Drug Targeting Organ-Specific Strategies

210 8 Strategies for Specific Drug Targeting to Tumour Cells
IgGs, IgG2a is the one which is most efficient in mediating human ADCC, whereas IgG3 can
mediate potent C-dependent cytolysis [39].
Some MAbs have the ability to signal target cells to undergo cell cycle arrest (CCA) or
apoptosis.The prototypic example of such a MAb is anti-Fas that signals apoptosis in all Faspositive
cells [40,41]. However, because of the ubiquitous expression of Fas, administration of
anti-Fas is lethal. Other MAbs, particularly when used as homodimers [42] which hypercrosslink
their antigenic targets, can induce CCA or apoptosis. Both anti-CD19 and anti-
CD22 induce CCA in several Burkitt’s lymphoma cell lines both in vitro and in mice
xenografted with human tumours [43]. Anti-Id MAbs are also thought to be of therapeutic
value because of their ability to direct negative signals to tumour cells [44].
More recently, our knowledge of cellular signalling pathways has led to the development
of MAbs which target molecules involved in the regulation of tumour cell growth. Cytostatic
or cytotoxic effects can result from the binding of a MAb to growth factors or cellular
growth factor receptors which are required for tumour cell survival [45]. For example, many
adult carcinomas depend, in part, on the autocrine or paracrine effects of epidermal growth
factor (EGF) or transforming growth factor-α (TGF-α).As a result, some anti-EGF receptor
MAbs have anti-tumour activity in tumours of the breast, vulva, cervix, and in squamous cell
carcinomas [45]. Other MAbs targeting various cell surface growth factor receptors have also
effectively induced CCA or apoptosis in tumour cells [40,46,47].
To potentiate the cytotoxic effects of MAbs with low endogenous activity, cytokines and
activated effector cells have been co-administered [48]. Cytokines can increase extravasation
of MAbs into the tumour and, by inducing local inflammatory responses, enhance the influx
of effector cells. For example, the addition of interleukin-2 (IL-2) or the concomitant adoptive
transfer of lymphokine-activated killer cells (LAKs) can enhance the activity of MAbs.
Other cytokines, such as interferon-gamma (IFNγ) and IFNα can augment the delivery of
MAbs to tumour targets by upregulating antigen expression [48,49]. The use of activated effector
cells (peripheral blood mononuclear cells or granulocytes) in combination with MAbs
has also resulted in their increased cytotoxicity to various tumours [48].
8.5.1.2.1 Potential Disadvantages and Limitations of the MAb Approach
Unfortunately, the clinical efficacy of MAb-directed therapy is often limited. One important
factor in this respect is that the target antigen is expressed on normal as well as malignant
cells. With the exception of MAbs to idiotypic domains of B-lymphocytes, MAbs which are
exclusively tumour-specific have not been identified. Rather, most currently used MAbs recognize
tumour-associated antigens expressed at higher density on malignant cells relative to
normal cells. Furthermore, MAbs are murine in origin, particularly those used in past research.As
a consequence, human anti-mouse antibody (HAMA) responses developed in patients
treated with murine MAbs, led to accelerated clearance of the administered MAb and
blocking of the therapeutic effect.
As mentioned in Section 8.4.2, elevated interstitial pressure, heterogeneous and reduced
functional vasculature, and the relatively large distances that Mabs have to travel in the tumour
interstitium, are hurdles which need to be overcome in the pursuit of efficient drug targeting.
The relatively large molecular weight of Mabs (approximately 150 kDa) [2,14], also