Monoclonal Antibodies in Cancer
Cancer is the second leading cause of death in the United States with one of every four deaths attributable to cancer (Jemal et al. 2006). The first references to cancer date back to Egyptian papyrus circa 1600 BC. The introduction of nitrogen mustards in
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Monoclonal Antibodies in Cancer Amy Grimsley, Katherine S. Shah, and Trevor McKibbin
INTRODUCTION Cancer is the second leading cause of death in the United States with one of every four deaths attributable to cancer (Jemal et al. 2006). The first references to cancer date back to Egyptian papyrus circa 1600 BC. The introduction of nitrogen mustards in the 1940s can be considered the origin of modern, systemic antineoplastic therapies (Papac 2001). Rapid improvements in the understanding of cancer biology, medicinal chemistry, and biopharmaceutical technology have provided rationally designed drugs exploiting differences in normal and malignant cells. Monoclonal antibodies (MABs) bind to a specific epitope. This allows for a targeting approach for the development of effective anticancer compounds with relatively less and/or nonoverlapping toxicity compared to other cytotoxic drugs used to treat cancer. In cancer treatment, MABs have been developed that exert a wide array of pharmacologic effects. This chapter focuses on FDAapproved MABs for the treatment of cancer and cancer-related symptoms. Antibodies are organized based on their target. Table 17.1 summarizes the current FDA-approved MABs for cancer indications, year of approval, target, and the indications that are discussed within the chapter.
A. Grimsley, PharmD Department of Pharmacy Practice, Mercer University College of Pharmacy and Health Sciences, Atlanta, GA, USA K.S. Shah, PharmD • T. McKibbin, PharmD, MS, BCPS (*) Department of Pharmaceutical Services, Emory University Hospital/Winship Cancer Institute, 1365 Clifton RD, Building C, Atlanta 30322, GA, USA e-mail: [email protected]
CLASSES OF MONOCLONAL ANTIBODIES: CD ANTIGENS ■ Alemtuzumab
Pharmacology and Pharmacokinetics Alemtuzumab is an unconjugated, humanized, IgG1 kappa MAB directed against the 21–28 kDa cell surface glycoprotein CD52 (Frampton and Wagstaff 2003). Most lymphocytes (including 95 % of B and T cells at various stages of differentiation), monocytes, natural killer cells, macrophages, and eosinophils, as well as cells lining the male reproductive tract, express CD52; however, it is not found on erythrocytes, platelets, or stem cells (Liu and O’Brien 2004). While CD52 is highly expressed in some forms of chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), and acute lymphoblastic leukemia (ALL), it is not shed or internalized, making it an ideal therapeutic target (Liu and O’Brien 2004). Malignant CD52 expression occurs not only in CLL, low-grade lymphomas, and T-cell malignancies but also in some cases of myeloid, monocytic, and acute lymphoblastic leukemias. The compound exerts its anticancer effects by binding to CD52 antigenic sites and stimulating crosslinking by antibodies, which promotes antibodydependent cellular cytotoxicity and direct cellular apoptosis via natural killer activity as shown in Fig. 17.1 (O’Brien et al. 2005). Pharmacokinetic parameters of alemtuzumab were determined in a phase I dose-escalation trial. Patients with B-cell CLL and NHL w
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