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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.

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.

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).

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.

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.