Oligonucleotide-Based Drug Development: Considerations for Clinical Pharmacology and Immunogenicity

Wang, Jian; Lon, Hoi‐Kei; Lee, Shwu‐Luan; Burckart, Gilbert J.; Pisetsky, David S.

doi:10.1177/2168479015592195

Cited by 11 publications

(3 citation statements)

References 56 publications

(62 reference statements)

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“…Although the number of products in some of the product type categories is low, product types with known immunogenicity risk factors based on past regulatory experience, such as enzyme replacement therapies, had an established immunogenicity‐related PMR/PMC 1,10 . Additionally, more recent product modalities, such as oligonucleotides, 11 which may have greater uncertainty because of limited FDA experience, also had an immunogenicity‐related PMR/PMC. Therefore, for this set of products, the establishment of immunogenicity‐related PMRs/PMCs for products with known factors than can increase the immunogenicity risk is consistent with risk‐based approach discussed in the FDA guidance for evaluating immunogenicity 1…”

Section: Discussionmentioning

confidence: 99%

Elucidating the Impact of Immunogenicity Assessment Postapproval: A Targeted Analysis of Immunogenicity Postmarketing Requirements and Commitments

Guinn

Madabushi

Wang

et al. 2020

Clin Pharma and Therapeutics

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Insufficient availability of data to evaluate immunogenicity incidence or clinical impact during regulatory review could require further evaluation postapproval. Through a keyword search of all postmarketing requirements and commitments (PMRs/PMCs) associated with products with their original US Food and Drug Administration (FDA) approvals between 2009 and 2018, we identified products that had PMRs/PMCs established to address concerns or uncertainty related to immunogenicity. Of the 113 relevant products, 50% had an immunogenicity‐related PMR/PMC; of these, 68% were related to developing immunogenicity assays and 48% requested an assessment of clinical impact. Fifty‐five percent of the products with a fulfilled PMR/PMC had a change in the immunogenicity information in their labeling immediately following fulfillment. This work highlights that there are often unknowns associated with immunogenicity incidence and/or impact at the time of approval. Earlier regulatory discussions on immunogenicity assessments in premarket development could improve the understanding and communication of the risk/benefit profile and reduce the need for some immunogenicity PMRs/PMCs.

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Section: Discussionmentioning

confidence: 99%

Elucidating the Impact of Immunogenicity Assessment Postapproval: A Targeted Analysis of Immunogenicity Postmarketing Requirements and Commitments

Guinn

Madabushi

Wang

et al. 2020

Clin Pharma and Therapeutics

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“…Compared to protein therapeutic products, the immunogenicity of oligonucleotides is relatively low due to their biological and chemical nature (24). Oligonucleotides are structurally related to nucleic acids (DNA and RNA) that tend to be low in immunogenicity (25), and they are smaller in size and have fewer immunogenicity epitopes than their protein analogs. Nonetheless, oligonucleotides can trigger an immune response by interacting with internal DNA sensors such as toll-like receptors; thus, the possible production of anti-drug antibodies needs to be examined.…”

Section: Immunogenicity Considerationsmentioning

confidence: 99%

Bioanalysis in the Age of New Drug Modalities

Shi

Chen

Diao

et al. 2021

AAPS J

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In the absence of regulatory guidelines for the bioanalysis of new drug modalities, many of which contain multiple functional domains, bioanalytical strategies have been carefully designed to characterize the intact drug and each functional domain in terms of quantity, functionality, biotransformation, and immunogenicity. The present review focuses on the bioanalytical challenges and considerations for RNA-based drugs, bispecific antibodies and multi-domain protein therapeutics, prodrugs, gene and cell therapies, and fusion proteins. Methods ranging from the conventional ligand binding assays and liquid chromatography-mass spectrometry assays to quantitative polymerase chain reaction or flow cytometry often used for oligonucleotides and cell and gene therapies are discussed. Best practices for method selection and validation are proposed as well as a future perspective to address the bioanalytical needs of complex modalities.

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“…backbone extension, side-chain truncation) to achieve low picomolar binding, JB-181 (PDB ID: 6D2U; Shortridge et al, 2018). Sequences of the BIV-Tat ARM (68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81), peptide mimic BIV-0, and β-hairpin mimetics BIV-1 -BIV-8. Reported K d s were measured by electromobility shift assays (EMSA) (nb = no binding) (Athanassiou et al, 2004).…”

Section: Section 7: Summarymentioning

confidence: 99%

Design of RNA-targeting macrocyclic peptides

Walker

Varani

2019

Methods in Enzymology

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RNA structures play a pivotal role in many biological processes and the progression of human disease, making them an attractive target for therapeutic development. Often RNA structures operate through the formation of complexes with RNA-binding proteins, however, much like protein-protein interactions, RNA-protein interactions span large surface areas and often lack traditional druggable properties, making it challenging to target them with small molecules. Peptides provide much greater surface areas and therefore greater potential for forming specific and high affinity interactions with RNA. In this chapter, we discuss our approach for engineering peptides that bind to structured RNAs by highlighting methods and design strategies from previous successful projects aimed at inhibiting the HIV Tat-TAR interaction and the biogenesis of oncogenic microRNAs. Section 1: Introduction RNA molecules play crucial roles in regulating healthy and diseased cellular processes (e.g. transcription, splicing, mRNA transport, translation, etc) and are therefore tightly regulated transcriptionally and post-transcriptionally, often through their interactions with other RNAs and with RNA binding proteins. RNAs and RNA-protein interactions regulate viral replication or the expression of proto-oncogenes, and are mis-regulated in many infectious and chronic diseases (Cooper, Wan, & Dreyfuss, 2009; Esteller, 2011) making these RNA structures and RNA-protein surfaces an untapped source of potential drug targets (Burnett, & Rossi, 2012; Ling, Fabbri, & Calin, 2013). However, RNA-protein interactions are much more challenging to target with small molecules than traditional enzymatic active sites (Warner, Hajdin, & Weeks, 2018). These interactions span large surface areas and often lack structural complexity (

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Oligonucleotide-Based Drug Development: Considerations for Clinical Pharmacology and Immunogenicity

Cited by 11 publications

References 56 publications

Elucidating the Impact of Immunogenicity Assessment Postapproval: A Targeted Analysis of Immunogenicity Postmarketing Requirements and Commitments

Elucidating the Impact of Immunogenicity Assessment Postapproval: A Targeted Analysis of Immunogenicity Postmarketing Requirements and Commitments

Bioanalysis in the Age of New Drug Modalities

Design of RNA-targeting macrocyclic peptides

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