Phase I Trial of ISIS 104838, a 2′-Methoxyethyl Modified Antisense Oligonucleotide Targeting Tumor Necrosis Factor-α

Sewell, K. Lea; Geary, Richard S.; Baker, Brenda F.; Glover, Josephine M.; Mant, Timothy; Yu, Rosie Z.; Tami, Joseph A.; Dorr, F. Andrew

doi:10.1124/jpet.102.036749

Cited by 114 publications

(73 citation statements)

References 28 publications

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“…The published clinical experience to date confirms a lack of complement activation associated with 29-MOE-modified ASOs following subcutaneous or short-term intravenous infusion (Sewell et al, 2002;Chi et al, 2005;Kastelein et al, 2006). This is consistent with a query of the Isis Clinical Safety Database that indicated no meaningful or dosedependent increase in complement split products (e.g., $2Â ULN for Bb) in 767 subjects with subcutaneous administration of 29-MOE-modified ASOs at typical therapeutic doses (50-400 mg total dose).…”

Section: Discussionmentioning

confidence: 67%

“…Although the concern for complement activation in clinical trials has been effectively addressed through dosing paradigms (Glover et al, 1997;Nemunaitis et al, 1999;Sewell et al, 2002), it is still of interest to better understand complement activation in monkeys and the potential relevance to other laboratory animals and humans. Over the years, it has become clear that complement activation does not occur in mice, rats, pigs, or dogs with 29-MOE ASOs (Isis internal data).…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic Understanding for the Greater Sensitivity of Monkeys to Antisense Oligonucleotide–Mediated Complement Activation Compared with Humans

Shen

Frazer‐Abel

Reynolds

et al. 2014

J Pharmacol Exp Ther

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Differences in sensitivity of monkeys and humans to antisense oligonucleotide (ASO)-induced complement alternative pathway (AP) activation were evaluated in monkeys, humans, and in serum using biochemical assays. Transient AP activation was evident in monkeys at higher doses of two 29-O-methoxyethyl (29-MOE) ASOs (ISIS 426115 and ISIS 183750). No evidence of AP activation was observed in humans for either ASO, even with plasma ASO concentrations that reached the threshold for activation in monkeys. The absence of complement activation in humans is consistent with a query of the Isis Clinical Safety Database containing 767 subjects. The in vivo difference in sensitivity was confirmed in vitro, as monkey and human serum exposed to increasing concentrations of ASO indicated that monkeys were more sensitive to AP activation with this class of compounds. The mechanistic basis for the greater sensitivity of monkeys to AP activation by 29-MOE ASO was evaluated using purified human or monkey factor H protein. The binding affinities between a representative 29-MOE ASO and either purified protein are similar. However, the IC 50 of fluid-phase complement inhibition for monkey factor H is about 3-fold greater than that for human protein using either monkey serum or factor H-depleted human serum. Interestingly, there is a sequence variant in the monkey complement factor H gene similar to a single nucleotide polymorphism in humans that is correlated with decreased factor H protein function. These findings show that monkeys are more sensitive to 29-MOE ASO-mediated complement activation than humans likely because of differences in factor H inhibitory capacity.

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Mechanistic Understanding for the Greater Sensitivity of Monkeys to Antisense Oligonucleotide–Mediated Complement Activation Compared with Humans

Shen

Frazer‐Abel

Reynolds

et al. 2014

J Pharmacol Exp Ther

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“…Oligonucleotides based on the phosphorothioate backbone are highly promising compounds for therapeutic antisense applications. The first of these antisense oligonucleotides was admitted to market in 1998 and further RNase H activating phosphorothioate oligonucleotides are currently in various stages of clinical trial [3,[19][20][21]. Investigation of the dissociation pattern of phosphorothioate, and phosphodiester oligodeoxyribonucleotides in gas-phase revealed that both backbone modifications yield the same types of fragment ions [22,23].…”

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confidence: 99%

Gas-phase dissociation of oligoribonucleotides and their analogs studied by electrospray ionization tandem mass spectrometry

Tromp

Schürch

2005

J. Am. Soc. Mass Spectrom.

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Oligoribonucleotides (RNA) and modified oligonucleotides were subjected to low-energy collision-induced dissociation in a hybrid quadrupole time-of-flight mass spectrometer to investigate their fragmentation pathways. Only very restricted data are available on gas-phase dissociation of oligoribonucleotides and their analogs and the fundamental mechanistic aspects still need to be defined to develop mass spectrometry-based protocols for sequence identification. Such methods are needed, because chemically modified oligonucleotides can not be submitted to standard sequencing protocols.In contrast to the dissociation of DNA, dissociation of RNA was found to be independent of nucleobase loss and it is characterized by cleavage of the 5=-POO bond, resulting in the formation of c-and their complementary y-type ions. To evaluate the influence of different 2=-substituents, several modified tetraribonucleotides were analyzed. Oligoribonucleotides incorporating a 2=-methoxy-ribose or a 2=-fluoro-ribose show fragmentation that does not exhibit any preferred dissociation pathway because all different types of fragment ions are generated with comparable abundance. To analyze the role of the nucleobases in the fragmentation of the phosphodiester backbone, an oligonucleotide lacking the nucleobase at one position has been studied. Experiments indicated that the dissociation mechanism of RNA is not influenced by the nucleobase, thus, supporting a mechanism where dissociation is initiated by formation of an intramolecular cyclic transition state with the 2=-hydroxyl proton bridged to the 5=-phosphate oxygen. A ntisense oligonucleotides are nucleic acids of about 12 to 20 nucleobases, which are designed to hybridize to a complementary messenger RNA (mRNA) sequence, thus, inhibiting gene expression [1][2][3]. Therefore, they are of great interest in human cancer therapy and for diagnostic applications. Besides the high binding specificity of antisense oligonucleotides to their target mRNA, affinity, bioavailability, and biostability are of foremost importance. However, a major drawback of the application of unmodified phosphodiester DNA or RNA oligonucleotides is that these structures are subjected to rapid nuclease degradation under physiological conditions. To improve these factors, oligonucleotide analogs, exhibiting chemical modifications of the phosphodiester backbone, of the ribose, and, to a limited extent, also of the nucleobases, are evaluated.Mechanisms of inhibition of gene expression by antisense oligonucleotides involve mRNA degrading enzymes such as RNase H, blockade of translation initiation, or modulation of splicing [4][5][6][7]. These mechanisms allow the application of new chemical modifications to increase the binding affinity and the nuclease resistance. Possible positions of the modifications are the phosphodiester backbone, the sugar unit and the nucleobases. Introduction of a phosphorothioate backbone increases nuclease resistance of antisense oligonucleotides and simultaneously serves as a very efficient su...

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“…NAPs may be of therapeutic benefit to treat many viral infections, as NAPs share the well-conserved pharmacokinetic characteristics of PS-ONs in mammalian species: following administration, PS-ONs are rapidly cleared from the blood (typically less than 1 h), with significant and durable accumulations in the kidney, liver, spleen, and lung (levels of accumulation are greatest in the kidney, with decreasing but still significant amounts in liver, spleen, and lung), and up to 40% of the administered dose accumulates in the liver (13)(14)(15)(16). Consistent with this behavior, NAPs have been shown to be active in vivo against virus infections with tropism in these organs: CMV, HCV, LCMV, influenza virus A, and respiratory syncytial virus (RSV) (7, 10, 11; A. Vaillant, unpublished observation).…”

mentioning

confidence: 99%

Nucleic Acid Polymers Inhibit Duck Hepatitis B Virus InfectionIn Vitro

Noordeen

Vaillant²,

Jilbert

2013

Antimicrob Agents Chemother

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A pproximately 2 billion individuals are infected with hepatitis B virus (HBV) at some point in their life. Of these, over 400 million develop chronic HBV infection, with persistent HBV DNA and HBV surface antigen (HBsAg) in serum due to continuous production of HBV antigens and HBV DNA in the liver (1). The consequences of chronic HBV infection include cirrhosis, hepatocellular carcinoma (HCC), and liver failure. These end stage disease outcomes cause over a million deaths each year (1, 2). Currently approved drugs for chronic HBV infection work well to suppress HBV replication during treatment, but virus replication generally rebounds when treatment is stopped. In addition, adverse reactions to the commonly used immunomodulators 2-alpha interferon (IFN-2␣) and pegylated IFN-2␣ (pegIFN-2␣) and the development of resistance to nucleotide/nucleoside-based viral polymerase inhibitors justify the need for research into new therapeutic agents for HBV (3, 4).Nucleic acid polymers (NAPs) are water soluble and amphipathic in nature. These NAPs are constructed from oligonucleotides in which phosphorothioation of a nonbridging oxygen atom in the phosphodiester linkage, traditionally used as a modification to stabilize oligonucleotides against nuclease attack, is used to enhance the amphipathic properties of oligonucleotides (5).

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Phase I Trial of ISIS 104838, a 2′-Methoxyethyl Modified Antisense Oligonucleotide Targeting Tumor Necrosis Factor-α

Cited by 114 publications

References 28 publications

Mechanistic Understanding for the Greater Sensitivity of Monkeys to Antisense Oligonucleotide–Mediated Complement Activation Compared with Humans

Mechanistic Understanding for the Greater Sensitivity of Monkeys to Antisense Oligonucleotide–Mediated Complement Activation Compared with Humans

Gas-phase dissociation of oligoribonucleotides and their analogs studied by electrospray ionization tandem mass spectrometry

Nucleic Acid Polymers Inhibit Duck Hepatitis B Virus InfectionIn Vitro

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