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Supplementary Figure 12 shows the ELISA assay with the dose-dependent C1q binding to plate-adsorbed sasanlimab and the ADCC assay of sasanlimab performed with activated T cells (target cells) and stimulated PBMCs (effector cells).

Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.

Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.

We have developed instrumentation for collecting the luminescence spectrum from solid samples while they are irradiated by electrons of sufficient energy to produce point defects. This instrumentation is used to investigate the evolution of the broad region of the zinc oxide luminescence spectrum which lies between 250 nm and 650 nm (4.95 eV to 1.90 eV). Electron irradiation is at 0.55 MeV and 1.0 MeV. Irradiation at 0.55 MeV produces only defects associated with displaced oxygen. Irradiation at 1.0 MeV produces defects which can be associated with displacement of either oxygen or Zn. The samples were held at liquid-nitrogen temperature to give the best possible defect lifetime for any defect created. A luminescent band centered at 415 nm (2.99 eV) was observed to grow with increasing irradiation dose in samples grown by pulsed laser deposition. There was no difference in the growth of the luminescence during irradiation at 0.55 MeV and 1.0 MeV. No discernible luminescence or alteration of the luminescence from the traditional green band region was observed during irradiation of these samples.

A fast ion loss detector has been constructed and implemented on the Madison Symmetric Torus (MST) to investigate energetic ion losses and transport due to energetic particle and MHD instabilities. The detector discriminates particle orbits solely on pitch and consists of two thin-foil, particle collecting plates that are symmetric with respect to the device aperture. One plate collects fast ion signal, while the second aids in the minimization of background and noise effects. Initial measurements are reported along with suggestions for the next design phase of the detector.

Studies directed toward the process research, development, and scale-up preparation of the potential αvβ3 integrin antagonist 1 are described. A convergent approach is detailed wherein tetrahydropyrimidine hydroxybenzoic acid 2 is linked to the β-amino acid ester 3 via a diisoproylcarbodiimide, catalytic HOBt coupling reaction. Saponification of the resulting ethyl ester, isolation of the corresponding zwitterion, H3PO4 salt formation, crystallization, and acetonitrile-to-acetone exchange give rise to 1 as a crystalline monohydrate in 67% overall yield from 4.

The process development of a peptide coupling with CDI is discussed. Various solvents, addition orders, stoichiometries, and reaction temperatures were investigated. A reliable crystallization procedure was also developed. The new process was piloted to provide 342 kg of product in two batches with an average 85% yield and 99% assay.

The heat of reaction is an important parameter in the safe, successful scale-up of chemical processes. Reaction heat data is used to calculate the potential adiabatic temperature rise of the desire...

Studies directed toward the process research and development of a scalable method for preparing tetrahydropyrimidine 2, a key intermediate to the αvβ3 integrin antagonist 1, are described. A linear approach employing 3-amino-5-hydroxybenzoic acid, methyl isothiocyanate, and 1,3-diaminopropan-2-ol as key reagents is detailed. The results of process development research, a successful pilot run, and a production campaign are explained.

Described are studies directed toward the chemical research and development of an alternative synthesis to 9, the penultimate intermediate of clofencet (1), a novel wheat-hybridizing agent. Retrosynthetic analyses as well as the results obtained from feasibility studies are detailed, leading to the successful development of an alternative process. The key features of the novel route are a method for preparing on-scale ethyl diazoacetate (28) in a safe and effective manner, and the Lewis acid-catalyzed reaction of 28 with hydrazonoacetaldehyde 29, affording β-ketoester 30. The synthesis is completed via propionylation of 30, acid-catalyzed cyclization of 31 to pyridazinecarboxylic acid ester 32, followed by saponification and isolation of carboxylic acid 9. The results and challenges of eight pilot-plant runs are reported. The baseline process developed produced over 45 kg of 9 in 43−45% yield.

Described are four process research investigations directed toward discerning a scalable, enantioselective method for preparing (S)-β-amino acid ester 3, a key intermediate to the αvβ3 integrin antagonist 1. Reported are an asymmetric Michael reaction approach, attempts to enantioselectively hydrogenate an enamine, resolution of (±)-3 via diastereomeric salt formation, and a synthetic route employing a novel, diastereoselective imino-Reformatsky reaction. This last research initiative proved successful and was employed as the enabling route to initial API supply. Process development of this enabling chemistry is reported. The technical issues researched and optimized were (1) the necessity of employing MEM-protection for high yield and diastereoselectivity in the imino-Reformatsky reaction, (2) the reaction kinetics of MEM chloride hydrolysis and the application of these data to an on-scale quench procedure, (3) the efficient formation of the (S)-phenylglycinol imine 15 in NMP and a dehydration of this pr...

Ethyl diazoacetate is an important organic chemistry synthon, but its use as an industrial intermediate is limited due in part to the safety concerns associated with its instability and high reactivity. Reported are the reaction calorimetry results obtained from a new ethyl diazoacetate preparative method, the results from its use in a novel, exothermic reaction and the application of this data toward process development, a successful pilot plant campaign and full-scale reactor design. The results indicate that, given the proper engineering design, in situ preparation and use of ethyl diazoacetate solutions can be used at production scale without significant risk.

Ethyl diazoacetate is an important organic chemistry synthon, but its use as an industrial intermediate is limited due in part to the safety concerns associated with its instability and high reactivity. In a continuing effort to understand the risk of employing ethyl diazoacetate as an industrial reagent, detonation tests were completed. The results of these studies indicate that ethyl diazoacetate does not show detonation properties.

Ethyl diazoacetate (EDA) is an important organic chemistry synthon, but its use as an industrial intermediate is limited due in part to the safety concerns associated with its instability and high reactivity. In a continuing effort to understand the risk of employing EDA as an industrial reagent, the thermal stability of EDA was studied. Reported are the results of accelerating rate and differential scanning calorimetry (DSC) experiments.

Ethyl diazoacetate is an important organic chemistry synthon, but its use as an industrial intermediate is limited due in part to the safety concerns associated with its instability and high reactivity. Reported are the reaction calorimetry results obtained from a new ethyl diazoacetate preparative method, the results from its use in a novel, exothermic reaction and the application of this data toward process development, a successful pilot plant campaign and full-scale reactor design. The results indicate that, given the proper engineering design, in situ preparation and use of ethyl diazoacetate solutions can be used at production scale without significant risk.

Convergent synthesis of 8-fluoronaphthalen-1-ylamine (6) was achieved through the reaction of 1H-naphtho[1,8-de][1,2,3]triazine (15) with HF-pyridine under mild conditions. This new synthesis for the preparation of 6 overcame many scale-up challenges that exist in the methods reported in the literature and provided a practical alternative synthesis of 1-(8-fluoronaphthalen-1-yl)piperazine (1).

We report the discovery of two giant planets orbiting the K giant HD 33844 based on radial velocity data from three independent campaigns. The planets move on nearly circular orbits with semimajor axes $a_b=1.60\pm$0.02 AU and $a_c=2.24\pm$0.05 AU, and have minimum masses (m sin $i$) of $M_b=1.96\pm$0.12 Mjup and $M_c=1.76\pm$0.18 Mjup. Detailed N-body dynamical simulations show that the two planets remain on stable orbits for more than $10^6$ years for low eccentricities, and are most likely trapped in a mutual 3:5 mean-motion resonance., Accepted for publication in ApJ

Electron drift velocities in mixtures of SiF4 and Ar have been measured using a pulsed‐Townsend type drift tube. A set of vibrational excitation cross sections of electron scattering in SiF4 has been subsequently determined by the swarm analyses of measured transport data in highly dilute SiF4−Ar mixtures. The derived cross sections are consistent with the electron transport properties over an order of magnitude in SiF4 concentration in gas mixtures, thus providing evidence that the main features of their near threshold behavior, and of their absolute magnitude have been captured.

Electron drift velocities were measured for argon gas mixtures containing 25 ppm to 0.5% boron trichloride additive using a pulsed‐Townsend drift tube. These results show a marked sensitivity to mixture ratio and the gas mixtures also show negative differential conductivity and strong attachment at low electric field/gas number density.

Summary form only given, as follows. Plasma processing of materials has emerged as the enabling technology for many industrial applications ranging from the fabrication of microelectronic circuits to coatings for advanced combustion engines. There are also applications in waste treatment, chemical processing, and medicine. After impressive, mainly empirical successes, further developments now require more precise control and understanding of the mechanisms for selective deposition, etching, or reaction. The electron temperature of a non-equilibrium plasma can easily be 20,000 K while the gas temperature is less than 500 K. The reactivity of the plasma-excited gases is often enhanced by many orders of magnitude. Reliable collisional data for non-traditional gases such as BCl/sub 3/, (C/sub 2/H/sub 5/O)/sub 4/Si, SiF/sub 4/, and ((C/sub 2/H/sub 5/)/sub 2/N)/sub 4/Ti are critical to modeling and scaling industrial processes. Electron and ion collisions, especially those causing dissociation of the initial gases, and reactions of the resulting radicals with gases and at surfaces are crucial. Extant collisional data and methods are reviewed in the context of emerging technological requirements. Examples are presented for i) 'crossed-beam' and 'swarm' studies of electron-molecule collisions, ii) Fourier Transform Mass Spectroscopy probes of dissociative ionization, attachment, and charge-transfer collisions, and iii) Surface Desorption Spectroscopy examinations of surface reactions.

The unmasking of primary amines via the heterocycloreversion of N-alkyl-2-azanorbornenes can be catalyzed by either copper(II) or a sulfonic acid based ion exchange resin which obviates the necessity of employing a reactive dienophile to trap the cyclopentadiene as it is produced

L'influence accelerante de l'eau comme solvant, sur la vitesse de la transposition de Claisen a ete demontree pour divers substrats

The unmasking of primary amines via the heterocycloreversion of N-alkyl-2-azanorbornenes can be catalyzed by either copper(II) or a sulfonic acid based ion exchange resin which obviates the necessity of employing a reactive dienophile to trap the cyclopentadiene as it is produced

Le compose du titre est obtenu via un C-12 O-carbamate (issu lui-meme de l'acylation d'un alcool allylique derive de la O-methyl-6 erythromycine A) qui se cyclise ensuite entre C-11 et C-12 par une reaction de Michael intramoleculaire

L'influence accelerante de l'eau comme solvant, sur la vitesse de la transposition de Claisen a ete demontree pour divers substrats

EPR data for NiSiF6⋅6H2O at Ku band and Ka band between 77 and 298 °K were fitted to an isotropic g value of approximately 2.25 with ‖D‖ varying from (0.166±0.005) cm−1 at 77 °K to (0.51±0.01) cm−1 at 298 °K. The values g∥=2.26±0.01 and ‖D‖= (0.125±0.005) cm−1 were obtained from a Ku band measurement at 4.2 °K. The magnitude of the temperature gradient ∂D/∂T had a broad maximum of about 1.8×10−3 cm−1/ °K near 200 °K, decreasing to about 1.5×10−3 cm−1/ °K near room temperature. The spin–lattice relaxation rate was determined from linewidth measurements to vary as T2 above 200 °K. From an expression for the Raman process in the high temperature limit, the Debye Temperature ϑD was deduced to be approximately 107 °K.

Le compose du titre est obtenu via un C-12 O-carbamate (issu lui-meme de l'acylation d'un alcool allylique derive de la O-methyl-6 erythromycine A) qui se cyclise ensuite entre C-11 et C-12 par une reaction de Michael intramoleculaire

EPR data for NiSiF6⋅6H2O at Ku band and Ka band between 77 and 298 °K were fitted to an isotropic g value of approximately 2.25 with ‖D‖ varying from (0.166±0.005) cm−1 at 77 °K to (0.51±0.01) cm−1 at 298 °K. The values g∥=2.26±0.01 and ‖D‖= (0.125±0.005) cm−1 were obtained from a Ku band measurement at 4.2 °K. The magnitude of the temperature gradient ∂D/∂T had a broad maximum of about 1.8×10−3 cm−1/ °K near 200 °K, decreasing to about 1.5×10−3 cm−1/ °K near room temperature. The spin–lattice relaxation rate was determined from linewidth measurements to vary as T2 above 200 °K. From an expression for the Raman process in the high temperature limit, the Debye Temperature ϑD was deduced to be approximately 107 °K.