A Monovalent Anti-Human CD28 Domain Antibody Antagonist: Preclinical Efficacy and Safety

作者：Suchard Suzanne J^*; Davis Patricia M; Kansal Selena; Stetsko Dawn K; Brosius Ruth; Tamura James; Schneeweis Lumelle; Bryson James; Salcedo Theodora; Wang Haiqing; Yang Zheng; Fleener Catherine A; Ignatovich Olga; Plummer Christopher; Grant Steven; Nadler Steven G

来源：The Journal of Immunology, 2013, 191(9): 4599-4610.

DOI：10.4049/jimmunol.1300470

Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 +/- 14 ng/ml for inhibition of proliferation. The EC50 of 53 +/- 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4-mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell-dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases.

• 出版日期2013-11-1