Induction and Impact of Anti-Drug Responses Elicited by a Human Recombinant Coagulation Factor FXaI16L in Preclinical Species.

This paper presents a systemic investigation of ADA development and ADA impact of a human coagulation factor in nonclinical species during drug development and provides insights into potential implications in human if a similar ADA occurs. FXaI16L-induced ADA response was characterized in monkey, mouse, rat, and dog in different studies, and ADA effects on pharmacokinetic and/or pharmacodynamics of FXaI16L were further examined in ADA-negative and ADA-positive animals. After repeated administrations, FXaI16L elicited a dose and exposure day-dependent ADA response which ranged from no response to a transient or persistent response. Increase in exposure day and increase in dose generally enhanced ADA incidence except for a decrease in ADA incidence was observed in monkeys after repeated high-dose administrations. The observable ADA impact on pharmacokinetics was only found in some ADA+ animals and included decrease in clearance and increase in systemic exposure but no increase in half-life. In addition, no or limited effect on pharmacodynamics by ADA was observed. The earliest ADA response was observed after three exposure days, marked elevation of drug exposure was observed in some animals at log titer > 2.0, and the highest antibody titer excited was about 4 (Log10) in all species. A correlation between ADA induction and accumulative exposure after various repeat treatments in different species was found for FXaI16L. In addition, potential immunogenicity risk and mitigation of ADA in clinics are discussed.

Autoantibody-mediated arthritis in the absence of C3 and activating Fcγ receptors: C5 is activated by the coagulation cascade.

INTRODUCTION: The effector functions of immunoglobulin G (IgG) are mediated by interaction of its Fc region with Fc receptors (FcγRs) and/or the complement system. The three main pathways of complement activation converge at C3. However, C3-independent pathways can activate C5 and other downstream complement components during IgG-initiated inflammatory responses. These C3-independent pathways of C5 activation are triggered by activating FcγRs in some systems or can be activated by factors of the coagulation cascade such as thrombin. Here we studied the interplay of C3, C5, and activating FcγRs in a model of spontaneous autoantibody-driven arthritis. METHODS: We utilized the K/BxN TCR transgenic mouse model of arthritis. We bred K/BxN mice bearing targeted or naturally-occurring mutations in one or more of the genes encoding complement components C3, C5, and FcRγ, the cytoplasmic signaling chain shared by the activating FcγRs. We measured arthritis development, the production of arthritogenic autoantibodies, T cell activation status and cytokine synthesis. In addition, we treated mice with anti-C5 monoclonal antibodies or with the thrombin inhibitor argatroban. RESULTS: We have previously shown that genetic deficiency of C5 protects K/BxN mice from the development of arthritis. We found here that C3-deficient K/BxN mice developed arthritis equivalent in severity to C3-sufficient animals. Arthritis also developed normally in K/BxN mice lacking both C3 and FcRγ, but could be ameliorated in these animals by treatment with anti-C5 monoclonal antibody or by treatment with argatroban. Production of arthritogenic autoantibodies, T cell activation, and T cell cytokine production were not affected by the absence of C3, C5, and/or FcRγ. CONCLUSIONS: In K/BxN mice, C5-dependent autoantibody-driven arthritis can occur in the genetic absence of both complement C3 and activating FcγRs. Our findings suggest that in this setting, thrombin activates C5 to provoke arthritis.

Effect of influenza vaccination on international normalized ratio during chronic warfarin therapy.

WHAT IS KNOWN AND OBJECTIVE: Warfarin is a widely used anticoagulant, well-known for its interactions with medications and foods. Vaccinations, particularly the influenza vaccine, have been thought to potentially interfere with anticoagulation response in those on chronic warfarin. Our objective was to systematically review the literature to assess the validity and clinical significance of this association. METHODS: A primary literature search was performed using MEDLINE (1966 - June 2011) and EMBASE (1980 - June 2011). Additional studies were obtained by performing a manual bibliographical review of literature from the initial results and by searching The Cochrane Database of Systematic Reviews. All English-language, peer-reviewed publications identified were evaluated. Reviews, case studies and trials reporting anticoagulation response using an unconverted prothrombin time ratio were excluded. RESULTS AND DISCUSSION: Thirty-one abstracts were initially reviewed, and seven studies were identified for inclusion in this review. Significant changes in mean INR post-vaccination between the study and comparator groups were documented in one trial. Through subgroup analysis, another study noted that elderly patients spent more time in the subtherapeutic range post-vaccination when compared with baseline INR levels. No other significant changes in mean INR levels were documented following influenza vaccination. Adverse bleeding events reported after immunization were limited and minor in nature. WHAT IS NEW AND CONCLUSION: Overall, our review does not indicate a consistent, clinically relevant effect of influenza vaccines on INR of patients on chronic warfarin therapy. Isolated reports of variations in INR following influenza vaccination are likely due to other factors.