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Book ; Online ; E-Book: Single nucleotide polymorphisms

Sauna, Zuben E. / Kimchi-Sarfaty, Chava

human variation and a coming revolution in biology and medicine

2022

Author's details	Zuben E. Sauna, Chava Kimchi-Sarfaty editors
Keywords	Single nucleotide polymorphisms
Subject code	611.01816
Language	English
Size	1 Online-Ressource (xviii, 234 Seiten), Illustrationen, 24 cm
Publisher	Springer
Publishing place	Cham
Publishing country	Switzerland
Document type	Book ; Online ; E-Book
Remark	Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
HBZ-ID	HT021449662
ISBN	978-3-031-05616-1 ; 9783031056147 ; 3-031-05616-7 ; 3031056140
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Factor VIII moiety of recombinant Factor VIII Fc fusion protein impacts Fc effector function and CD16

Lagassé, H A Daniel / Ou, Jiayi / Sauna, Zuben E / Golding, Basil

Frontiers in immunology

2024 Volume 15, Page(s) 1341013

Abstract: Recombinant Factor VIII-Fc fusion protein (rFVIIIFc) is an enhanced half-life therapeutic protein product used for the management of hemophilia A. Recent studies have demonstrated that rFVIIIFc interacts with Fc gamma receptors (FcγR) resulting in the ... ...

Abstract	Recombinant Factor VIII-Fc fusion protein (rFVIIIFc) is an enhanced half-life therapeutic protein product used for the management of hemophilia A. Recent studies have demonstrated that rFVIIIFc interacts with Fc gamma receptors (FcγR) resulting in the activation or inhibition of various FcγR-expressing immune cells. We previously demonstrated that rFVIIIFc, unlike recombinant Factor IX-Fc (rFIXFc), activates natural killer (NK) cells via Fc-mediated interactions with FcγRIIIA (CD16). Additionally, we showed that rFVIIIFc activated CD16
MeSH term(s)	Humans ; Cell Degranulation/immunology ; Factor VIII/chemistry ; Factor VIII/immunology ; GPI-Linked Proteins/immunology ; GPI-Linked Proteins/metabolism ; Hemophilia A/immunology ; Hemophilia A/drug therapy ; Immunoglobulin Fc Fragments/immunology ; Interferon-gamma/metabolism ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Lymphocyte Activation/immunology ; Lymphocyte Activation/drug effects ; Protein Binding ; Receptors, IgG/metabolism ; Receptors, IgG/immunology ; Recombinant Fusion Proteins
Chemical Substances	Factor VIII (9001-27-8) ; factor VIII-Fc fusion protein ; FCGR3B protein, human ; GPI-Linked Proteins ; Immunoglobulin Fc Fragments ; Interferon-gamma (82115-62-6) ; Receptors, IgG ; Recombinant Fusion Proteins
Language	English
Publishing date	2024-04-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1341013
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Emerging approaches to induce immune tolerance to therapeutic proteins.

Noel, Justine C / Lagassé, Daniel / Golding, Basil / Sauna, Zuben E

Trends in pharmacological sciences

2023 Volume 44, Issue 12, Page(s) 1028–1042

Abstract: Immunogenicity affects the safety and efficacy of therapeutic proteins. This review is focused on approaches for inducing immunological tolerance to circumvent the immunogenicity of therapeutic proteins in the clinic. The few immune tolerance strategies ... ...

Abstract	Immunogenicity affects the safety and efficacy of therapeutic proteins. This review is focused on approaches for inducing immunological tolerance to circumvent the immunogenicity of therapeutic proteins in the clinic. The few immune tolerance strategies that are used in the clinic tend to be inefficient and expensive and typically involve global immunosuppression, putting patients at risk of infections. The hallmark of a desirable immune tolerance regimen is the specific alleviation of immune responses to the therapeutic protein. In the past decade, proof-of-principle studies have demonstrated that emerging technologies, including nanoparticle-based delivery of immunomodulators, cellular targeting and depletion, cellular engineering, gene therapy, and gene editing, can be leveraged to promote tolerance to therapeutic proteins. We discuss the potential of these novel approaches and the barriers that need to be overcome for translation into the clinic.
MeSH term(s)	Humans ; Immune Tolerance ; Immunologic Factors ; Gene Editing
Chemical Substances	Immunologic Factors
Language	English
Publishing date	2023-10-29
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2023.10.002
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Understanding preclinical and clinical immunogenicity risks in novel biotherapeutics development.

Sauna, Zuben E / Jawa, Vibha / Balu-Iyer, Sathy / Chirmule, Narendra

Frontiers in immunology

2023 Volume 14, Page(s) 1151888

Abstract: Immunogenicity continues to pose a challenge in the development of biotherapeutics like conventional therapeutic-proteins and monoclonal antibodies as well as emerging modalities such as gene-therapy components, gene editing, and CAR T cells. The ... ...

Abstract	Immunogenicity continues to pose a challenge in the development of biotherapeutics like conventional therapeutic-proteins and monoclonal antibodies as well as emerging modalities such as gene-therapy components, gene editing, and CAR T cells. The approval of any therapeutic is based on a benefit-risk evaluation. Most biotherapeutics address serious medical conditions where the standard of care has a poor outcome. Consequently, even if immunogenicity limits the utility of the therapeutic in a sub-set of patients, the benefit-risk assessment skews in favor of approval. Some cases resulted in the discontinuation of biotherapeutics due to immunogenicity during drug development processes, This special issue presents a platform for review articles offering a critical assessment of accumulated knowledge as well as novel findings related to nonclinical risks that extend our understanding of the immunogenicity of biotherapeutics. Some of the studies in this collection leveraged assays and methodologies refined over decades to support more clinically relevant biological samples. Others have applied rapidly advancing methodologies in pathway-specific analyses to immunogenicity. Similarly, the reviews address urgent issues such as the rapidly emerging cell and gene therapies which hold immense promise but could have limited reach as a significant number of the patient population could potentially not benefit due to immunogenicity. In addition to summarizing the work presented in this special issue we have endeavored to identify areas where additional studies are required to understand the risks of immunogenicity and develop appropriate mitigation strategies.
MeSH term(s)	Humans ; Antibodies, Monoclonal/therapeutic use ; Risk Assessment
Chemical Substances	Antibodies, Monoclonal
Language	English
Publishing date	2023-05-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1151888
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: A machine learning approach for identifying variables associated with risk of developing neutralizing antidrug antibodies to factor VIII.

Rawal, Atul / Kidchob, Christopher / Ou, Jiayi / Yogurtcu, Osman N / Yang, Hong / Sauna, Zuben E

Heliyon

2023 Volume 9, Issue 6, Page(s) e16331

Abstract: A key unmet need in the management of hemophilia A (HA) is the lack of clinically validated markers that are associated with the development of neutralizing antibodies to Factor VIII (FVIII) (commonly referred to as inhibitors). This study aimed to ... ...

Abstract	A key unmet need in the management of hemophilia A (HA) is the lack of clinically validated markers that are associated with the development of neutralizing antibodies to Factor VIII (FVIII) (commonly referred to as inhibitors). This study aimed to identify relevant biomarkers for FVIII inhibition using Machine Learning (ML) and Explainable AI (XAI) using the My Life Our Future (MLOF) research repository. The dataset includes biologically relevant variables such as age, race, sex, ethnicity, and the variants in the
Language	English
Publishing date	2023-05-23
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e16331
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The MHC Associated Peptide Proteomics assay is a useful tool for the non-clinical assessment of immunogenicity.

Jankowski, Wojciech / Kidchob, Christopher / Bunce, Campbell / Cloake, Edward / Resende, Ricardo / Sauna, Zuben E

Frontiers in immunology

2023 Volume 14, Page(s) 1271120

Abstract: The propensity of therapeutic proteins to elicit an immune response, poses a significant challenge in clinical development and safety of the patients. Assessment of immunogenicity is crucial to predict potential adverse events and design safer biologics. ...

Abstract	The propensity of therapeutic proteins to elicit an immune response, poses a significant challenge in clinical development and safety of the patients. Assessment of immunogenicity is crucial to predict potential adverse events and design safer biologics. In this study, we employed MHC Associated Peptide Proteomics (MAPPS) to comprehensively evaluate the immunogenic potential of re-engineered variants of immunogenic FVIIa analog (Vatreptacog Alfa). Our finding revealed the correlation between the protein sequence affinity for MHCII and the number of peptides identified in a MAPPS assay and this further correlates with the reduced T-cell responses. Moreover, MAPPS enable the identification of "relevant" T cell epitopes and may contribute to the development of biologics with lower immunogenic potential.
MeSH term(s)	Humans ; Proteomics ; Peptides/metabolism ; Amino Acid Sequence ; Histocompatibility Antigens ; Biological Products
Chemical Substances	Peptides ; Histocompatibility Antigens ; Biological Products
Language	English
Publishing date	2023-10-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1271120
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Dose optimization of an adjuvanted peptide-based personalized neoantigen melanoma vaccine.

Valega-Mackenzie, Wencel / Rodriguez Messan, Marisabel / Yogurtcu, Osman N / Nukala, Ujwani / Sauna, Zuben E / Yang, Hong

PLoS computational biology

2024 Volume 20, Issue 3, Page(s) e1011247

Abstract: The advancements in next-generation sequencing have made it possible to effectively detect somatic mutations, which has led to the development of personalized neoantigen cancer vaccines that are tailored to the unique variants found in a patient's cancer. ...

Abstract	The advancements in next-generation sequencing have made it possible to effectively detect somatic mutations, which has led to the development of personalized neoantigen cancer vaccines that are tailored to the unique variants found in a patient's cancer. These vaccines can provide significant clinical benefit by leveraging the patient's immune response to eliminate malignant cells. However, determining the optimal vaccine dose for each patient is a challenge due to the heterogeneity of tumors. To address this challenge, we formulate a mathematical dose optimization problem based on a previous mathematical model that encompasses the immune response cascade produced by the vaccine in a patient. We propose an optimization approach to identify the optimal personalized vaccine doses, considering a fixed vaccination schedule, while simultaneously minimizing the overall number of tumor and activated T cells. To validate our approach, we perform in silico experiments on six real-world clinical trial patients with advanced melanoma. We compare the results of applying an optimal vaccine dose to those of a suboptimal dose (the dose used in the clinical trial and its deviations). Our simulations reveal that an optimal vaccine regimen of higher initial doses and lower final doses may lead to a reduction in tumor size for certain patients. Our mathematical dose optimization offers a promising approach to determining an optimal vaccine dose for each patient and improving clinical outcomes.
MeSH term(s)	Humans ; Melanoma/genetics ; Cancer Vaccines/genetics ; Antigens, Neoplasm/genetics ; Adjuvants, Immunologic ; Peptides
Chemical Substances	Cancer Vaccines ; Antigens, Neoplasm ; Adjuvants, Immunologic ; Peptides
Language	English
Publishing date	2024-03-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1011247
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Investigation of thrombin concentration at the time of clot formation in simultaneous thrombin and fibrin generation assays.

Tarandovskiy, Ivan D / Surov, Stepan S / Parunov, Leonid A / Liang, Yideng / Jankowski, Wojciech / Sauna, Zuben E / Ovanesov, Mikhail V

Scientific reports

2024 Volume 14, Issue 1, Page(s) 9225

Abstract: Thrombin generation (TG) and fibrin clot formation represent the central process of blood coagulation. Up to 95% of thrombin is considered to be generated after the clot is formed. However, this was not investigated in depth. In this study, we conducted ... ...

Abstract	Thrombin generation (TG) and fibrin clot formation represent the central process of blood coagulation. Up to 95% of thrombin is considered to be generated after the clot is formed. However, this was not investigated in depth. In this study, we conducted a quantitative analysis of the Thrombin at Clot Time (TCT) parameter in 5758 simultaneously recorded TG and clot formation assays using frozen plasma samples from commercial sources under various conditions of activation. These samples were supplemented with clotting factor concentrates, procoagulant lipid vesicles and a fluorogenic substrate and triggered with tissue factor (TF). We found that TCT is often close to a 10% of thrombin peak height (TPH) yet it can be larger or smaller depending on whether the sample has low or high TPH value. In general, the samples with high TPH are associated with elevated TCT. TCT appeared more sensitive to some procoagulant phenotypes than other commonly used parameters such as clotting time, TPH or Thrombin Production Rate (TPR). In a minority of cases, TCT were not predicted from TG parameters. For example, elevated TCT (above 15% of TPH) was associated with either very low or very high TPR values. We conclude that clotting and TG assays may provide complementary information about the plasma sample, and that the TCT parameter may serve as an additional marker for the procoagulant potential in plasma sample.
MeSH term(s)	Thrombin/metabolism ; Humans ; Fibrin/metabolism ; Blood Coagulation ; Blood Coagulation Tests/methods ; Thromboplastin/metabolism ; Thromboplastin/analysis
Chemical Substances	Thrombin (EC 3.4.21.5) ; Fibrin (9001-31-4) ; Thromboplastin (9035-58-9)
Language	English
Publishing date	2024-04-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-47694-5
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: HLA Variants and Inhibitor Development in Hemophilia A: A Retrospective Case-Controlled Study Using the ATHNdataset.

McGill, Joseph R / Simhadri, Vijaya L / Sauna, Zuben E

Frontiers in medicine

2021 Volume 8, Page(s) 663396

Abstract: In hemophilia A (HA) patients, ...

Abstract	In hemophilia A (HA) patients,
Language	English
Publishing date	2021-05-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2021.663396
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A machine learning approach for identifying variables associated with risk of developing neutralizing antidrug antibodies to factor VIII

Rawal, Atul / Kidchob, Christopher / Ou, Jiayi / Yogurtcu, Osman N. / Yang, Hong / Sauna, Zuben E.

Heliyon. 2023 June, v. 9, no. 6 p.e16331-

2023

Abstract	A key unmet need in the management of hemophilia A (HA) is the lack of clinically validated markers that are associated with the development of neutralizing antibodies to Factor VIII (FVIII) (commonly referred to as inhibitors). This study aimed to identify relevant biomarkers for FVIII inhibition using Machine Learning (ML) and Explainable AI (XAI) using the My Life Our Future (MLOF) research repository. The dataset includes biologically relevant variables such as age, race, sex, ethnicity, and the variants in the F8 gene. In addition, we previously carried out Human Leukocyte Antigen Class II (HLA-II) typing on samples obtained from the MLOF repository. Using this information, we derived other patient-specific biologically and genetically important variables. These included identifying the number of foreign FVIII derived peptides, based on the alignment of the endogenous FVIII and infused drug sequences, and the foreign-peptide HLA-II molecule binding affinity calculated using NetMHCIIpan. The data were processed and trained with multiple ML classification models to identify the top performing models. The top performing model was then chosen to apply XAI via SHAP, (SHapley Additive exPlanations) to identify the variables critical for the prediction of FVIII inhibitor development in a hemophilia A patient. Using XAI we provide a robust and ranked identification of variables that could be predictive for developing inhibitors to FVIII drugs in hemophilia A patients. These variables could be validated as biomarkers and used in making clinical decisions and during drug development. The top five variables for predicting inhibitor development based on SHAP values are: (i) the baseline activity of the FVIII protein, (ii) mean affinity of all foreign peptides for HLA DRB 3, 4, & 5 alleles, (iii) mean affinity of all foreign peptides for HLA DRB1 alleles), (iv) the minimum affinity among all foreign peptides for HLA DRB1 alleles, and (v) F8 mutation type.
Keywords	HLA antigens ; biomarkers ; data collection ; drug development ; drugs ; genes ; hemophilia ; models ; mutation ; nationalities and ethnic groups ; patients ; peptides ; prediction ; risk ; Factor VIII ; Immunogenicity ; Machine learning ; Explainable AI (XAI) ; Anti-drug antibodies
Language	English
Dates of publication	2023-06
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e16331
Database	NAL-Catalogue (AGRICOLA)

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