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https://www.readbyqxmd.com/read/28776673/molecular-characterization-of-excipients-preferential-interactions-with-therapeutic-monoclonal-antibodies
#1
Jehoon Kim, Mark R H Krebs, Bernhardt L Trout
OBJECTIVES: This study reports global and local monoclonal antibody (mAb)-excipient interactions and the resulting thermodynamic and stabilization effects. METHODS: Molecular dynamics simulations are applied to quantify the interactions of key excipients (sucrose, sorbitol, arginine, citrate, histidine and NaCl) used in the formulations of three mAbs. The dynamic surface properties of the mAbs and preferential interaction coefficients for the excipients based on validated potential parameters are computed, in addition to the spatial aggregation propensity...
August 4, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28758834/preferential-interactions-of-trehalose-l-arginine-hcl-and-sodium-chloride-with-therapeutically-relevant-igg1-monoclonal-antibodies
#2
Chaitanya Sudrik, Theresa Cloutier, Phuong Pham, Hardeep S Samra, Bernhardt L Trout
Preferential interactions of weakly interacting formulation excipients govern their effect on the equilibrium and kinetics of several reactions of protein molecules in solution. Using vapor pressure osmometry, we characterized the preferential interactions of commonly used excipients trehalose, L-arginine.HCl and NaCl with three therapeutically-relevant, IgG1 monoclonal antibodies that have similar size and shape, but differ in their surface hydrophobicity and net charge. We further characterized the effect of these excipients on the reversible self-association, aggregation and viscosity behavior of these antibody molecules...
July 31, 2017: MAbs
https://www.readbyqxmd.com/read/28754261/elucidating-the-weak-protein-protein-interaction-mechanisms-behind-the-liquid-liquid-phase-separation-of-a-mab-solution-by-different-types-of-additives
#3
Guoliang Wu, Shujing Wang Co-First, Zhou Tian, Ning Zhang, Han Sheng, Weiguo Dai, Feng Qian
Liquid-liquid phase separation (LLPS) has long been observed during the physical stability investigation of therapeutic protein formulations. The buffer conditions and the presence of various excipients are thought to play important roles in the formulation development of monoclonal antibodies (mAbs). In this study, the effects of several small-molecule excipients (histidine, alanine, glycine, sodium phosphate, sodium chloride, sorbitol and sucrose) with diverse physical-chemical properties on LLPS of a model IgG1 (JM2) solutions were investigated by multiple techniques, including UV-vis spectroscopy, circular dichroism, differential scanning calorimetry/fluorimetry, size exclusion chromatography and dynamic light scattering...
July 25, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28737447/pmab-52-specific-and-sensitive-monoclonal-antibody-against-cat-podoplanin-for-immunohistochemistry
#4
Shinji Yamada, Shunsuke Itai, Takuro Nakamura, Miyuki Yanaka, Noriko Saidoh, Yao-Wen Chang, Saori Handa, Hiroyuki Harada, Yumiko Kagawa, Osamu Ichii, Satoru Konnai, Mika K Kaneko, Yukinari Kato
Podoplanin (PDPN) is expressed in several normal tissues, such as lymphatic endothelial cells, podocytes of renal glomerulus, and type I alveolar cells of lung. PDPN activates platelet aggregation by binding to C-type lectin-like receptor-2 (CLEC-2) on platelet. Although monoclonal antibodies (mAbs) against human PDPN, mouse PDPN, rat PDPN, rabbit PDPN, dog PDPN, and bovine PDPN have been established, anticat PDPN (cPDPN) mAbs have not been developed. In this study, we immunized mice with Chinese hamster ovary (CHO)-K1 cell lines expressing cPDPN, and developed anti-cPDPN mAbs...
July 24, 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/28722325/polymer-mediated-flocculation-of-transient-cho-cultures-as-a-simple-high-throughput-method-to-facilitate-antibody-discovery
#5
Matthew G Schmitt, Yashas Rajendra, Maria D Hougland, Jeffrey S Boyles, Gavin C Barnard
Most biopharmaceutical drugs, especially monoclonal antibodies (mAbs), bispecific antibodies (BsAbs) and Fc-fusion proteins, are expressed using Chinese Hamster Ovary (CHO) cell lines. CHO cells typically yield high product titers and high product quality. Unfortunately, CHO cell lines also generate high molecular weight (HMW) aggregates of the desired product during cell culture along with CHO host cell protein (HCP) and CHO DNA. These immunogenic species, co-purified during Protein A purification, must be removed in a multi-step purification process...
July 19, 2017: Biotechnology Progress
https://www.readbyqxmd.com/read/28697935/continuous-countercurrent-tangential-chromatography-for-mixed-mode-post-capture-operations-in-monoclonal-antibody-purification
#6
Amit K Dutta, Dmitriy Fedorenko, Jasmine Tan, Joseph A Costanzo, David S Kahn, Andrew L Zydney, Oleg Shinkazh
Continuous Countercurrent Tangential Chromatography (CCTC) has been shown to demonstrate significant advantages over column chromatography including higher productivity, lower operational pressure, disposable flow path, and lower resin use. Previous applications of CCTC have been limited to initial capture of monoclonal antibodies (mAb) from clarified cell culture harvest. In this present article, a CCTC system was designed and tested for a post-capture antibody purification step. Mixed mode cation exchange-hydrophobic interaction chromatography resins with two different particle sizes were used to reduce host cell protein (HCP), leached protein A, DNA, and aggregates from a mAb stream after a protein A operation...
June 22, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28674748/platelet-activating-factor-podoplanin-from-discovery-to-drug-development
#7
Ai Takemoto, Kenichi Miyata, Naoya Fujita
Tumor cell-induced platelet aggregation facilitates hematogenous metastasis by promoting tumor embolization, preventing immunological assaults and shear stress, and the platelet-releasing growth factors support tumor growth and invasion. Podoplanin, also known as Aggrus, is a type I transmembrane mucin-like glycoprotein and is expressed on wide range of tumor cells. Podoplanin has a role in platelet aggregation and metastasis formation through the binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2)...
July 3, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28668371/the-versatility-of-heart-cutting-and-comprehensive-two-dimensional-liquid-chromatography-in-monoclonal-antibody-clone-selection
#8
Koen Sandra, Mieke Steenbeke, Isabel Vandenheede, Gerd Vanhoenacker, Pat Sandra
In recent years, two-dimensional liquid chromatography (2D-LC) has seen an enormous evolution and one of the fields where it is being widely adopted is in the analysis of therapeutic monoclonal antibodies (mAbs). We here further add to the many flavours of this powerful technology. Workflows based on heart-cutting (LC-LC) and comprehensive (LC×LC) 2D-LC are described that allow to guide the clone selection process in mAb and biosimilar development. Combining Protein A affinity chromatography in the first dimension with size exclusion (SEC), cation exchange (CEX) or reversed-phase liquid chromatography-mass spectrometry (RPLC-MS) in the second dimension simultaneously allows to assess mAb titer and critical structural aspects such as aggregation, fragmentation, charge heterogeneity, molecular weight (MW), amino acid sequence and glycosylation...
June 19, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28662102/a-novel-monoclonal-antibody-against-the-n-terminus-of-a%C3%AE-1-42-reduces-plaques-and-improves-cognition-in-a-mouse-model-of-alzheimer-s-disease
#9
Hai-Yan Xing, Bin Li, Dan Peng, Chun-Yan Wang, Guan-Ying Wang, Pan Li, Ying-Ying Le, Ji-Ming Wang, George Ye, Jian-Hong Chen
Senile plaques consisting of Amyloid-beta (Aβ) peptides, in particular Aβ1-42, are the hallmark of Alzheimer's disease (AD) and have been the primary therapeutic targets. Passive immunotherapy with monoclonal antibodies (mAbs) has shown initial success in mouse models of AD. However, the existing Aβ-directed mAbs mostly were tested on animal models or patients with advanced disease. The effects and mechanisms of mAbs on animals or human trial participants in the prodromal phase of AD are not fully clarified...
2017: PloS One
https://www.readbyqxmd.com/read/28639328/immunogenicity-of-protein-aggregates-of-a-monoclonal-antibody-generated-by-forced-shaking-stress-with-siliconized-and-nonsiliconized-syringes-in-balb-c-mice
#10
Tomonobu Uchino, Yasunori Miyazaki, Takuto Yamazaki, Yoshiyuki Kagawa
OBJECTIVE: In this study, we aimed to investigate the immunogenicity of protein aggregates of monoclonal antibodies (mAbs), generated by forced shaking stress with siliconized and nonsiliconized syringes in a mouse model. METHODS: Samples were filled in siliconized and nonsiliconized syringes with shaking and headspace air. Characterization studies were performed using high-performance size-exclusion chromatography, nanoparticle tracking analysis, flow cytometry, micro-flow imaging and resonant mass measurement...
June 21, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28618451/multicenter-comparison-of-cd34-myeloid-cell-count-by-flow-cytometry-in-low-risk-myelodysplastic-syndrome-is-it-feasible
#11
Patricia Font, Dolores Subirá, Sergio Matarraz, Celina Benavente, María Teresa Cedena, Marta Morado, Ana Pérez Corral, José María Bellón, José Luis Díez-Martín
BACKGROUND: Accuracy of bone marrow (BM) blast count in low-risk myelodysplastic syndromes (MDS) still remains a challenge though it is essential for prognosis. We investigated whether the enumeration of CD34+ myeloid cells by flow cytometry immunophenotyping (FCI) could be used as a consistent parameter for clinical MDS studies. METHODS: Six clinical centres entered the study and information on their FCI protocols was recorded. Sixty-seven flow cytometry listmodes from BM samples of patients with low-risk MDS with <5% BM blasts were exchanged among participants in two different rounds...
June 15, 2017: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/28617076/characterization-of-highly-concentrated-antibody-solution-a-toolbox-for-the-description-of-protein-long-term-solution-stability
#12
Marie-Therese Schermeyer, Anna K Wöll, Bas Kokke, Michel Eppink, Jürgen Hubbuch
High protein titers are gaining importance in biopharmaceutical industry. A major challenge in the development of highly concentrated mAb solutions is their long-term stability and often incalculable viscosity. The complexity of the molecule itself, as well as the various molecular interactions, make it difficult to describe their solution behavior. To study the formulation stability, long- and short-range interactions and the formation of complex network structures have to be taken into account. For a better understanding of highly concentrated solutions, we combined established and novel analytical tools to characterize the effect of solution properties on the stability of highly concentrated mAb formulations...
June 15, 2017: MAbs
https://www.readbyqxmd.com/read/28593474/high-throughput-prediction-approach-for-monoclonal-antibody-aggregation-at-high-concentration
#13
Mitja Zidar, Ana Šušterič, Miha Ravnik, Drago Kuzman
PURPOSE: Characterization of the monoclonal antibody aggregation process and identification of stability factors that could be used as indicators of aggregation propensity with an emphasis on a large number of samples and low protein material consumption. METHODS: Differential scanning calorimetry, dynamic light scattering and size exclusion chromatography were used as the main methodological approaches. Conformational stability, colloidal stability and aggregation kinetics were assessed for two different IgG monoclonal antibody (mAbs) subclasses...
September 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28590212/evidence-for-intermolecular-domain-exchange-in-the-fab-domains-of-dimer-and-oligomers-of-an-igg1-monoclonal-antibody
#14
Yin Luo, Stephen W Raso, Judith Gallant, Colleen Steinmeyer, Yasuko Mabuchi, Zhaojiang Lu, Clifford Entrican, Jason C Rouse
Recombinant protein therapeutics have become increasingly useful in combating human diseases, such as cancer and those of genetic origin. One quality concern for protein therapeutics is the content and the structure of the aggregated proteins in the product, due to the potential immunogenicity of these aggregates. Collective efforts have led to a better understanding of some types of protein aggregates, and have revealed the diversity in the structure and cause of protein aggregation. In this work we used a broad range of analytical techniques to characterize the quinary structure (complexes in which each composing unit maintains native quaternary structure) of the stable non-covalent dimer and oligomers of a monoclonal IgG1λ antibody...
August 2017: MAbs
https://www.readbyqxmd.com/read/28512676/different-fermentation-processes-produced-variants-of-an-anti-cd52-monoclonal-antibody-that-have-divergent-in-vitro-and-in-vivo-characteristics
#15
Chao Zhuang, Chen Zheng, Yantian Chen, Zheng Huang, Yanchao Wang, Qiang Fu, Chen Zeng, Tong Wu, Liming Yang, Nianmin Qi
The anti-CD52 antibody has already been approved for the treatment of patients with resistant chronic lymphocytic leukemia, relapsing-remitting multiple sclerosis, and has demonstrable efficacy against stem cell transplantation rejection. A CHO cell line expressing a humanized anti-CD52 monoclonal antibody (mAb-TH) was cultivated in both fed-batch and perfusion modes, and then purified. The critical quality attributes of these mAb variants were characterized and the pharmacokinetics (PK) properties were investigated...
May 16, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28498096/characterization-of-the-anti-bovine-podoplanin-monoclonal-antibody-pmab-44
#16
Shinji Yamada, Ryusuke Honma, Mika K Kaneko, Takuro Nakamura, Miyuki Yanaka, Noriko Saidoh, Michiaki Takagi, Satoru Konnai, Yukinari Kato
A type I transmembrane sialoglycoprotein podoplanin (PDPN) is expressed in several normal cells, including podocytes of the kidney, type I alveolar cells of the lung, and lymphatic endothelial cells. We recently produced an anti-bovine PDPN (bovPDPN) monoclonal antibody (mAb), PMab-44, by immunizing mice with recombinant proteins of bovPDPN. In this study, we determined the critical epitope of PMab-44 for the recognition of bovPDPN using many deletion mutants and point mutants of bovPDPN. Flow cytometric analyses revealed that the epitope of PMab-44 was Glu46-Thr50, which corresponds to platelet aggregation-stimulating (PLAG) domain-3...
June 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/28472993/humanized-monoclonal-antibody-armanezumab-specific-to-n-terminus-of-pathological-tau-characterization-and-therapeutic-potency
#17
Michael G Agadjanyan, Karen Zagorski, Irina Petrushina, Hayk Davtyan, Konstantin Kazarian, Maxim Antonenko, Joy Davis, Charles Bon, Mathew Blurton-Jones, David H Cribbs, Anahit Ghochikyan
BACKGROUND: The experience from clinical trials indicates that anti-Aβ immunotherapy could be effective in early/pre-clinical stages of AD, whereas at the late stages promoting the clearing of Aβ alone may be insufficient to halt the disease progression. At the same time, pathological tau correlates much better with the degree of dementia than Aβ deposition. Therefore, targeting pathological tau may provide a more promising approach for the treatment of advanced stages of AD. Recent data demonstrates that the N-terminal region of tau spanning aa 2-18 termed "phosphatase activation domain" that is normally hidden in the native protein in 'paperclip'-like conformation, becomes exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and in aggregation of tau...
May 5, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28464235/multi-criteria-manufacturability-indices-for-ranking-high-concentration-monoclonal-antibody-formulations
#18
Yang Yang, Ajoy Velayudhan, Nina F Thornhill, Suzanne S Farid
The need for high-concentration formulations for subcutaneous delivery of therapeutic monoclonal antibodies (mAbs) can present manufacturability challenges for the final ultrafiltration/diafiltration (UF/DF) step. Viscosity levels and the propensity to aggregate are key considerations for high-concentration formulations. This work presents novel frameworks for deriving a set of manufacturability indices related to viscosity and thermostability to rank high-concentration mAb formulation conditions in terms of their ease of manufacture...
September 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28447132/high-throughput-analysis-of-sub-visible-mab-aggregate-particles-using-automated-fluorescence-microscopy-imaging
#19
Albert Jesuran Paul, Fabian Bickel, Martina Röhm, Lisa Hospach, Bettina Halder, Nina Rettich, René Handrick, Eva Maria Herold, Hans Kiefer, Friedemann Hesse
Aggregation of therapeutic proteins is a major concern as aggregates lower the yield and can impact the efficacy of the drug as well as the patient's safety. It can occur in all production stages; thus, it is essential to perform a detailed analysis for protein aggregates. Several methods such as size exclusion high-performance liquid chromatography (SE-HPLC), light scattering, turbidity, light obscuration, and microscopy-based approaches are used to analyze aggregates. None of these methods allows determination of all types of higher molecular weight (HMW) species due to a limited size range...
April 27, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28430651/doxorubicin-loaded-platelets-conjugated-with-anti-cd22-mabs-a-novel-targeted-delivery-system-for-lymphoma-treatment-with-cardiopulmonary-avoidance
#20
Peipei Xu, Huaqin Zuo, Rongfu Zhou, Fan Wang, Xu Liu, Jian Ouyang, Bing Chen
B-cell lymphoma accounts for approximately 85% of all adult non-Hodgkin's lymphoma cases. Doxorubicin (DOX) is an indispensable drug for the treatment of non-Hodgkin's lymphoma. However, DOX causes severe cardiotoxicity, which limits its use in conventional treatment strategies. In this study, we developed a novel drug delivery system for lymphoma treatment: DOX-loaded platelets that were conjugated with anti-CD22 monoclonal antibodies (mAbs) (DOX-platelet-CD22). Platelets are bio- and immune-compatible drug carriers that can prolong the circulation time of drugs...
April 6, 2017: Oncotarget
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