Abstract
Single chain variable domain (Fv) fragments (scFv) are powerful tools in research and clinical settings, owing to better pharmacokinetic properties compared to the parent monoclonal antibodies and the relative ease of producing them in large quantities, at low cost. Though they offer several advantages, they suffer from lower binding affinity and rapid clearance from circulation, which limits their therapeutic potential. However, these fragments can be genetically modified to enhance desirable properties, such as multivalency, high target retention and slower blood clearance, and as such, a variety of scFv formats have been generated. ScFvs can be administered by systemic injection for diagnostic and therapeutic purposes. They can be expressed in vivo through viral vectors in instances where large infection rates and sustenance of high levels of the antibody is required. ScFvs have found applications as tools for in vivo loss-of-function studies and inactivation of specific protein domains, diagnostic imaging, tumor therapy and treatment for neurodegenerative and infectious diseases. This review will focus on their in vivo applications.
Highlights
Antibodies are the body’s defense system to neutralize bacteria and viruses
In the effort to develop scFv therapeutics for neurodegenerative diseases where the target is in the brain, a major challenge has been the difficulty of crossing the blood-brain barrier to deliver the therapy
In order to sustain the expression of antibody fragments over long periods, scFvs can be cloned in a viral vector and delivered by injection of the virus (Figure 2)
Summary
Antibodies are the body’s defense system to neutralize bacteria and viruses. They recognize and bind a target molecule through the antigen binding sites located on the two Fab segments, which are specific to a particular epitope on an antigen. Advances in antibody engineering have enabled the further reduction of mAbs to single chain Fv fragments (scFvs), monovalent Fabs, diabodies and minibodies [7,8,9,10] The properties of these fragments have been tailored to optimize their binding affinity, in vivo pharmacokinetics, stability and expression levels [11]. They display improved pharmacokinetic properties, such as better tissue penetration and rapid blood clearance, which may be beneficial in radiotherapy and diagnostic applications These fragments can penetrate more rapidly into tumors compared to an intact antibody [24,25]. In vitro display technologies (phage, yeast) have taken over hybridoma technology, because of their adaptability to high throughput formats They can be manipulated to optimize scFv properties and generate a population of extremely diverse and highly functional antibodies [37,38]. Synthetic antibody libraries specially eliminate the need to obtain antibodies from immunized host and enable the introduction of extreme diversity in the scFvs, as they allow manipulating the CDR regions through synthetic DNA [37,38]
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