A new proton conductor, RbMg 1Àx H 2x (PO 3 ) 3 $yH 2 O, was synthesized by the coprecipitation method followed by sintering at 540 K. The range of solid solution for RbMg 1Àx H 2x (PO 3 ) 3 $yH 2 O was 0.00 < x < 0.18 and the highest conductivity of 5.5 Â 10 À3 S cm À1 was observed at 443 K for the composition of x ¼ 0.11. The structure of RbMg 1Àx H 2x (PO 3 ) 3 $yH 2 O was determined from 298 to 553 K by Rietveld refinement with multi-profile analysis using X-ray and neutron diffraction data. The framework structure is composed of PO 4 tetrahedra connected with each other by corner-sharing to form spiral PO 4 chains along the c-direction. One-dimensional tunnels are formed between these spiral chains, in which water molecules are located. The water molecules form one-dimensional spiral chains and are connected to the spiral PO 4 chain by hydrogen bonding. The introduction of acidic, hydrophilic head groups (-PO 3 H) into the PO 4 framework by the formation of a solid solution provides binding sites for water and an environment for the efficient diffusion of protons. One-dimensional proton diffusion, similar to proton channels in biological systems, could be explained by the vehicle mechanism of H 3 O + along the one-dimensional water chain.

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Efficient production of bispecific antibodies (BsAbs) in single mammalian cells is essential for basic research and industrial manufacturing. However, preventing unwanted pairing of heavy chains (HCs) and light chains (LCs) is a challenging task. To address this, we created an engineering technology for preferential cognate HC/LC and HC/HC paring called FAST-Ig (Four-chain Assembly by electrostatic Steering Technology – Immunoglobulin), and applied it to NXT007, a BsAb for the treatment of hemophilia A. We introduced charged amino-acid substitutions at the HC/LC interface to facilitate the proper assembly for manufacturing a standard IgG-type BsAb. We generated CH1/CL interface-engineered antibody variants that achieved > 95% correct HC/LC pairing efficiency with favorable pharmacological properties and developability. Among these, we selected a design (C3) that allowed us to separate the mis-paired species with an unintended pharmacological profile using ion-exchange chromatography. Crystal structure analysis demonstrated that the C3 design did not affect the overall structure of both Fabs. To determine the final design for HCs-heterodimerization, we compared the stability of charge-based and knobs into hole-based Fc formats in acidic conditions and selected the more stable charge-based format. FAST-Ig was also applicable to stable CHO cell lines for industrial production and demonstrated robust chain pairing with different subclasses of parent BsAbs. Thus, it can be applied to a wide variety of BsAbs both preclinically and clinically.

Starting from the integrable two-loop spin-chain Hamiltonian describing the anomalous dimensions of scalar operators in the planar N = 6 superconformal Chern-Simons theory of ABJM, we perform a direct coordinate Bethe ansatz computation of the corresponding two-loop S-matrix. The result matches with the weak-coupling limit of the scalar sector of the all-loop S-matrix which we have recently proposed. In particular, we confirm that the scattering of A and B particles is reflectionless. As a warm up, we first review the analogous computation of the one-loop S-matrix from the one-loop dilatation operator for the scalar sector of planar N = 4 superconformal Yang-Mills theory, and compare the result with the all-loop SU(2|2) 2 S-matrix. ArXiv ePrint: 0901.3334 Exact factorized S-matrices [1] play a key role in the understanding of integrable models. Planar four-dimensional N = 4 superconformal Yang-Mills (YM) theory (and therefore, according to the AdS 5 /CF T 4 correspondence [2], a certain type IIB superstring theory on AdS 5 ×S 5 ) is believed to be integrable (see [3]-[6] and references therein). A corresponding exact factorized S-matrix with SU(2|2) 2 symmetry has been proposed (see [7]-[14] and references therein), which leads [8, 15, 16] to the all-loop Bethe ansatz equations (BAEs) [17].Aharony, Bergman, Jafferis and Maldacena (ABJM) [18] recently proposed an analogous AdS 4 /CF T 3 correspondence relating planar three-dimensional N = 6 superconformal Chern-Simons (CS) theory to type IIA superstring theory on AdS 4 × CP 3 . Minahan and Zarembo [19] subsequently found that the scalar sector of N = 6 CS is integrable at the leading two-loop order, and proposed two-loop BAEs for the full theory (see also [20]). Moreover, evidence for classical integrability of the dual string sigma model (large-coupling limit) was discovered in [21][22][23]. On the basis of these results, and assuming integrability to all orders, Gromov and Vieira then conjectured all-loop BAEs [24].Based on the symmetries and the spectrum of elementary excitations [19,25,26], we proposed an exact factorized AdS 4 /CF T 3 S-matrix [28]. As a check, we verified that this

Background Emicizumab (HEMLIBRA®) is a factor (F) VIII function-mimetic therapeutic bispecific antibody (BsAb) to FIXa and FX able to prevent bleeding in persons with hemophilia A (PwHA) when injected subcutaneously once every 1, 2 or 4 weeks. To develop a next generation version, we sought an agent able to keep hemostatic potential in non-hemophilic range with more convenient dosing regimen (dosing frequency/volume). We successfully created the emicizumab-based engineered four-chain BsAbs, NXT series. Among these, we selected NXT007 as a clinical candidate. Objectives The aim of this study is to clarify the in vitro and in vivo properties of NXT007 and predict its therapeutic potency non-clinically. Methods We evaluated the pharmacological activities of NXT007 in vitro using a thrombin generation assay (TGA) with FVIII-deficient patient plasma, and in vivo by inducing bleeding in FVIII-neutralizing antibody-treated acquired hemophilia A cynomolgus monkey (cyno) model. To clarify the FVIII-cofactor activity of NXT007, we performed an enzymatic kinetics analysis of FIXa-catalyzed FX activation with and without NXT007, as well as surface plasmon resonance analysis to determine the dissociation constant (KD) of NXT007 to FIX, FIXa, FX and FXa. We obtained its pharmacokinetic (PK) profile in non-human primates in a single dose SC/IV study. Results In vitro addition of NXT007 at 30 μg/mL increased the peak height of TGA in FVIII-deficient plasma to the same levels achieved by recombinant human FVIII at 40-100 IU/dL (FXIa-triggering) or 100-150 IU/dL (tissue factor-triggering). A single bolus intravenous injection of NXT007 (0.075 mg/kg) ameliorated bleeding symptoms in the cyno model to similar as a twice daily intravenous injection of recombinant porcine FVIII (20 U/kg). The in vitro and in vivo results were roughly concordant. NXT007 increased the turnover rate (kcat) of FIXa-catalyzed FX activation by approximately 4,000-folds compared to the condition without cofactor. The impact of NXT007 on the kcat was similar to that of emicizumab. As for binding affinities, the KD values of NXT007 to FIX, FIXa, FX and FXa were 1.08, 0.728, 0.0538 and 0.0231 μM, respectively in buffer solution. Compared to emicizumab, NXT007 bound more strongly to FX/FXa and with similar affinity to FIX/FIXa. This means that NXT007 would have an ability to form more FIX-BsAb-FX ternary complex than emicizumab. Calculated using the above KD values, at 30 μg/mL of BsAb the estimated concentration of FIX-NXT007-FX ternary complex in plasma is approximately 10-fold higher than that of the FIX-emicizumab-FX ternary complex which is roughly concordant with the difference in their FVIII equivalent thrombin generation activity. Prothrombin time (PT) was not clearly prolonged suggesting minimal impact on FX function by in vitro addition of NXT007 at up to 30 μg/mL, which was enough to induce sufficient thrombin burst in FVIII-deficient plasma as described above. A half-life of NXT007 was 19.6 to 24.4 days (0.02-2 mg/kg, SC) and SC bioavailability was 84.4% (2 mg/kg) in the in vivo cyno PK study, in which no obvious change in plasma FIX or FX levels was observed after 0.02-2 mg/kg single SC administration. Conclusions Based on the nonclinical results, NXT007, delivered in every-4-week SC injections, will keep a non-hemophilic range of equivalent FVIII thrombin generation in PwHA, Compared with emicizumab, NXT007's improved cofactor activity may be attributed to its more efficient ternary complex formation while keeping turnover rate with minimal impact on FX function suggested by PT value and antigen accumulation. A phase 1/2 clinical study of NXT007 is now on-going (NXTAGE; JapicCTI-194919). Disclosures Yamaguchi: Chugai Pharmaceutical Co., Ltd: Current Employment. Soeda:Chugai Pharmaceutical Co., Ltd.: Current Employment. Sato:Chugai Pharmaceutical Co., Ltd.: Current Employment. Shibahara:Chugai Pharmaceutical Co., Ltd.: Current Employment. Koga:Chugai Pharmaceutical Co., Ltd.: Current Employment. Ichiki:Chugai Pharmaceutical Co., Ltd.: Current Employment. Joyashiki:Chugai Pharmaceutical Co., Ltd.: Current Employment. Teranishi:Chugai Pharmaceutical Co., Ltd.: Current Employment. Nishimura:Chugai Pharmaceutical Co., Ltd.: Current Employment. Shiraiwa:Chugai Pharmaceutical Co., Ltd.: Current Employment. Kitamura:Chugai Pharmaceutical Co., Ltd.: Current Employment. Igawa:Chugai Pharmaceutical Co., Ltd.: Current Employment. Konishi:Chugai Pharmaceutical Co., Ltd.: Current Employment. Kitazawa:Chugai Pharmaceutical Co., Ltd.: Current Employment.