). With the groundbreaking FDA approval of two radiolabeled mAbs, Zevalin and Bexxar, for the treatment of non-Hodgkin's lymphoma (NHL), additional targeted radiation therapy products seem very probable (Srivastava and Dadachova 2001).

Fig. 6.1. Monoclonal antibodies are linked to radionuclides through methods based on the chemical characteristics of that element. Halogens, such as 131I, are routinely introduced by direct halogenation of tyro-sine residues of the protein. Metallic radionuclides, such as mIn or 90Y, require chela-tion of the metal through a suitable ligand. This chelat-ing agent frequently targets N-terminal and E-amines of lysine residues. Linking moieties include isothiocyanates, bromoacetamides, maleim-ides (post-thiolation of the protein), and active esters. Variations of these moieties are also employed for the indirect introduction of radio-halogens (Milenic et al. 2004)

Table 6.1. Selection of monoclonal antibodies in advanced radioimmunotherapy clinical trials (Milenic et al. 2004)

CLL chronic lymphocytic leukemia, NHL non-Hod-gkin's lymphoma, PEM polymorphic epithelial mucin, CEA carcinogenic embryonic antigen, HLA human leukocyte antigen, mu murine, hu humanized

Antibody

Antibody form

Radionuclide

Antigen

Disease

Clinical trial

Bexxar

mu IgG2a

131I

CD20

NHL

FDA

approved

Lymphocide

hu IgG1 (LL2)

90Y

CD22

NHL

Phase III

CEA-cide

hu IgG1

90Y

CEA

Colorectal, breast, lung, pan-

Phase III

creatic, stomach carcinoma

Cotara

hu IgG

90Y

DNA

Glioblastoma multiforme,

Phase II/III

anaplastic astrocytoma

Oncolym

hu IgG1

131I

HLA-DR10

NHL, CLL

Phase II/III

Theragyn

mu IgG1

90Y

PEM

Ovarian, gastric carcinoma

Phase II/III

Zevalin

mu IgG1

90Y

CD20

NHL

FDA

approved

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