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ADME of Novel Modalities Synopsis
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ADME of Novel Modalities Synopsis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 6593

Special Issue Editors

Dr. Jerome Hochman

E-Mail Website
Guest Editor
Modalities ADME, West Point, PA 19486, USA
Interests: Peptides; Proteins; RNA therapeutics; Vaccines
Dr. Vikram Sinha

E-Mail Website
Co-Guest Editor
Takeda Pharmaceutical Co., Boston, MA, USA
Interests: Pharmacodynamics; Drug development; Biomarker; Oncology
Dr. Anna Kwiatkowska

E-Mail Website
Co-Guest Editor
Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada
Interests: peptides and peptidomimetics; proteolytic enzymes; structure-based drug design; prostate cancer; infectious diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the past 20 years, the translation of basic research tools to clinically relevant therapeutic entities has accelerated, expanding the therapeutic tool box beyond conventional small molecule drugs. Currently, recombinant antibodies, genetically and chemically modified proteins, antibody-drug conjugates, de novo designed peptides, oligonucleotides, viruses, protein-degraders, as well as conventional small molecule drugs, are being pursued in the clinic and approved for disease treatment. These modalities not only offer alternative platforms for target intervention, but  expand the landscape for disease intervention, complimenting both the scope of druggable target space, and introducing novel biological mechanisms that can fundamentally remedy disease processes. The realization of these therapeutic opportunities requires an understanding of the physiological, biochemical, and biological barriers that control exposure to the drug target and resulting biological response. Consequently, the successful application of ADME and PK/PD to characterization of novel therapeutics needs to consider the unique attributes conferred by the therapeutic modality and the desired and potential off-target biological responses.

The theme of these issues is to highlight how barriers to exposure, and the translation of exposure to efficacy can change across different modalities. Examples of the interpretation of ADME and PK/PD will be presented in the context of mechanistic aspects of therapeutic action and biological barriers unique to specific modalities, supporting gene therapy and gene editing, immunomodulation, modulation of protein–protein interaction, and target inhibition/suppression.

Dr. Jerome Hochman
Dr. Vikram Sinha
Dr. Anna Kwiatkowska
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gene therapy
  • gene editing
  • immunomodulation
  • modulation of protein–protein interaction
  • target inhibition/suppression

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Published Papers (2 papers)

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11 pages, 10968 KiB  
Article
2-Pyridine Carboxaldehyde for Semi-Automated Soft Spot Identification in Cyclic Peptides
by Haiying Zhang, Silvi Chacko and Joe R. Cannon
Int. J. Mol. Sci. 2022, 23(8), 4269; https://doi.org/10.3390/ijms23084269 - 12 Apr 2022
Cited by 4 | Viewed by 2412
Abstract
Cyclic peptides are an attractive option as therapeutics due to their ability to disrupt crucial protein–protein interactions and their flexibility in display type screening strategies, but they come with their own bioanalytical challenges in metabolite identification. Initial amide hydrolysis of a cyclic peptide [...] Read more.
Cyclic peptides are an attractive option as therapeutics due to their ability to disrupt crucial protein–protein interactions and their flexibility in display type screening strategies, but they come with their own bioanalytical challenges in metabolite identification. Initial amide hydrolysis of a cyclic peptide results in a ring opening event in which the sequence is linearized. Unfortunately, the mass of the singly hydrolyzed sequence is the same (M + 18.0106 Da) irrespective of the initial site of hydrolysis, or soft spot. Soft spot identification at this point typically requires time-consuming manual interpretation of the tandem mass spectra, resulting in a substantial bottleneck in the hit to lead process. To overcome this, derivatization using 2-pyridine carboxaldehyde, which shows high selectivity for the alpha amine on the N-terminus, was employed. This strategy results in moderate- to high-efficiency derivatization with a unique mass tag and diagnostic ions that serve to highlight the first amino acid in the newly linearized peptide. The derivatization method and analytical strategy are demonstrated on a whole cell lysate digest, and the soft spot identification strategy is shown with two commercially available cyclic peptides: JB1 and somatostatin. Effective utilization of the automated sample preparation and interpretation of the resulting spectra shown here will serve to reduce the hit-to-lead time for generating promising proteolytically stable peptide candidates. Full article
(This article belongs to the Special Issue ADME of Novel Modalities Synopsis)
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17 pages, 3058 KiB  
Article
Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Prediction of Monoclonal Antibody Tumor Disposition
by Brandon M. Bordeau, Joseph Ryan Polli, Ferdinand Schweser, Hans Peter Grimm, Wolfgang F. Richter and Joseph P. Balthasar
Int. J. Mol. Sci. 2022, 23(2), 679; https://doi.org/10.3390/ijms23020679 - 8 Jan 2022
Cited by 4 | Viewed by 3347
Abstract
The prediction of monoclonal antibody (mAb) disposition within solid tumors for individual patients is difficult due to inter-patient variability in tumor physiology. Improved a priori prediction of mAb pharmacokinetics in tumors may facilitate the development of patient-specific dosing protocols and facilitate improved selection [...] Read more.
The prediction of monoclonal antibody (mAb) disposition within solid tumors for individual patients is difficult due to inter-patient variability in tumor physiology. Improved a priori prediction of mAb pharmacokinetics in tumors may facilitate the development of patient-specific dosing protocols and facilitate improved selection of patients for treatment with anti-cancer mAb. Here, we report the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with tumor penetration of the contrast agent gadobutrol used as a surrogate, to improve physiologically based pharmacokinetic model (PBPK) predictions of cetuximab pharmacokinetics in epidermal growth factor receptor (EGFR) positive xenografts. In the initial investigations, mice bearing Panc-1, NCI-N87, and LS174T xenografts underwent DCE-MRI imaging with the contrast agent gadobutrol, followed by intravenous dosing of an 125Iodine-labeled, non-binding mAb (8C2). Tumor concentrations of 8C2 were determined following the euthanasia of mice (3 h–6 days after 8C2 dosing). Potential predictor relationships between DCE-MRI kinetic parameters and 8C2 PBPK parameters were evaluated through covariate modeling. The addition of the DCE-MRI parameter Ktrans alone or Ktrans in combination with the DCE-MRI parameter Vp on the PBPK parameters for tumor blood flow (QTU) and tumor vasculature permeability (σTUV) led to the most significant improvement in the characterization of 8C2 pharmacokinetics in individual tumors. To test the utility of the DCE-MRI covariates on a priori prediction of the disposition of mAb with high-affinity tumor binding, a second group of tumor-bearing mice underwent DCE-MRI imaging with gadobutrol, followed by the administration of 125Iodine-labeled cetuximab (a high-affinity anti-EGFR mAb). The MRI-PBPK covariate relationships, which were established with the untargeted antibody 8C2, were implemented into the PBPK model with considerations for EGFR expression and cetuximab-EGFR interaction to predict the disposition of cetuximab in individual tumors (a priori). The incorporation of the Ktrans MRI parameter as a covariate on the PBPK parameters QTU and σTUV decreased the PBPK model prediction error for cetuximab tumor pharmacokinetics from 223.71 to 65.02%. DCE-MRI may be a useful clinical tool in improving the prediction of antibody pharmacokinetics in solid tumors. Further studies are warranted to evaluate the utility of the DCE-MRI approach to additional mAbs and additional drug modalities. Full article
(This article belongs to the Special Issue ADME of Novel Modalities Synopsis)
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