Limits...
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

Biochemical investigation of NMRI-nude mice after human regulatory macrophage (Mreg_UKR) treatment. NMRI-nude mice were allocated to three groups of five animals. Mice received injections of either 106 or 107 viable human M regs resuspended in Ringer’s lactate solution plus 5% human serum albumin and 60 U heparin, or were given a vehicle-only injection. Seven days after Mreg_UKR administration, recipient mice were killed and serum levels of albumin, alkaline phosphatase, aspartate transaminase, creatinine and glucose were investigated. No signficant differences were observed between treatment groups, except for a marginal increase in aspartate transaminase levels in mice treated with 107 M regs (Kruksall–Wallis test; 107 Mreg_UKR versus vehicle-only, *P = 0.036).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4362366&req=5

fig4: Biochemical investigation of NMRI-nude mice after human regulatory macrophage (Mreg_UKR) treatment. NMRI-nude mice were allocated to three groups of five animals. Mice received injections of either 106 or 107 viable human M regs resuspended in Ringer’s lactate solution plus 5% human serum albumin and 60 U heparin, or were given a vehicle-only injection. Seven days after Mreg_UKR administration, recipient mice were killed and serum levels of albumin, alkaline phosphatase, aspartate transaminase, creatinine and glucose were investigated. No signficant differences were observed between treatment groups, except for a marginal increase in aspartate transaminase levels in mice treated with 107 M regs (Kruksall–Wallis test; 107 Mreg_UKR versus vehicle-only, *P = 0.036).

Mentions: Given that Mreg_UKR distributed primarily to liver, recipient mice were investigated for markers of liver injury: serum albumin (Figure 4a) and alkaline phosphatase (Figure 4b) levels were not significantly different between treatment groups; however, a marginal increase in serum aspartate transaminase (AST) was observed in group 3 (Figure 4c). The biological relevance of such a small difference serum AST levels is presently unknown. Notably, among the 21 patients treated with M reg-containing cell products, who are all more than 5 years posttreatment, no incidents of disturbed liver function tests were reported. Serum alkaline phosphatase is also a marker of increased bone resorption and serum albumin levels are typically reduced as part of the acute phase response; therefore, no biochemical evidence was found of increased bone turnover or systemic inflammation caused by Mreg_UKR. To investigate the possibility that Mreg_UKR affect renal function by embolising (in the form of individual cells, cell aggregates, dead cells, or immune complexes) to renal glomeruli, serum creatinine levels were measured as an indicator of filtrative capacity: no differences were observed between treatment groups (Figure 4d). Glucose levels are a sensitive, albeit very unspecific, parameter to screen for adverse drug reactions: Hypoglycemia might result from sepsis, disturbances of the hypothalamic–pituitary–adrenal axis resulting in reduced glucocorticoid production or disturbed insulin production (or IGF-2 production); hyperglycemia may result from pituitary, adrenal, or pancreatic dysfunction or could indicate ischemic disease or infections. No significant changes in glucose levels were observed (Figure 4e).


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)

Biochemical investigation of NMRI-nude mice after human regulatory macrophage (Mreg_UKR) treatment. NMRI-nude mice were allocated to three groups of five animals. Mice received injections of either 106 or 107 viable human M regs resuspended in Ringer’s lactate solution plus 5% human serum albumin and 60 U heparin, or were given a vehicle-only injection. Seven days after Mreg_UKR administration, recipient mice were killed and serum levels of albumin, alkaline phosphatase, aspartate transaminase, creatinine and glucose were investigated. No signficant differences were observed between treatment groups, except for a marginal increase in aspartate transaminase levels in mice treated with 107 M regs (Kruksall–Wallis test; 107 Mreg_UKR versus vehicle-only, *P = 0.036).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Biochemical investigation of NMRI-nude mice after human regulatory macrophage (Mreg_UKR) treatment. NMRI-nude mice were allocated to three groups of five animals. Mice received injections of either 106 or 107 viable human M regs resuspended in Ringer’s lactate solution plus 5% human serum albumin and 60 U heparin, or were given a vehicle-only injection. Seven days after Mreg_UKR administration, recipient mice were killed and serum levels of albumin, alkaline phosphatase, aspartate transaminase, creatinine and glucose were investigated. No signficant differences were observed between treatment groups, except for a marginal increase in aspartate transaminase levels in mice treated with 107 M regs (Kruksall–Wallis test; 107 Mreg_UKR versus vehicle-only, *P = 0.036).
Mentions: Given that Mreg_UKR distributed primarily to liver, recipient mice were investigated for markers of liver injury: serum albumin (Figure 4a) and alkaline phosphatase (Figure 4b) levels were not significantly different between treatment groups; however, a marginal increase in serum aspartate transaminase (AST) was observed in group 3 (Figure 4c). The biological relevance of such a small difference serum AST levels is presently unknown. Notably, among the 21 patients treated with M reg-containing cell products, who are all more than 5 years posttreatment, no incidents of disturbed liver function tests were reported. Serum alkaline phosphatase is also a marker of increased bone resorption and serum albumin levels are typically reduced as part of the acute phase response; therefore, no biochemical evidence was found of increased bone turnover or systemic inflammation caused by Mreg_UKR. To investigate the possibility that Mreg_UKR affect renal function by embolising (in the form of individual cells, cell aggregates, dead cells, or immune complexes) to renal glomeruli, serum creatinine levels were measured as an indicator of filtrative capacity: no differences were observed between treatment groups (Figure 4d). Glucose levels are a sensitive, albeit very unspecific, parameter to screen for adverse drug reactions: Hypoglycemia might result from sepsis, disturbances of the hypothalamic–pituitary–adrenal axis resulting in reduced glucocorticoid production or disturbed insulin production (or IGF-2 production); hyperglycemia may result from pituitary, adrenal, or pancreatic dysfunction or could indicate ischemic disease or infections. No significant changes in glucose levels were observed (Figure 4e).

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