title: Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody-drug Conjugate.
abstract: Phosphodiesterase 4 (PDE4) inhibitors are approved for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects in the central nervous system and gastrointestinal tract, including nausea, emesis, headache, and diarrhea, have impeded the broader therapeutic application of PDE4 inhibitors. We sought to exploit the wealth of validation surrounding PDE4 inhibition by improving the therapeutic index through generation of an antibody-drug conjugate (ADC) that selectively targets immune cells through the CD11a antigen. The resulting ADC consisted of a human αCD11a antibody (based on efalizumab clone hu1124) conjugated to an analog of the highly potent PDE4 inhibitor GSK256066. Both the human αCD11a ADC and a mouse surrogate αCD11a ADC (based on the M17 clone) rapidly internalized into immune cells and suppressed lipololysaccharide (LPS)-induced TNFα secretion in primary human monocytes and mouse peritoneal cells, respectively. In a carrageenan-induced air pouch inflammation mouse model, treatment with the ADC significantly reduced inflammatory cytokine production in the air pouch exudate. Overall, these results provide compelling evidence for the feasibility of delivering drugs with anti-inflammatory activity selectively to the immune compartment via CD11a and the development of tissue-targeted PDE4 inhibitors as a promising therapeutic modality for treating inflammatory diseases.
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Pearson
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Reyna Kv
authors.initials: RK
authors.lastname: Lim
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Rodgers
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Sijia
authors.initials: S
authors.lastname: Li
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Holly B
authors.initials: HB
authors.lastname: Parker
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Weglarz
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Hampton
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bollong
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Zambaldo
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Woods
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Wright
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.|Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Kazane
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Travis S
authors.initials: TS
authors.lastname: Young
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Tremblay
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism*; D000818:Animals; D018845:CD11 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010537:Peritoneum / Q000187:drug effects / Q000276:immunology; D058988:Phosphodiesterase 4 Inhibitors / Q000378:metabolism*; D013450:Sulfones / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C549469:6-((3-((dimethylamino)carbonyl)phenyl)sulfonyl)-8-methyl-4-((3-methyloxyphenyl)amino)-3-quinolinecarboxamide; D000634:Aminoquinolines; D018845:CD11 Antigens; D018796:Immunoconjugates; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha