title: An Fc domain protein-small molecule conjugate as an enhanced immunomodulator.
abstract: Proteins as well as small molecules have demonstrated success as therapeutic agents, but their pharmacologic properties sometimes fall short against particular drug targets. Although the adenosine 2a receptor (A(2A)R) has been identified as a promising target for immunotherapy, small molecule A(2A)R agonists have suffered from short pharmacokinetic half-lives and the potential for toxicity by modulating nonimmune pathways. To overcome these limitations, we have tethered the A(2A)R agonist CGS-21680 to the immunoglobulin Fc domain using expressed protein ligation with Sf9 cell secreted protein. The protein small molecule conjugate Fc-CGS retained potent Fc receptor and A(2A)R interactions and showed superior properties as a therapeutic for the treatment of a mouse model of autoimmune pneumonitis. This approach may provide a general strategy for optimizing small molecule therapeutics.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Meng-Jung
authors.initials: MJ
authors.lastname: Chiang
authors.forename: Marc A
authors.initials: MA
authors.lastname: Holbert
authors.forename: Jay H
authors.initials: JH
authors.lastname: Kalin
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Ahn
authors.forename: John
authors.initials: J
authors.lastname: Giddens
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Amin
authors.forename: Martin S
authors.initials: MS
authors.lastname: Taylor
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Collins
authors.forename: Yee
authors.initials: Y
authors.lastname: Chan-Li
authors.forename: Adam
authors.initials: A
authors.lastname: Waickman
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Hsiao
authors.forename: David
authors.initials: D
authors.lastname: Bolduc
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Leahy
authors.forename: Maureen R
authors.initials: MR
authors.lastname: Horton
authors.forename: Lai-Xi
authors.initials: LX
authors.lastname: Wang
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018796:Immunoconjugates / Q000737:chemistry* / Q000494:pharmacology*; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000494:pharmacology*; D007155:Immunologic Factors / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D010627:Phenethylamines / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007155:Immunologic Factors; D010627:Phenethylamines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine