The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 102

improve drug biodistribution via passive targeting, but would also provide higher
specificity via the active targeting component (Park et al. 2009 ).

3 Specific Internalizing Molecules for Targeted Delivery

Currently, the development of the internalizing molecules specifically targeting
membrane receptors and their adaptation for active drug targeting has drawn atten-
tion in the field of targeted therapy. In the following section internalizing molecule-
mediated active targeting will be discussed in greater detail.

3.1 Antibody-Mediated Drug Delivery

Antibodies (Abs, also known as immunoglobulins) that are used by the immune
system to identify and neutralize foreign objects can specifically identify and
bind their unique antigens. Due to the specificity of antigen-antibody binding,
different internalizing antibodies and their genetically engineered fragments have
been widely investigated as active targeting molecules (Wu and Senter 2005 ;
Schrama et al. 2006 ). These include anti-CD33 monoclonal antibodies (mAb)
(Simard and Leroux 2010 ), anti-HER2 mAb (anti-CD90 mAb) (Park et al. 2002 ;
Chiu et al. 2004a ), anti-CD7 mAb (Kumar et al. 2008 ), anti-HIV envelop gp120
mAb (Song et al. 2005 ), anti-b7 integrin mAb (Peer et al. 2008 ), anti-JL1 mAb
(Suh et al. 2001 ), anti-EGF receptor Ab (Wu et al. 2004 ; Mamot et al. 2005 ),
anti-CD31 (Li et al. 2000 ), anti-GAD Ab (Jeong et al. 2005 ), anti-D4.2 mAb
(Ho et al. 1987 ), anti-H-2K k mAb (Connor and Huang 1986 ), anti-HLA-DR Ab
(Gagne et al. 2002 ), anti-DC-SIGN mAb (Tacken et al. 2005 ; Dakappagari et al.
2006 ) and so on. Four representative antibodies targeting cancer cells or HIV
infected cells are described below.

3.1.1 Anti-CD33 Antibody

The CD33 receptor is a 67 kDa glycoprotein expressed on the surface of leukemia
cells in most patients with acute myeloid leukemia (AML) (Griffin et al. 1984 ;
Scheinberg et al. 1989 ). Previous studies have demonstrated that CD33 can be rap-
idly internalized into leukemia cells after antibody binding (Simard and Leroux
2009 ). Therefore, anti-CD33 mAbs have been conjugated with cytotoxic agents or
nanocarriers for targeted delivery. For example, Mylotag (Gemtuzumab Ozogamicin),
a recombinant, humanized anti-CD33 antibody which was approved by the US
Food and Drug Administration in 2000 as a single-agent therapy for CD33-positive
AML, was linked with an anticancer agent (calicheamicin) and the resulting conjugate
showed excellent clinical promise (Larson et al. 2005 ). Recently, an anti-CD33