Antibody fragments: Prolonging circulation half-life special issue-antibody research

Abstract

Antibodies are currently the fastest growing class of therapeutic proteins. When antibody fragments are included, there are over thirty-five antibody-based medicines approved for human therapy. Many more antibody and antibody-like fragments are being evaluated clinically. Production of antibody fragments can be efficient and their compact size can allows for better tissue extravasation into solid tumors than full antibodies. Unfortunately, a key limitation of antibody fragments for systemic use is their short half-life in circulation. Prolonging their circulation half-life can be accomplished clinically by the covalent conjugation of the antibody fragment to the water-soluble polymer, poly(ethylene glycol) (PEG). Many polymers and strategies are also being pursued to increase antibody fragment half-life.

Antibody Fragments and Their Purification by Protein L Affinity Chromatography

“…An scFv comprises the complete antigen-binding site of its parental antibody molecule [41] but, lacking the Fc region, is unable to initiate effector functions [42] or bind as appreciably as intact Abs to Protein A. Phage display and related technologies [43][44][45] are readily adapted to scFv development. As such scFv's are currently viewed as promising therapeutic fragments, with several having been in clinical trials [3,7,9,46]. Recently scFv fragments which can be internalized by cells were suggested as potentially novel agents for tumor modulation [47].…”

“…When prolonged serum half-life, but not the other physiological functions associated with Fc is desired, Ab-fragments can be modified by various chemicals or polymers [3] or recombinantly fused to serum albumin, or antibody constant regions [51]. "PEGylation" is currently the most established route, due to the maturity of the technology and the success of several PEGylated biopharmaceuticals.…”

“…There are in excess of 35 therapeutic monoclonal antibodies (mAbs) approved for clinical use [1][2][3][4] with hundreds of new mAbs in various stages of clinical development or evaluation. There may be over one thousand mAbs currently under study as biopharmaceutical agents, with approximately 300 new candidates being added each year [5].…”

“…In 2010 those three products had total sales of over $3.5 billion (USD) [7]. Many more Ab-fragments are under development [3,[8][9][10][11][12][13][14][15][16][17][18][19][20].…”

“…The latter is advantageous in some applications (see below). Ab-fragments, including fragment antigen-binding fragments (Fabs), single-chain variable fragments (scFvs), such as pexelizumab (Alexion), and single-domain antibody fragments (dAbs) (Figure 2 Although lack of an Fc region should reduce the circulation half-life of Ab fragments various recombinant chemical modifications such as "PEGylation" can enhance Ab-fragment circulation life [3,[12][13][14][15]. Cimzia® is one example of a PEGylated Ab fragment.…”