Joint EFPIA/CHMP SWP workshop: the Emerging Use of Omic Technologies for Regulatory Non-Clinical Safety Testing

2005 ◽  
Vol 6 (2) ◽  
pp. 181-184 ◽  
Author(s):  
Peter Kasper ◽  
Gerry Oliver ◽  
Beatriz Silva Lima ◽  
Thomas Singer ◽  
David Tweats
Keyword(s):  
Clinical Safety ◽  
Safety Testing

Gelucire and Gelucire-PEG400 formulations; tolerability in species used for non-clinical safety testing after oral (gavage) dosing

2016 ◽  
Vol 36 (11) ◽  
pp. 1430-1436 ◽  
Author(s):  
Mikael Elander ◽  
Jette B. Boll ◽  
Anne S. Hojman ◽  
Allan D. Rasmussen
Keyword(s):  
Oral Gavage ◽  
Clinical Safety ◽  
Safety Testing

scholarly journals Distribution of FcRn Across Species and Tissues

2017 ◽  
Vol 65 (6) ◽  
pp. 321-333 ◽  
Author(s):  
Sari Latvala ◽  
Bjoern Jacobsen ◽  
Michael B. Otteneder ◽  
Annika Herrmann ◽  
Sven Kronenberg
Keyword(s):  
Endothelial Cells ◽  
Monoclonal Antibodies ◽  
Transgenic Mouse ◽  
Expression Pattern ◽  
Clinical Safety ◽  
Safety Testing ◽  
Type Molecule ◽  
Negative Effect ◽  
Von Willebrand ◽  
First Time

The neonatal Fc receptor (FcRn) is a major histocompatibility complex class I type molecule that binds to, transports, and recycles immunoglobulin G (IgG) and albumin, thereby protecting them from lysosomal degradation. Therefore, besides the knowledge of FcRn affinity, FcRn protein expression is critical in understanding the pharmacokinetic behavior of Fc-containing biotherapeutics such as monoclonal antibodies. The goal of this investigation was to achieve for the first time a comparative assessment of FcRn distribution across a variety of tissues and species. FcRn was mapped in about 20 tissues including placenta from human and the most frequently used species in non-clinical safety testing of monoclonal antibodies (mouse, rat, cynomolgus monkey). In addition, the FcRn expression pattern was characterized in two humanized transgenic mouse lines (Tg32 and Tg276) expressing human FcRn under different promoters, and in the severe combined immunodeficient (SCID) mouse. Consecutive sections were stained with specific markers, namely, anti-CD68 for macrophages and anti–von Willebrand Factor for endothelial cells. Overall, the FcRn expression pattern was comparable across species and tissues with consistent expression of FcRn in endothelial cells and interstitial macrophages, Kupffer cells, alveolar macrophages, enterocytes, and choroid plexus epithelium. The human FcRn transgenic mouse Tg276 showed a different and much more widespread staining pattern of FcRn. In addition, immunodeficiency and lack of IgG in SCID mice had no negative effect on FcRn expression compared with wild-type mice.

scholarly journals The Interleukin-17 Receptor Plays a Gender-Dependent Role in Host Protection against Porphyromonas gingivalis-Induced Periodontal Bone Loss

2008 ◽  
Vol 76 (9) ◽  
pp. 4206-4213 ◽  
Author(s):  
Jeffrey J. Yu ◽  
Matthew J. Ruddy ◽  
Heather R. Conti ◽  
Kanitsak Boonanantanasarn ◽  
Sarah L. Gaffen
Keyword(s):  
Bone Loss ◽  
Porphyromonas Gingivalis ◽  
Alveolar Bone ◽  
Gene Knockout ◽  
Bone Destruction ◽  
Mouse Strains ◽  
Interleukin 17 ◽  
Clinical Safety ◽  
Safety Testing ◽  
Chronic Inflammatory Condition

ABSTRACT Interleukin-17 (IL-17) is a proinflammatory cytokine secreted by the newly described CD4+ Th17 subset, which is distinct from classic Th1 and Th2 lineages. IL-17 contributes to bone destruction in rheumatoid arthritis but is essential in host defense against pathogens that are susceptible to neutrophils. Periodontal disease (PD) is a chronic inflammatory condition initiated by anaerobic oral pathogens such as Porphyromonas gingivalis, and it is characterized by host-mediated alveolar bone destruction due primarily to the immune response. The role of IL-17 in PD is controversial. Whereas elevated IL-17 levels have been found in humans with severe PD, we recently reported that female C57BL/6J mice lacking the IL-17 receptor (IL-17RAKO) are significantly more susceptible to PD bone loss due to defects in the chemokine-neutrophil axis (J. J. Yu, M. J. Ruddy, G. C. Wong, C. Sfintescu, P. J. Baker, J. B. Smith, R. T. Evans, and S. L. Gaffen, Blood 109:3794-3802, 2007). Since different mouse strains exhibit differences in susceptibility to PD as well as Th1/Th2 cell skewing, we crossed the IL-17RA gene knockout onto the BALB/c background and observed a similar enhancement in alveolar bone loss following P. gingivalis infection. Unexpectedly, in both strains IL-17RAKO female mice were much more susceptible to PD bone loss than males. Moreover, female BALB/c-IL-17RAKO mice were defective in producing anti-P. gingivalis immunoglobulin G and the chemokines KC/Groα and MIP-2. In contrast, male mice produced normal levels of chemokines and anti-P. gingivalis antibodies, but they were defective in granulocyte colony-stimulating factor upregulation. This study demonstrates a gender-dependent effect of IL-17 signaling and indicates that gender differences should be taken into account in the preclinical and clinical safety testing of anti-IL-17 biologic therapies.

Pre-clinical safety testing supporting clinical use of allogeneic multipotent adult progenitor cells

Cytotherapy ◽  
2008 ◽  
Vol 10 (7) ◽  
pp. 730-742 ◽  
Author(s):  
M. Kovacsovics-Bankowski ◽  
K. Mauch ◽  
A. Raber ◽  
Pr Streeter ◽  
Rj Deans ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Clinical Use ◽  
Clinical Safety ◽  
Safety Testing ◽  
Multipotent Adult Progenitor Cells

scholarly journals Challenges of non-clinical safety testing for biologics: A Report of the 9th BioSafe European Annual General Membership Meeting

mAbs ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 1938796
Author(s):  
Thomas Kissner ◽  
Guenter Blaich ◽  
Andreas Baumann ◽  
Sven Kronenberg ◽  
Adam Hey ◽  
...  
Keyword(s):  
Annual General ◽  
Clinical Safety ◽  
Safety Testing

Basics on Clinical Safety Testing

2000 ◽  
pp. 79-94 ◽  
Author(s):  
Peter J. Dykes ◽  
Anthony D. Pearse
Keyword(s):  
Clinical Safety ◽  
Safety Testing

scholarly journals Rapid cGMP Manufacturing of COVID-19 monoclonal antibody using stable CHO cell pools

2021 ◽  
Author(s):  
Rita Agostinetto ◽  
Jessica Dawson ◽  
Angela Lim ◽  
Mirva Hejjaoui-simoneau ◽  
Cyril Boucher ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Large Scale ◽  
High Titer ◽  
Phase 1 ◽  
Scale Up ◽  
Formulation Development ◽  
Clinical Safety ◽  
Cell Bank ◽  
Safety Testing

Therapeutic proteins, including monoclonal antibodies, are typically manufactured using clonally-derived, stable host cell lines, since consistent and predictable cell culture performance is highly desirable. However, selecting and preparing banks of stable clones takes considerable time, which inevitably extends overall development timelines for new therapeutics by delaying the start of subsequent activities, such as the scale-up of manufacturing processes. In the context of the COVID-19 pandemic, with its intense pressure for accelerated development strategies, we used a novel transposon-based Leap-In Transposase® system to rapidly generate high-titer stable pools and then used them directly for large scale-manufacturing of an anti-SARS-CoV2 monoclonal antibody under cGMP. We performed the safety testing of our non-clonal cell bank, then used it to produce material at a 200L-scale for pre-clinical safety studies and formulation development work, and thereafter at 2000L scale for supply of material for a Phase 1 clinical trial. Testing demonstrated the comparability of critical product qualities between the two scales and, more importantly, that our final clinical trial product met all pre-set product quality specifications. The above expediated approach provided clinically-ready material within 4.5 months, in comparison to 12-14 months for production of clinical trial material via the conventional approach.

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