An Fc variant with two mutations confers prolonged serum half-life and enhanced effector functions on IgG antibodies

The pH-selective interaction between the immunoglobulin G (IgG) fragment crystallizable region (Fc region) and the neonatal Fc receptor (FcRn) is critical for prolonging the circulating half-lives of IgG molecules through intracellular trafficking and recycling. By using directed evolution, we successfully identified Fc mutations that improve the pH-dependent binding of human FcRn and prolong the serum persistence of a model IgG antibody and an Fc-fusion protein. Strikingly, trastuzumab-PFc29 and aflibercept-PFc29, a model therapeutic IgG antibody and an Fc-fusion protein, respectively, when combined with our engineered Fc (Q311R/M428L), both exhibited significantly higher serum half-lives in human FcRn transgenic mice than their counterparts with wild-type Fc. Moreover, in a cynomolgus monkey model, trastuzumab-PFc29 displayed a superior pharmacokinetic profile to that of both trastuzumab-YTE and trastuzumab-LS, which contain the well-validated serum half-life extension Fcs YTE (M252Y/S254T/T256E) and LS (M428L/N434S), respectively. Furthermore, the introduction of two identified mutations of PFc29 (Q311R/M428L) into the model antibodies enhanced both complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity activity, which are triggered by the association between IgG Fc and Fc binding ligands and are critical for clearing cancer cells. In addition, the effector functions could be turned off by combining the two mutations of PFc29 with effector function-silencing mutations, but the antibodies maintained their excellent pH-dependent human FcRn binding profile. We expect our Fc variants to be an excellent tool for enhancing the pharmacokinetic profiles and potencies of various therapeutic antibodies and Fc-fusion proteins.Subject terms: Antibody therapy, Molecularly targeted therapy, Drug development     

Preparation and electrochemical performance of titanium nitride-graphene nanocomposite with high Ti contents and tailored morphology

Titanium nitride (TiN) - graphene (G) nanocomposites are promising for electrochemical charge storage where a high content of Ti species is desired. Herein, we propose an effective method for the preparation of TiN-G nanocomposites with a high concentration of Ti species. These nanocomposites can be successfully achieved through a further deposition of Ti on Ti-graphene oxide (GO) or a thermally exfoliated Ti-GO. Depending on the annealing condition employed (NH₃ and N₂), two types of TiN-G nanocomposites (NH₃ annealing for TiN/G and TiN/G-TE, TE: thermal exfoliation) and a TiO₂-G nanocomposite (N₂ annealing for TiO₂/G-TE) were prepared. These nanocomposites were then investigated for potential application as an electrochemical supercapacitor. Compare with TiO₂/G-TE, the TiN-G nanocomposites both exhibited a higher specific capacitance, although one of these nanocomposites had a lower surface area than TiO₂/G-TE. Among the nanocomposites prepared, TiN/G-TE delivered the best electrochemical performance. The relationship between the physical properties and the capacitive performance of the nanocomposites were systematically evaluated.     

Prüfung von Genussmilehsäure und Weinsäure

Analytical and Bioanalytical Chemistry -     

Characteristic polynomials of complement of graph bundles and their applications

We study the structure of the complement of an F-bundle over a graph G when it can be expressed as an F-bundle over another graph G. In particular, we compute the characteristie polynomial of the complement of an F-bundle when its voltages lie in and abelian subgroup Г of Aut(F) which acts freely and transitively on the vertices of the fiber F Some applications to regular embeddings of graph bundles into Euclidean spaces are also discussed     

Chattering alleviation in vibration control of smart beam structures using piezofilm actuators: Experimental verification

This paper presents a new discrete-time sliding mode controller to alleviate undesirable chattering in vibration control of a flexible beam structure. A smart beam featuring a piezoelectric film is devised and its governing equation of motion is derived. A discrete-time sliding mode controller which consists of discontinuous part and equivalent part is then designed by considering the separation principle. By doing this, undesirable chattering of the beam structure can be attenuated in the settled phase. The proposed controller is experimentally realized, and both transient and forced vibration control responses are evaluated in time domain.     

Importance of aliphatic C–H hydrogen bonding on anion recognition

We have designed and synthesised new anion receptors 1 and 2, both of their C–H groups were at the α positions to carbonyl groups and further polarised by the attached polarising substituents. This enabled us to study hydrogen bonding donor ability of C–H bonds. The polarising substituents are electron withdrawing cyano group for host 1, while charged pyridinium group for host 2. As expected from charge effects, host 2 shows roughly an order of magnitude higher binding constants against various anion guests than those of receptor 1. Since the magnitude of polarisation change should be greatest for C–H group among various hydrogen bonding groups, this indicates the importance of C–H hydrogen bonding. In contrast, the relative order of binding constants was the same for both host 1 and 2. The order of association constants was found to be (CH₃)₂POO^? > CH₃COO^? > C₆H₅COO^? > Cl^? > Br^?. DFT calculation results were in good agreement with experimental binding constants and confirmed the importance of charged group substitution. In addition, receptor 1 showed the highest association constant for dimethyl phosphinate, which is implicated in many metabolic diseases.     

Isoperimetric numbers of graph bundles

The main aim of this paper is to give some upper and lower bounds for the isoperimetric numbers of graph coverings or graph bundles, with exact values in some special cases. In addition, we show that the isoperimetric number of any covering graph is not greater than that of the base graph. Mohar's theorem for the isoperimetric number of the cartesian product of a graph and a complete graph can be extended to a more general case: The isoperimetric numberi(G × K _2n) of the cartesian product of any graphG and a complete graphK _2n on even vertices is the minimum of the isoperimetric numberi(G) andn, and it is also a sharp lower bound of the isoperimetric numbers of all graph bundles over the graphG with fiberK _2n. Furthermore, ifn 2i(G) then the isoperimetric number of any graph bundle overG with fibreK _n is equal to the isoperimetric numberi(G) ofG. Partially supported by The Ministry of Education, Korea.