Positron annihilation in cardo-based polymer membranes.

Positron annihilation lifetime spectroscopy (PALS) is applied to a series of bis(aniline)fluorene and bis(xylidine)fluorene-based cardo polyimide and bis(phenol)fluorene-based polysulfone membranes. It was found that favorable amounts of positronium (Ps, the positron-electron bound state) form in cardo polyimides with the 2,2-bis(3,4-dicarboxyphenyl) hexafluoropropane dianhydride (6FDA) moiety and bis(phenol)fluorene-based cardo polysulfone, but no Ps forms in most of the polyimides with pyromellitic dianhydride (PMDA) and 3,3',4,4'-biphenyltetracarboxylic dianhydride (BTDA) moieties. A bis(xylidine)fluorene-based polyimide membrane containing PMDA and BTDA moieties exhibits a little Ps formation but the ortho-positronium (o-Ps, the triplet state of Ps) lifetime of this membrane anomalously shortens with increasing temperature, which we attribute to chemical reaction of o-Ps. Correlation between the hole size (V(h)) deduced from the o-Ps lifetime and diffusion coefficients of O2 and N2 for polyimides with the 6FDA moiety and cardo polysulfone showing favorable Ps formation is discussed based on free volume theory of gas diffusion. It is suggested that o-Ps has a strong tendency to probe larger holes in rigid chain polymers with wide hole size distributions such as those containing cardo moieties, resulting in deviations from the previously reported correlations for common polymers such as polystyrene, polycarbonate, polysulfone, and so forth.

Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation.

BACKGROUND: We previously reported that a humanized anti-factor IXa/X bispecific antibody, hBS23, mimics the function of FVIII even in the presence of FVIII inhibitors, and has preventive hemostatic activity against bleeding in an animal model of acquired hemophilia A. After further molecular engineering of hBS23, we recently identified an improved humanized bispecific antibody, ACE910, for clinical investigation. OBJECTIVES: To elucidate the in vivo hemostatic potency of ACE910 by examining its effect against ongoing bleeds, and to determine its pharmacokinetic parameters for discussion of its potency for prophylactic use. METHODS: A non-human primate model of acquired hemophilia A was established by injecting anti-primate FVIII neutralizing antibody. When bleeds emerged following an artificial bleed-inducing procedure, either ACE910 or recombinant porcine FVIII (rpoFVIII) was intravenously administered. rpoFVIII was additionally administered twice daily on the following 2 days. Bleeding symptoms were monitored for 3 days. A pharmacokinetic study and multiple-dosing simulations of ACE910 were also performed. RESULTS: A single bolus of 1 or 3 mg kg-1 ACE910 showed hemostatic activity comparable to that of 10 U kg-1 (twice daily) rpoFVIII against ongoing bleeds. The determined ACE910 pharmacokinetic parameters included a long half-life (3 weeks) and high subcutaneous bioavailability (nearly 100%). The simulation results based on pharmacokinetic parameters indicated that the above hemostatic level could be maintained with once-weekly subcutaneous administration of ACE910, suggesting the possibility of more effective prophylaxis. CONCLUSIONS: ACE910 may offer an alternative on-demand treatment option for patients with hemophilia A, as well as user-friendly and aggressive routine supplementation.

Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation.

BACKGROUND: We previously reported that a humanized anti-factor IXa/X bispecific antibody, hBS23, mimics the function of FVIII even in the presence of FVIII inhibitors, and has preventive hemostatic activity against bleeding in an animal model of acquired hemophilia A. After further molecular engineering of hBS23, we recently identified an improved humanized bispecific antibody, ACE910, for clinical investigation. OBJECTIVES: To elucidate the in vivo hemostatic potency of ACE910 by examining its effect against ongoing bleeds, and to determine its pharmacokinetic parameters for discussion of its potency for prophylactic use. METHODS: A nonhuman primate model of acquired hemophilia A was established by injecting anti-primate FVIII neutralizing antibody. When bleeds emerged following an artificial bleed-inducing procedure, either ACE910 or recombinant porcine FVIII (rpoFVIII) was intravenously administered. rpoFVIII was additionally administered twice daily on the following 2 days. Bleeding symptoms were monitored for 3 days. A pharmacokinetic study and multiple-dosing simulations of ACE910 were also performed. RESULTS: A single bolus of 1 or 3 mg kg⁻¹ ACE910 showed hemostatic activity comparable to that of 10 U kg⁻¹ (twice daily) rpoFVIII against ongoing bleeds. The determined ACE910 pharmacokinetic parameters included a long half-life (3 weeks) and high subcutaneous bioavailability (nearly 100%). The simulation results based on pharmacokinetic parameters indicated that the above hemostatic level could be maintained with once-weekly subcutaneous administration of ACE910, suggesting the possibility of more effective prophylaxis. CONCLUSIONS: ACE910 may offer an alternative on-demand treatment option for patients with hemophilia A, as well as user-friendly and aggressive routine supplementation.

Engineered antibody Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa(R131) and FcγRIIa(H131).

Engaging inhibitory FcγRIIb by Fc region has been recently reported to be an attractive approach for improving the efficacy of antibody therapeutics. However, the previously reported S267E/L328F variant with enhanced binding affinity to FcγRIIb, also enhances binding affinity to FcγRIIa(R131) allotype to a similar degree because FcγRIIb and FcγRIIa(R131) are structurally similar. In this study, we applied comprehensive mutagenesis and structure-guided design based on the crystal structure of the Fc/FcγRIIb complex to identify a novel Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa(R131) and FcγRIIa(H131). This novel variant has more than 200-fold stronger binding affinity to FcγRIIb than wild-type IgG1, while binding affinity to FcγRIIa(R131) and FcγRIIa(H131) is comparable with or lower than wild-type IgG1. This selectivity was achieved by conformational change of the C(H)2 domain by mutating Pro to Asp at position 238. Fc variant with increased binding to both FcγRIIb and FcγRIIa induced platelet aggregation and activation in an immune complex form in vitro while our novel variant did not. When applied to agonistic anti-CD137 IgG1 antibody, our variant greatly enhanced the agonistic activity. Thus, the selective enhancement of FcγRIIb binding achieved by our Fc variant provides a novel tool for improving the efficacy of antibody therapeutics.

Estimate of gas transfer rates of an intravascular membrane oxygenator.

An asymmetric hollow fiber membrane was prepared from a newly synthesized fluorinated aromatic polyimide (6FDA-6FAP) by using a dry/wet phase inversion process. The membrane was used in a membrane oxygenator over a long period of time. In this study, the potential of the membrane for intravascular membrane oxygenation (IVOX) was studied in respect to oxygen transfer. The gas permeance of the membrane and three commercially available hollow fiber membranes for membrane oxygenators was measured in a gas-gas system and a gas-liquid system and discussed relative to the membrane structures. The oxygen transfer rates of the IVOX devices using these four membranes were estimated by a mathematical kinetic model, with the oxygen permeance measured in the gas-liquid system. The results showed that the device using the 6FDA-6FAP hollow fiber membrane has the highest oxygen transfer rate and is believed to be applicable to IVOX. The methods to determine oxygen transfer rate of a hollow fiber membrane and the mathematical kinetic model, are useful for developing a hollow fiber membrane and a device for oxygenation.