ARTICLE ANNOTATION

Article Annotation

Article Annotation: Antibody Engineering and Modification Technologies

David Filpula

I Introduction

Antibodies are routinely used to concentrate doses of radiation in tissues for both therapeutic and diagnostic purposes. Common isotopes used to this end include iodine-131, yttrium-90, indium-111 and technicium-99. Tumour killing by unlabelled mAbs is limited by the degree of antigen density on the tumour cell and the ability to penetrate tumours adequately.  

II.                 Risk perception

 A sound understanding of the biochemical pathway being targeted is central to the 'wish list' for a mAb therapeutic. In many applications the recruitment of host effector functions through Fc receptors (including complement fixation and antibody-dependent cell-mediated cytotoxicity) is essential.  

III.             Risk analyses

In humans the IgG1 isotype is the preferred therapeutic choice for triggering effector cascades.An approved antibody with the potential to trigger effector function is Herceptin, an anti-HER2/neu antibody used in the treatment of breast cancer. In addition to the well-described ability to block Her2-dependent growth, some of the clinical benefit from Herceptin treatment is thought to arise from an ability to promote antibody-dependent cell-mediated cytotoxicity]. Conversely, when target neutralization is the only goal, it may be preferable to use the IgG4 isotype that is incapable of triggering these cascades. Irrespective of isotype there are several additional benefits to the IgG format. Divalent IgG molecules have the potential to cross-link cell-surface antigen in the absence of macrophage/natural killer cell Fc receptors. For example, in some CD20-positive cell lines cross-linking has been shown to induce apoptosis. An alternative to using this is to use antibody fragments such as Fab or scFv. Both of these formats are unable to trigger effector function and because of a reduced size have an increased tumour penetration. These fragments are especially suited to the delivery of 'payload'. One obvious drawback of Fabs/scFvs is a reduced half-life (hours compared with 2- 3 weeks with IgG). It is, however, possible to improve the serum longevity of these proteins by conjugating to inert polymers such as poly(ethylene)glycols]. Examples of cancer targets where neutralization is the primary goal include matrix metalloproteases ('MMPs'), urokinase plasminogen activator ('uPA') and vascular endothelial growth factor ('VEGF'), which are all secreted proteins associated with tumour progression (McCartney, J et. al. 2006)

IV.             Public concerns about risky technologies.

The completion of the human genome combined with advances in proteomics technologies have helped to enhance our understanding of the complex interplay between genetic, transcriptional and translational alterations in human cancers. Although bioinformaticians have made strides in identifying potentially interesting novel cancer targets there is a central bottleneck at the point when cancer biologists must investigate each individual gene for therapeutic potential. These assays are time-consuming and labour-intensive. Looking at the current crop of approved antibody targets, they have all benefited from around 10-20 years of detailed academic research. The future goal will be to design high-throughput biology modes to move novel cancer targets quickly towards clinical development. Three general strategies have now been developed to reduce the immunogenicity of mAbs. Firstly, advances in molecular biology have made it possible to substitute human sequences ...