SPECIFIC ANTI-dsDNA B CELL TOLERANCE IN VIVO

Stephen M. Coutts, Cecile M. Berner, G. Michael Iverson and Marian L. Plunkett. Presented at the B Lymphocytes and Autoimmunity Conference, May 21-25, 1996, Prague, The Czech Republic.

La Jolla Pharmaceutical Company, San Diego, CA

The principle of single signal anergy was used to construct a toleragen, LJP 394, for suppressing B cells specific for anti-dsDNA antibodies. Anti-dsDNA is thought to be pathogenic for lupus nephritis. LJP 394 inhibited anti-oligonucleotide (ON) antibodies and anti-ON-specific B cells in a dose-dependent manner in immunized C57BL/6 mice (ip) and in male BXSB mice (iv). The drug also extended survival and lowered proteinuria in BXSB mice. LJP 394 was well tolerated and safe in rats, monkeys and man (phase I). The drug has a pharmacokinetic half life of forty min to one hour in man and mice. LJP 394 has been tested in lupus patients by three protocols, in (a) single dose (N=4), (b) repeat escalating dose (N=2), and (c) dose ranging (N=49) studies, using an endpoint of anti-dsDNA levels (Farr). The single dose protocol (100 mg) resulted in immediate reduction of anti-dsDNA in all four patients (a mean of ~50%), with antibodies levels remaining suppressed for one to four weeks, consistent with dual mechanisms of immunoadsorption and tolerance. Clinically significant activation of complement was not observed. The repeat escalating dose study also resulted in immediate drops in serum anti-dsDNA in both patients; these levels remained reduced 6 weeks after the last dose. Data from the dose ranging study will be presented elsewhere. LJP 394 will next be tested in phase II/III clinical studies in lupus patients.

Presented at the B Lymphocytes and Autoimmunity Conference, May 21-25, 1996, Prague, The Czech Republic.