ITP is an autoimmune bleeding disorder characterized by platelet destruction and suppression of platelet production. In the majority of patients, platelet destruction due to IgG antibodies reactive with platelet GPIIbIIIa results in platelet phagocytosis by phagocytic cells in the mononuclear phagocytic system. Anti-D is an effective first-line therapy for patients with ITP and was originally brought into practice based on the ability of anti-D to competitively inhibit opsonized-platelet clearance by phagocytic cells. Similar to anti-D, an RBC-specific monoclonal antibody (TER-119) is also able to inhibit platelet clearance in a murine model of passive ITP, also ostensibly due to RBC clearance and competitive inhibition of phagocytic cells. Here, we show that TER-119 only caused measurable anemia after 3 hours post-injection while its ability to ameliorate thrombocytopenia in the passive-murine ITP model was clearly evident by 30 minutes post-injection. Further, TER-119 mediated maximal anemia 4 days after its injection, yet displayed no measurable ameliorative effects in passive-ITP at this time point. Based on these observations, we hypothesized that anti-inflammatory activity, rather than simple competitive inhibition of opsonized-platelet clearance, might be involved in this mechanism. To test this hypothesis, the ability of TER-119 to successfully treat inflammatory diseases not involving antibody-mediated splenic cellular sequestration were examined. In the K/BxN serum-transfer model of arthritis, recipient C57BL/6 mice are injected with K/BxN serum and a rapidly progressing arthritis occurs due to antibodies specific to the self-protein glucose-6-phosphate isomerase. Using this model, the same dose of TER-119 (50 μg/mouse) which was effective in murine ITP could significantly prevent the induction of inflammatory arthritis. In separate experiments, mice were allowed to develop significant arthritis for 5 days and then injected with TER-119. These arthritic mice underwent a reversal in disease severity with significant and substantial decreases in joint swelling and clinical score evident 24 hours after injection of TER-119. In fact three days after injection with TER-119, clinical scores and ankle width measurements returned to baseline. The function of the Fc region was important in the anti-inflammatory activity of TER-119 as deglycosylation of the Fc region of the antibody (known to inhibit IgG Fc region effector functions) dramatically reduced anti-inflammatory function in the arthritis model. To determine if TER-119 could also ameliorate disease activity in an unrelated (non-autoimmune) inflammatory disease model, TER-119 was also examined in a murine model of transfusion-related acute lung injury (TRALI). TRALI is a syndrome of respiratory distress primarily triggered by leukocyte-reactive antibodies from blood product transfusions and is the leading cause of transfusion-related mortality. TRALI was induced by injecting mice with the anti-MHC class I antibody (34-1-2s) which induced a rapid decrease in body temperature and induced significant lung damage, assessed by the presence of pulmonary edema. Mice pretreated with TER-119 (50 μg) underwent a rescue from hypothermia and exhibited an almost complete inhibition of lung edema. We conclude that TER-119 has significant anti-inflammatory activity and suggest that RBC specific antibodies such as anti-D may have significant therapeutic potential in inflammatory disorders beyond just ITP.
Semple: Novartis: Consultancy; Rigel: Consultancy; Amgen: Consultancy; UCB: Consultancy. Lazarus: CSL pharmaceuticals: Research Funding; Momenta pharmaceuticals: Honoraria; Rigel pharmaceuticals: Research Funding; St.Michael's Hosp/The Canadian Blood Services: Other: Patents on monoclonal antibodies as IVIg and anti-D replacements.
Asterisk with author names denotes non-ASH members.