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In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies.

Broichhausen C, Riquelme P, Ahrens N, Wege AK, Koehl GE, Schlitt HJ, Banas B, Fändrich F, Geissler EK, Hutchinson JA - Mol Ther Methods Clin Dev (2014)

Bottom Line: These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion.On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products.By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Surgery, Department of Surgery, University Hospital Regensburg , Regensburg, Germany.

ABSTRACT
A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

No MeSH data available.


Related in: MedlinePlus

Distribution and fate of Mreg_UKR in NSG mice. Recipient mice were given 5 × 106 viable M regs or vehicle-only by slow intravenous injection. The tissue distribution of M regs was then assessed on days 1 to 7 post-injection by flow cytometry. Human M regs defined by expression of human CD45, CD11b and HLA-DR were detected in lung, blood and liver at all timepoints. Although the engrafted M regs remained CD14-, CD16 expression was regained by day 1. Data are representative of at least two animals per timepoint from at least two independent experiments.
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fig1: Distribution and fate of Mreg_UKR in NSG mice. Recipient mice were given 5 × 106 viable M regs or vehicle-only by slow intravenous injection. The tissue distribution of M regs was then assessed on days 1 to 7 post-injection by flow cytometry. Human M regs defined by expression of human CD45, CD11b and HLA-DR were detected in lung, blood and liver at all timepoints. Although the engrafted M regs remained CD14-, CD16 expression was regained by day 1. Data are representative of at least two animals per timepoint from at least two independent experiments.

Mentions: Human M regs were detectable in lung, blood, and liver for up to 7 days postinfusion (Figure 1). It was not possible to reliably detect human M regs at any time point in spleen and bone marrow, either because human M regs were not present or because they were indiscriminable from the large populations of mouse macrophages present in those tissues. M regs retained their CD11b+ HLA-DR+ CD14−/low phenotype throughout the 7-day observation period. In contrast, M regs upregulated CD16 expression within 1 day of infusion, which possibly reflects the absence of human immunoglobulins in NSG mice.27


In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies.

Broichhausen C, Riquelme P, Ahrens N, Wege AK, Koehl GE, Schlitt HJ, Banas B, Fändrich F, Geissler EK, Hutchinson JA - Mol Ther Methods Clin Dev (2014)

Distribution and fate of Mreg_UKR in NSG mice. Recipient mice were given 5 × 106 viable M regs or vehicle-only by slow intravenous injection. The tissue distribution of M regs was then assessed on days 1 to 7 post-injection by flow cytometry. Human M regs defined by expression of human CD45, CD11b and HLA-DR were detected in lung, blood and liver at all timepoints. Although the engrafted M regs remained CD14-, CD16 expression was regained by day 1. Data are representative of at least two animals per timepoint from at least two independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362366&req=5

fig1: Distribution and fate of Mreg_UKR in NSG mice. Recipient mice were given 5 × 106 viable M regs or vehicle-only by slow intravenous injection. The tissue distribution of M regs was then assessed on days 1 to 7 post-injection by flow cytometry. Human M regs defined by expression of human CD45, CD11b and HLA-DR were detected in lung, blood and liver at all timepoints. Although the engrafted M regs remained CD14-, CD16 expression was regained by day 1. Data are representative of at least two animals per timepoint from at least two independent experiments.
Mentions: Human M regs were detectable in lung, blood, and liver for up to 7 days postinfusion (Figure 1). It was not possible to reliably detect human M regs at any time point in spleen and bone marrow, either because human M regs were not present or because they were indiscriminable from the large populations of mouse macrophages present in those tissues. M regs retained their CD11b+ HLA-DR+ CD14−/low phenotype throughout the 7-day observation period. In contrast, M regs upregulated CD16 expression within 1 day of infusion, which possibly reflects the absence of human immunoglobulins in NSG mice.27

Bottom Line: These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion.On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products.By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Surgery, Department of Surgery, University Hospital Regensburg , Regensburg, Germany.

ABSTRACT
A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

No MeSH data available.


Related in: MedlinePlus