title: Targeted Delivery of LXR Agonist Using a Site-Specific Antibody-Drug Conjugate.
abstract: Liver X receptor (LXR) agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been hindered by on-target adverse effects in the liver mediated by excessive lipogenesis. Herein, we report a novel site-specific antibody-drug conjugate (ADC) that selectively delivers a LXR agonist to monocytes/macrophages while sparing hepatocytes. The unnatural amino acid para-acetylphenylalanine (pAcF) was site-specifically incorporated into anti-CD11a IgG, which binds the α-chain component of the lymphocyte function-associated antigen 1 (LFA-1) expressed on nearly all monocytes and macrophages. An aminooxy-modified LXR agonist was conjugated to anti-CD11a IgG through a stable, cathepsin B cleavable oxime linkage to afford a chemically defined ADC. The anti-CD11a IgG-LXR agonist ADC induced LXR activation specifically in human THP-1 monocyte/macrophage cells in vitro (EC50-27 nM), but had no significant effect in hepatocytes, indicating that payload delivery is CD11a-mediated. Moreover, the ADC exhibited higher-fold activation compared to a conventional synthetic LXR agonist T0901317 (Tularik) (3-fold). This novel ADC represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis.
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Reyna K V
authors.initials: RK
authors.lastname: Lim
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Cheng
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Sijia
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Nam-Jung
authors.initials: NJ
authors.lastname: Kim
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Victor
authors.initials: V
authors.lastname: Chi
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.|Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Tremblay
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Kazane
mesh_terms: D001565:Benzoates / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D001596:Benzylamines / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D040881:CD11a Antigen / Q000276:immunology*; D002460:Cell Line; D016503:Drug Delivery Systems; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D007074:Immunoglobulin G / Q000276:immunology; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001565:Benzoates; D001596:Benzylamines; D040881:CD11a Antigen; D006845:Hydrocarbons, Fluorinated; D018796:Immunoconjugates; D007074:Immunoglobulin G; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides