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Laszlo G.S.,Fred Hutchinson Cancer Research Center | Gudgeon C.J.,Fred Hutchinson Cancer Research Center | Harrington K.H.,Fred Hutchinson Cancer Research Center | Dell'Aringa J.,Amgen | And 7 more authors.
Blood | Year: 2014

CD33 is a valid target for acute myeloid leukemia (AML) but has proven challenging for antibody-drug conjugates. Herein, we investigated the cellular determinants for the activity of the novel CD33/CD3-directed bispecific T-cell engager antibody, AMG 330. In the presence of T cells, AMG 330 was highly active against human AML cell lines and primary AML cells in a dose- and effector to target cell ratio-dependent manner. Using cell lines engineered to express wild-type CD33 at increased levels, we found a quantitative relationship between AMG 330 cytotoxicity and CD33 expression; in contrast, AMG 330 cytotoxicity was neither affected by common CD33 single nucleotide polymorphisms nor expression of the adenosine triphosphate-binding cassette (ABC) transporter proteins, P-glycoprotein or breast cancer resistance protein. Unlike bivalent CD33 antibodies, AMG 330 did not reduce surface CD33 expression. The epigenetic modifier drugs, panobinostat and azacitidine, increased CD33 expression in some cell lines and augmented AMG 330-induced cytotoxicity. These findings demonstrate that AMG 330 has potent CD33-dependent cytolytic activity in vitro, which can be further enhanced with other clinically available therapeutics. As it neither modulates CD33 expression nor is affected by ABC transporter activity, AMG 330 is highly promising for clinical exploration as it may overcome some limitations of previous CD33-targeted agents. © 2014 by The American Society of Hematology.


Ertongur-Fauth T.,BRAIN AG | Hochheimer A.,BRAIN AG | Hochheimer A.,Amgen Research GmbH | Buescher J.M.,BRAIN AG | And 2 more authors.
Experimental Dermatology | Year: 2014

Sweating is an important physiological process to regulate body temperature in humans, and various disorders are associated with dysregulated sweat formation. Primary sweat secretion in human eccrine sweat glands involves Ca2+-activated Cl- channels (CaCC). Recently, members of the TMEM16 family were identified as CaCCs in various secretory epithelia; however, their molecular identity in sweat glands remained elusive. Here, we investigated the function of TMEM16A in sweat glands. Gene expression analysis revealed that TMEM16A is expressed in human NCL-SG3 sweat gland cells as well as in isolated human eccrine sweat gland biopsy samples. Sweat gland cells express several previously described TMEM16A splice variants, as well as one novel splice variant, TMEM16A(acΔe3) lacking the TMEM16A-dimerization domain. Chloride flux assays using halide-sensitive YFP revealed that TMEM16A is functionally involved in Ca2+-dependent Cl- secretion in NCL-SG3 cells. Recombinant expression in NCL-SG3 cells showed that TMEM16A(acΔe3) is forming a functional CaCC, with basal and Ca2+-activated Cl- permeability distinct from canonical TMEM16A(ac). Our results suggest that various TMEM16A isoforms contribute to sweat gland-specific Cl- secretion providing opportunities to develop sweat gland-specific therapeutics for treatment of sweating disorders. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Swaminath G.,Amgen Inc. | Jaeckel P.,Amgen Research GmbH | Guo Q.,Amgen Inc. | Cardozo M.,Amgen Inc. | And 5 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

FFA2 (GPR43) is a receptor for short-chain fatty acids (SCFAs), acetate, and propionate. FFA2 is predominantly expressed in islets, a subset of immune cells, adipocytes, and the gastrointestinal tract which suggest a possible role in inflammatory and metabolic conditions. We have previously described the identification and characterization of novel phenylacetamides as allosteric agonists of FFA2. In the current study, we have investigated the molecular determinants contributing to receptor activation with the endogenous and synthetic ligands as well as allosteric interactions between these two sites. The mutational analysis revealed previously unidentified sites that may allosterically regulate orthosteric ligand's function as well as residues potentially important for the interactions between orthosteric and allosteric binding sites. © 2011 Elsevier Inc.


Fox B.M.,Amgen Inc. | Natero R.,Amgen Inc. | Richard K.,Amgen Inc. | Connors R.,Amgen Inc. | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition. © 2011 Elsevier Ltd. All rights reserved.


Wang Y.,Amgen Inc. | Jiao X.,Amgen Inc. | Kayser F.,Amgen Inc. | Liu J.,Amgen Inc. | And 10 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor for which only short-chain fatty acids (SCFAs) have been reported as endogenous ligands. We describe the discovery and optimization of phenylacetamides as allosteric agonists of FFA2. These novel ligands can suppress adipocyte lipolysis in vitro and reduce plasma FFA levels in vivo, suggesting that these allosteric modulators can serve as pharmacological tools for exploring the potential function of FFA2 in various disease conditions. © 2009 Elsevier Ltd. All rights reserved.


Fan F.,Amgen Inc. | Hu R.,Amgen Inc. | Munzli A.,Amgen Research GmbH | Chen Y.,Amgen Inc. | And 7 more authors.
Toxicological Sciences | Year: 2015

Off-target effects of drugs on nuclear hormone receptors (NHRs) may result in adverse effects in multiple organs/ physiological processes. Reliable assessments of the NHR activities for drug candidates are therefore crucial for drug development. However, the highly permissive structures of NHRs for vastly different ligands make it challenging to predict interactions by examining the chemical structures of the ligands. Here, we report a detailed investigation on the agonistic and antagonistic activities of 615 known drugs or drug candidates against a panel of 6 NHRs: androgen, progesterone, estrogen α/β, and thyroid hormone α/β receptors. Our study revealed that 4.7 and 12.4% compounds have agonistic and antagonistic activities, respectively, against this panel of NHRs. Nonetheless, potent, unintended NHR hits are relatively rare among the known drugs, indicating that such interactions are perhaps not tolerated during drug development. However, we uncovered examples of compounds that unintentionally agonize or antagonize NHRs. In addition, a number of compounds showed multi-NHR activities, suggesting that the cross-talk between multiple NHRs co-operate to elicit in vivo effects. These data highlight the merits of counter screening drug candidate against NHRs during drug discovery/ development. © The Author 2015.


Hochheimer A.,BRAIN AG | Hochheimer A.,Amgen Research GmbH | Krohn M.,BRAIN AG | Rudert K.,BRAIN AG | And 4 more authors.
Chemical Senses | Year: 2014

Investigating molecular mechanisms underlying human taste sensation requires functionally dedicated and at the same time proliferating human taste cells. Here, we isolated viable human fungiform taste papillae cells from biopsy samples, adenovirally transduced proliferation promoting genes, and obtained stably proliferating cell lines. Analysis of gene expression of 1 human taste cell line termed HTC-8 revealed that these cells express 13 TAS2R bitter taste receptor genes, CD36, OXTR encoding oxytocin receptor, as well as genes implicated with signal transduction and cell fate control. Bitter tastants triggered functionally distinct signaling pathways in HTC-8 cells. Salicin elicited phospholipase C-dependent calcium signaling and no cell depolarization. In contrast, stimulation with saccharin, aristolochic acid, or phenylthiocarbamide triggered cell depolarization and phospholipase C-independent calcium influx. Simultaneous stimulation with salicin and saccharin revealed that saccharin can enhance the phospholipase C-dependent response to salicin indicating crosstalk of signaling pathways. Our results show that HTC-8 cells are programmed to bitter taste reception but are also responsive to fatty acids, oxytocin, and somatosensory stimuli, whereas HTC-8 cells are insensitive to compounds representing other basic taste qualities. © The Author 2014. Published by Oxford University Press.


Swaminath G.,Amgen Inc. | Jaeckel P.,Amgen Research GmbH | Guo Q.,Amgen Inc. | Cardozo M.,Amgen Inc. | And 5 more authors.
FEBS Letters | Year: 2010

FFAR2 (GPR43) is a receptor for short-chain fatty acids (SCFAs), acetate and propionate. In the current study, we investigate the molecular determinants contributing to receptor activation by endogenous ligands. Mutational analysis revealed several important residues located in transmembrane domains (TM) 3, 4, 5, 6, and 7 for acetate binding. Interestingly, mutations that abolished acetate activity, including the mutation in the well-conserved D(E)RY motif, could be rescued by a recently identified synthetic allosteric agonist. These findings provide additional insight into agonist binding and activation which may aid in designing allosteric ligands for targeting receptor function in various diseases. © 2010 Federation of European Biochemical Societies.


PubMed | Amgen Research GmbH
Type: Journal Article | Journal: Toxicological sciences : an official journal of the Society of Toxicology | Year: 2015

Off-target effects of drugs on nuclear hormone receptors (NHRs) may result in adverse effects in multiple organs/physiological processes. Reliable assessments of the NHR activities for drug candidates are therefore crucial for drug development. However, the highly permissive structures of NHRs for vastly different ligands make it challenging to predict interactions by examining the chemical structures of the ligands. Here, we report a detailed investigation on the agonistic and antagonistic activities of 615 known drugs or drug candidates against a panel of 6 NHRs: androgen, progesterone, estrogen /, and thyroid hormone / receptors. Our study revealed that 4.7 and 12.4% compounds have agonistic and antagonistic activities, respectively, against this panel of NHRs. Nonetheless, potent, unintended NHR hits are relatively rare among the known drugs, indicating that such interactions are perhaps not tolerated during drug development. However, we uncovered examples of compounds that unintentionally agonize or antagonize NHRs. In addition, a number of compounds showed multi-NHR activities, suggesting that the cross-talk between multiple NHRs co-operate to elicit in vivo effects. These data highlight the merits of counter screening drug candidate against NHRs during drug discovery/development.


For treatment of patients with prostate cancer (PCa), we developed a novel T cell-engaging (BiTE) antibody designated AMG 212 or BAY2010112 that is bispecific for prostate-specific membrane antigen (PSMA) and the CD3 epsilon subunit of the T cell receptor complex. AMG 212/BAY2010112 induced target cell-dependent activation and cytokine release of T cells, and efficiently redirected T cells for lysis of target cells. In addition to Chinese hamster ovary cells stably expressing human or cynomolgus monkey PSMA, T cells redirected by AMG 212/BAY2010112 also lysed human PCa cell lines VCaP, 22Rv1, MDA PCa 2b, C4-2, PC-3-huPSMA, and LnCaP at half maximal BiTE concentrations between 0.1 and 4 ng/mL (1.8-72 pmol/L). No lysis of PSMA-negative human PCa cell lines PC-3 and DU145 was observed. The subcutaneous (s.c.) formation of tumors from PC-3-huPSMA cells in NOD/SCID mice was significantly prevented by once daily intravenous (i.v.) injection of AMG 212/BAY2010112 at a dose level as low as 0.005 mg/kg/d. Rapid tumor shrinkage with complete remissions were observed in NOD/SCID mice bearing established s.c. 22Rv1 xenografts after repeated daily treatment with AMG 212/BAY2010112 by either the i.v. or s.c. route. Of note, 22Rv1 tumors were grown in the absence of human T cells followed by intraperitoneal injection of T cells 3 days before BiTE treatment. No effects on tumor growth were observed in the absence of human T cells or AMG 212/BAY2010112. On the basis of these preclinical results, AMG 212/BAY2010112 appears as a promising new BiTE antibody for the treatment of patients with PSMA-expressing PCa.

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