title: Antidote strategies to reverse anticoagulation with TB-402, a long-acting partial inhibitor of factor VIII.
abstract: BACKGROUND
  TB-402 is a partially inhibiting antibody of factor VIII that is under development as a long-acting anticoagulant.
  
  
  METHODS
  The reversibility of FVIII inhibition by TB-402 was evaluated in vitro after spiking with recombinant human FVIII (rhFVIII), human plasma-derived FVIII (hpdFVIII), recombinant activated human FVII (rhFVIIa), FVIII inhibitor bypassing activity (FEIBA), and prothrombin complex concentrate (PCC). Twelve subjects were randomized to placebo or 35 or 70 IU kg(-1) rhFVIII 48 h after a single dose of 620 μg kg(-1) TB-402. TB-402 concentrations, FVIII activity (FVIII:C), activated partial thromboplastin time (APTT) and thrombin generation were measured over a period of 8 weeks.
  
  
  RESULTS
  In spiked samples, TB-402 inhibited FVIII:C by 30%, prolonged APTT by 4.5 s, and reduced the peak height in the thrombin generation assay to 56% ± 13% of the control value. In the presence of 10 μg mL(-1) TB-402, rhFVIII restored FVIII:C and APTT to the values obtained in the absence of TB-402. The inhibitory effect of TB-402 on thrombin generation was entirely reversed by rhFVIII, hpdFVIII, rhFVIIa, FEIBA, and PCC. In men, the mean half-life (t(1/2) ) of TB-402 was 14.2 days. TB-402 lowered the endogenous thrombin potential by 23% for ~ 35 days. Infusion of 35 IU kg(-1) rhFVIII had a marginal effect, whereas 70 IU kg(-1) rhFVIII restored FVIII:C, reduced APTT back to baseline for 9 h, and restored thrombin generation for ~ 3 h.
  
  
  CONCLUSIONS
  TB-402 resulted in a stable long-term anticoagulant effect. rhFVIII and other procoagulants counteracted the effect of TB-402 temporarily, and may be effective antidotes for future clinical practice.
authors.affiliation: Research and Development, ThromboGenics NV, Heverlee, Belgium. M.Tangelder@umcutrecht.nl
authors.forename: M
authors.initials: M
authors.lastname: Tangelder
authors.forename: C
authors.initials: C
authors.lastname: Long
authors.forename: J
authors.initials: J
authors.lastname: Emmerechts
authors.forename: M
authors.initials: M
authors.lastname: Jacquemin
authors.forename: K
authors.initials: K
authors.lastname: Peerlinck
authors.forename: T
authors.initials: T
authors.lastname: Vanassche
authors.forename: S
authors.initials: S
authors.lastname: Glazer
authors.forename: P
authors.initials: P
authors.lastname: Giesen
authors.forename: M
authors.initials: M
authors.lastname: Hoylaerts
authors.forename: P
authors.initials: P
authors.lastname: Verhamme
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000931:Antidotes / Q000494:pharmacology*; D003029:Coagulants / Q000037:antagonists & inhibitors*; D004797:Enzyme-Linked Immunosorbent Assay; D005169:Factor VIII / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006801:Humans; D008297:Male; D010314:Partial Thromboplastin Time; D010919:Placebos; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants; D000931:Antidotes; D003029:Coagulants; D010919:Placebos; D011994:Recombinant Proteins; C559990:TB 402; D005169:Factor VIII