Therapeutic potential of toleragens in the management of antiphospholipid syndrome.
Autoantibodies to beta2-glycoprotein I (beta2GPI) are believed to be the primary cause of coagulation abnormalities in patients with antiphospholipid syndrome (APS). Clinical features include a range of life-threatening thrombotic events and microangiopathies affecting multiple organ systems. Current standard of care relies on long-term, high-intensity anticoagulation and is associated with a high risk for serious bleeding events. The relation between autoantibodies and the pathophysiology of APS is not clearly understood, but numerous in vitro studies have characterized the effects of antiphospholipid autoantibodies on various components of the coagulation cascade, including tissue factor and the protein C pathway. The fine specificity of autoantibodies to beta2GPI is a subject of considerable debate; however, a body of evidence may offer resolution by integrating concepts of antibody affinity and assay sensitivity with carefully designed molecular studies. An investigational new therapy for APS is based on the approach that pathogenic antibodies may be reduced via depletion of circulating autoantibodies and induction of immune tolerance at the B-cell level. Preliminary results from a phase I/II clinical trial with LJP 1082, a B-cell toleragen, indicate the drug was well tolerated and may warrant further development for reduction of thrombotic events in patients with APS.
Cockerill
Keith A
KA
La Jolla Pharmaceutical Company, San Diego, California, USA. keith.cockerill@ljpc.com
Iverson
G Michael
GM
Jones
David S
DS
Linnik
Matthew D
MD
D016736:Antiphospholipid Syndrome / Q000188:drug therapy* / Q000209:etiology; D001323:Autoantibodies / Q000009:adverse effects / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D006023:Glycoproteins / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology / Q000627:therapeutic use*; D008722:Methods; D008954:Models, Biological; D009930:Organic Chemicals; D011092:Polyethylene Glycols / Q000627:therapeutic use; D053482:beta 2-Glycoprotein I
D001323:Autoantibodies; D006023:Glycoproteins; D007166:Immunosuppressive Agents; C502536:LJP 1082; D009930:Organic Chemicals; C029248:Tolerogen; D053482:beta 2-Glycoprotein I; D011092:Polyethylene Glycols