IQ Consortium Perspective: Complementary LBA and LC–MS in Protein Therapeutics Bioanalysis and Biotransformation Assessment

Kaur, Surinder; Bateman, Kevin P.; Glick, Jim; Jairaj, Mark; Kellie, John F.; Sydor, Jens; Zeng, Jianing

doi:10.4155/bio-2019-0279

Cited by 27 publications

(32 citation statements)

References 42 publications

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“…Although intact protein LC-MS assays may need improvement with regards to sensitivity and data processing, the workflow has clear benefits and may help provide a better understanding of biotherapeutic PK. Specially, intact protein molecule PK can be complementary to (rather than a replacement for) standard LBAs and/or can help with LBA troubleshooting [22]. In laboratories equipped for LC-MS in early discovery, intact protein LC-MS may serve as a replacement for digestion-based assays, especially for initial PK studies where low limits of detection or quantitation are not required.…”

mentioning

confidence: 99%

Intact mAb LC–MS for Drug Concentration from Pre-Clinical Studies: Bioanalytical Method Performance and in-Life Samples

et al. 2020

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Background: Antibody biotherapeutic measurement from pharmacokinetic studies has not been traditionally based on intact molecular mass as is the case for small molecules. However, recent advancements in protein capture and mass spectrometer technology have enabled intact mass detection and quantitation for dosed biotherapeutics. A bioanalytical method validation is part of the regulatory requirement for sample analysis to determine drug concentration from in-life study samples. Results/methodology: Here, an intact protein LC–MS assay is subjected to mock bioanalytical method validation, and unknown samples are compared between intact protein LC–MS and established bioanalytical assay formats: Ligand-binding assay and peptide LC–MS/MS. Discussion/conclusion: Results are presented from the intact and traditional bioanalytical method evaluations, where the in-life sample concentrations were comparable across method types with associated data analyses presented. Furthermore, for intact protein LC–MS, modification monitoring and evaluation of data processing parameters is demonstrated.

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confidence: 99%

Intact mAb LC–MS for Drug Concentration from Pre-Clinical Studies: Bioanalytical Method Performance and in-Life Samples

et al. 2020

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“…In this review, the methods used for the determinations of vector genome, transgene mRNA, and the transgene product (protein) (Table III) as well as immunogenicity assays for rAAVbased gene therapy products (Table IV) are briefly summarized. The analytical method details can be found in other published literature reviews (21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Bioanalytical Support For Biodistribution and Viral Sheddingmentioning

confidence: 99%

“…-Reduces the assay variability by using an internal standard (IS) like an isotopically labeled peptide, a flanged peptide (with a tryptic cleavage site) or a full-length protein (24,35).…”

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confidence: 99%

The Perspective of DMPK on Recombinant Adeno-Associated Virus-Based Gene Therapy: Past Learning, Current Support, and Future Contribution

Chen

Sun

Chemuturi

et al. 2022

AAPS J

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Given the recent success of gene therapy modalities and the growing number of cell and gene-based therapies in clinical development across many different therapeutic areas, it is evident that this evolving field holds great promise for the unmet medical needs of patients. The recent approvals of Luxturna® and Zolgensma® prove that recombinant adeno-associated virus (rAAV)-based gene therapy is a transformative modality that enables curative treatment for genetic disorders. Over the last decade, Takeda has accumulated significant experience with rAAV-based gene therapies, especially in the early stage of development. In this review, based on the learnings from Takeda and publicly available information, we aim to provide a guiding perspective on Drug Metabolism and Pharmacokinetics (DMPK) substantial role in advancing therapeutic gene therapy modalities from nonclinical research to clinical development, in particular the characterization of gene therapy product biodistribution, elimination (shedding), immunogenicity assessment, multiple platform bioanalytical assays, and first-in-human (FIH) dose projection strategies.

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“…To minimize potential proteolysis of fusion or conjugate TPs, different strategies can be used . Integrated analytical strategies, often involving ligand binding assay (LBA) and hybrid immunoaffinity LC-MS platforms, are being adopted gradually over time to gain better understanding of biotransformation of TPs (Kaur et al, 2020).…”

Section: Metabolismmentioning

confidence: 99%

Absorption, Distribution, Metabolism, and Excretion of Therapeutic Proteins: Current Industry Practices and Future Perspectives

et al. 2022

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Therapeutics proteins (TPs) comprise a variety of modalities including antibody-based drugs, coagulation factors, recombinant cytokines, enzymes, growth factors, and hormones. TPs usually cannot traverse cellular barriers and exert their pharmacological activity by interacting with targets on the exterior membrane of cells or with soluble ligands in the tissue interstitial fluid/blood. Due to large size, lack of cellular permeability, variation in metabolic fate, and distinct physicochemical characteristics, TPs are subject to different absorption, distribution, metabolism, and excretion (ADME) processes as compared to small molecules.Limited regulatory guidance makes it challenging to determine the most relevant ADME data required for regulatory submissions. The TP ADME working group (WG) was sponsored by the Translational and ADME Sciences Leadership Group (TALG) within the Innovation and Quality (IQ) consortium with objectives to: i) better understand the current practices of ADME data generated for TPs across IQ member companies, ii) learn about their regulatory strategy and interaction experiences, and iii) provide recommendations on best practices for conducting ADME studies. To understand current ADME practices and regulatory strategies, an industry-wide survey was conducted within IQ member companies. In addition, ADME data submitted to FDA was also collated by reviewing regulatory submission packages of TPs approved between 2011-2020. This article summarizes the key learnings from the survey and an overview of ADME data presented in BLAs along with future perspectives and recommendations for conducting ADME studies for internal decision making as well as regulatory submissions for TPs.

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IQ Consortium Perspective: Complementary LBA and LC–MS in Protein Therapeutics Bioanalysis and Biotransformation Assessment

Cited by 27 publications

References 42 publications

Intact mAb LC–MS for Drug Concentration from Pre-Clinical Studies: Bioanalytical Method Performance and in-Life Samples

Intact mAb LC–MS for Drug Concentration from Pre-Clinical Studies: Bioanalytical Method Performance and in-Life Samples

The Perspective of DMPK on Recombinant Adeno-Associated Virus-Based Gene Therapy: Past Learning, Current Support, and Future Contribution

Absorption, Distribution, Metabolism, and Excretion of Therapeutic Proteins: Current Industry Practices and Future Perspectives

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