An orally active, primate selective antagonist of LFA-1 inhibits delayed-type hypersensitivity in a humanized-mouse model.
Compound I, a novel small molecule antagonist (Kd=6 nM) of human lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) was tested for activity in a humanized mouse model of delayed-type hypersensitivity (trans vivo delayed-type hypersensitivity). Trans vivo delayed-type hypersensitivity is a model for testing compounds with human targets in mice. Tetanus toxoid and 7-10x10(6) human peripheral blood mononuclear cells from tetanus-sensitized donors were coinjected into footpads of naive mice. Footpads were measured before and 24 h later. Injection of peripheral blood mononuclear cells plus antigen resulted in swelling of 0.178-0.254 mm, significantly greater than peripheral blood mononuclear cells or tetanus toxoid alone (P<0.05). Preincubation of peripheral blood mononuclear cells with anti-human major histocompatibility complex class II (MHCII) or anti-human LFA-1 monoclonal antibody (mAb), but not anti-mouse MHCII or anti-mouse LFA-1 mAb, significantly inhibited the response. Compound I inhibited footpad swelling in a dose related manner (0.1-100 mg/kg, p.o.; ED50 approximately 1 mg/kg), whereas its enantiomer had no effect. These data demonstrate the oral efficacy of a novel antagonist of LFA-1 in trans vivo delayed-type hypersensitivity.
Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceutical Inc., 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877-0368, USA. mpanzenb@rdg.boehringer-ingelheim.com
Maret J
MJ
Panzenbeck
Deborah D
DD
Jeanfavre
Terence A
TA
Kelly
Rene
R
Lemieux
Gerald
G
Nabozny
Patricia L
PL
Reilly
Sudha
S
Desai
D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000276:immunology / Q000517:prevention & control; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control*; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects* / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D023421:Models, Animal; D013744:Tetanus Toxin / Q000276:immunology
D000911:Antibodies, Monoclonal; D007093:Imidazoles; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D013744:Tetanus Toxin