Formatting antibody fragments to mediate specific therapeutic functions.
Monoclonal antibodies are increasingly being used as therapeutic agents in a wide range of indications, including oncology, inflammation and infectious disease. In most cases the basis of the therapeutic function is the high degree of specificity and affinity the antibody-based drug has for its target antigen. However, the mechanism of action (MOA), the way the drug takes advantage of this specificity to mediate a therapeutic effect, varies considerably from drug to drug. Three basic potential categories of MOAs exist: antagonists, agonists and specific delivery mechanisms to target an active function to a particular cell type. The latter functions include selective cell killing, based on Fc-mediated events, recruitment of effector cells, and drug or radioisotope delivery. The majority of these mechanisms are not necessarily optimally mediated by an IgG structure; clearly, in the case of antibody-dependent cellular cytotoxicity or complement-mediated lysis, Fc is required. However, Fab fragments (the fragment comprising one antigen-binding arm of the Y-shaped IgG molecule) can be formatted to mediate most mechanisms and have the advantage that valency and half-life can be controlled to simplify the drug and address only the mechanism required. Moreover, Fab fragments can be produced in microbial expression systems which address manufacturing issues such as scale of supply and cost of goods.
Weir
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Celltech R+D Ltd., 216 Bath Road, Slough, Berkshire SL1 4EN, UK. neil.weir@slh.celltechgroup.com
Nesbitt
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Chapman
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Popplewell
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Antoniw
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Lawson
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D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D006801:Humans; D007128:Immunoglobulin Fragments / Q000096:biosynthesis* / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000737:chemistry; D007375:Interleukin-1 / Q000276:immunology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D007375:Interleukin-1; D011994:Recombinant Proteins