title: An antidote approach to reduce risk and broaden utility of antibody-based therapeutics.
abstract: Antibody therapeutics offer effective treatment options for a broad range of diseases. One of the greatest benefits of antibody therapeutics is their extraordinarily long serum half-life, allowing infrequent dosing with long-lasting effects. A characteristic of antibodies that drives long half-life is the ability to interact with the recycling receptor, FcRn, in a pH-dependent manner. The benefit of long half-life, however, carries with it liabilities. Although the positive effects of antibody therapeutics are long-lasting, any acute adverse events or chronic negative impacts, such as immunosuppression in the face of an infection, are also long-lasting. Therefore, we sought to develop antibodies with a chemical handle that alone would enjoy the long half-life of normal antibodies but, upon addition of a small-molecule antidote, would interact with the chemical handle and inhibit the antibody recycling mechanism, thus leading to rapid degradation and shortened half-lifein vivoHere we present a proof of concept study where we identify sites to incorporate a non-natural amino acid that can be chemically modified to modulate FcRn interactionin vitroand antibody half-lifein vivoThis is an important first step in developing safer therapeutics, and the next step will be development of technology that can perform the modifying chemistryin vivo.
authors.affiliation: Departments of Antibody Discovery and Protein Engineering.
authors.forename: Alyse D
authors.initials: AD
authors.lastname: Portnoff
authors.affiliation: Departments of Antibody Discovery and Protein Engineering.
authors.forename: Cuihua
authors.initials: C
authors.lastname: Gao
authors.affiliation: Departments of Antibody Discovery and Protein Engineering.
authors.forename: M Jack
authors.initials: MJ
authors.lastname: Borrok
authors.affiliation: Translational Sciences, MedImmune, Gaithersburg, Maryland 20878.
authors.forename: Xizhe
authors.initials: X
authors.lastname: Gao
authors.affiliation: Departments of Antibody Discovery and Protein Engineering. Electronic address: gaoc@medimmune.com.
authors.forename: Changshou
authors.initials: C
authors.lastname: Gao
authors.affiliation: Departments of Antibody Discovery and Protein Engineering. Electronic address: jrainey@mabvax.com.
authors.forename: G Jonah
authors.initials: GJ
authors.lastname: Rainey
mesh_terms: D000906:Antibodies / Q000737:chemistry* / Q000627:therapeutic use; D000931:Antidotes / Q000737:chemistry* / Q000627:therapeutic use; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D011961:Receptors, Fc / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D000931:Antidotes; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; C100688:Fc receptor, neonatal
keywords: Fc receptor; antibody engineering; biotechnology; chemical biology; drug metabolism; immunoglobulin G (IgG); monoclonal antibody; pharmacokinetics; receptor recycling