Monoclonal Antibodies in Paediatric Acute Lymphoblastic Leukemia
Development of monoclonal antibodies (moAbs) for treatment of haematological malignancies is a rapidly growing field. Whereas unconjugated humanized antibodies are well tolerated and may be easily combined with chemotherapy, immunoconjugates delivering to
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Monoclonal Antibodies in Paediatric Acute Lymphoblastic Leukemia Arend von Stackelberg
12.1 History In 1975, Kohler et al. produced the first monoclonal antibodies (moAbs) by fusing a myeloma cell line with a specific antibody-producing B cell. This combined the unlimited growth potential of myeloma cells with the predetermined antibody specificity of normal immune spleen cells from an immunized mouse. The technique called somatic cell hybridization results in a hybridoma [1]. Humans receiving murine moAbs produce human anti-mouse antibodies (HAMA) leading to inactivation of the moAbs and allergic complications. The chimerization or humanization of moAbs via innovative recombinant DNA technology leads to a better tolerance to the compounds and has allowed for using the natural effector mechanisms of destroying with moAb-coated targets [2]. Whereas chimeric moAbs have antigenbinding parts (variable regions) of the mouse antibody and the effector parts (constant region, Fc) of a human antibody, in humanized compounds the mousederiving part of the moAb is reduced to the antigen-binding site (hypervariable region). The methodological approach to engineer the composition of moAbs is a broad and intensively developing field [3].
12.1.1 Structure of Monoclonal Antibodies (moAbs) A physiological IgG antibody consists of four polypeptide chains, two identical heavy chains and two identical light chains, which are covalently linked by interchain disulfide bonds. The chains have a variable (V) and a constant (C) region. The constant region of light chains consists of one C-domain, and the heavy chains have
A. von Stackelberg (*) Pädiatrische Onkologie/Hämatologie, Charité, OHC, Augustenburger Platz 13353, Berlin, Germany e-mail: [email protected] V. Saha and P. Kearns (eds.), New Agents for the Treatment of Acute Lymphoblastic Leukemia, DOI 10.1007/978-1-4419-8459-3_12, © Springer Science+Business Media, LLC 2011
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A. von Stackelberg CDRs Heavy chain
VH/L region
Light chain Disulfid bonds
CH1/L region Hinge region
Complement Interaction site
Fab domain
CH2 region CH3 region
Fc domain
Fig. 12.1 Structure of an immunoglobulin (Ig) G antibody. The light chain consists of a variable (VL) and a constant (CL) region. The heavy chain consists of a variable region (VH) and 3 constant regions (C1–3). The C2 region contains sites interacting with complement. The C2 and C3 domains of the two heavy-chain dimers form the Fc domain. The variable regions contain the antigen-specific complementarity-determining regions (CDR), called hypervariable regions. The V- and CL/C1 regions form the Fab domain, which is linked to the Fc domain via the flexible hinge region. Two pairs of a heavy and a light chin are linked together with disulphide bonds
two more C-domains, which together with two other C-domains form the dimeric heavy chain Fc domain. The four V-regions each together with one C-domain form the Fab-domain. The Fab and the Fc domains are linked by a flexible hinge region. The Fc domain interacts with Fc
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