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.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.

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

Assessing the immunogenicity of allogeneic mouse M regs in mice. BALB/c mice were either treated with 5 × 106 C3H-derived M regs (n = 4) or received no cells (n = 3). Eight days later, all mice were given a heterotopic heart transplant from a C3H donor. None of the transplants failed before day 7. On day 7, sera were harvested from all mice for measurement of antidonor IgG and IgM antibody titers by flow cytometry crossmatch. Mice treated with M regs 8 days before transplantation registered significantly lower levels of antidonor IgG than untreated controls (Mann–Whitney U-test; *P < 0.001). Gray line indicates limit of detection..
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Assessing the immunogenicity of allogeneic mouse M regs in mice. BALB/c mice were either treated with 5 × 106 C3H-derived M regs (n = 4) or received no cells (n = 3). Eight days later, all mice were given a heterotopic heart transplant from a C3H donor. None of the transplants failed before day 7. On day 7, sera were harvested from all mice for measurement of antidonor IgG and IgM antibody titers by flow cytometry crossmatch. Mice treated with M regs 8 days before transplantation registered significantly lower levels of antidonor IgG than untreated controls (Mann–Whitney U-test; *P < 0.001). Gray line indicates limit of detection..

Mentions: To formally assess the risk of humoral sensitization by M regs, donor-specific anti-major histocompatibility complex class I antibody responses were measured in BALB/c mice that received C3H cardiac allografts after preoperative treatment with donor strain-derived M regs. As previously published, no accelerated allograft lost was observed in the M reg-treated recipients, indicating that M reg administration on day 8 prior to transplantation did not sensitize recipients.10 Here, sera were harvested from mice 7 days after heart transplantation, and their alloantibody content was measured by flow cytometry cross-match. Consistent IgG responses were detected in transplanted mice without M reg treatment; in contrast, mice treated with 5 × 106 donor-derived M regs 8 days prior to transplantation had significantly lower levels of antidonor IgG (Figure 5). No antidonor IgM response was detected in either the control or M reg-treated group (data not shown). Therefore, there is no evidence that intravenous injection of allogeneic mouse M regs caused humoral sensitization.


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)

Assessing the immunogenicity of allogeneic mouse M regs in mice. BALB/c mice were either treated with 5 × 106 C3H-derived M regs (n = 4) or received no cells (n = 3). Eight days later, all mice were given a heterotopic heart transplant from a C3H donor. None of the transplants failed before day 7. On day 7, sera were harvested from all mice for measurement of antidonor IgG and IgM antibody titers by flow cytometry crossmatch. Mice treated with M regs 8 days before transplantation registered significantly lower levels of antidonor IgG than untreated controls (Mann–Whitney U-test; *P < 0.001). Gray line indicates limit of detection..
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Assessing the immunogenicity of allogeneic mouse M regs in mice. BALB/c mice were either treated with 5 × 106 C3H-derived M regs (n = 4) or received no cells (n = 3). Eight days later, all mice were given a heterotopic heart transplant from a C3H donor. None of the transplants failed before day 7. On day 7, sera were harvested from all mice for measurement of antidonor IgG and IgM antibody titers by flow cytometry crossmatch. Mice treated with M regs 8 days before transplantation registered significantly lower levels of antidonor IgG than untreated controls (Mann–Whitney U-test; *P < 0.001). Gray line indicates limit of detection..
Mentions: To formally assess the risk of humoral sensitization by M regs, donor-specific anti-major histocompatibility complex class I antibody responses were measured in BALB/c mice that received C3H cardiac allografts after preoperative treatment with donor strain-derived M regs. As previously published, no accelerated allograft lost was observed in the M reg-treated recipients, indicating that M reg administration on day 8 prior to transplantation did not sensitize recipients.10 Here, sera were harvested from mice 7 days after heart transplantation, and their alloantibody content was measured by flow cytometry cross-match. Consistent IgG responses were detected in transplanted mice without M reg treatment; in contrast, mice treated with 5 × 106 donor-derived M regs 8 days prior to transplantation had significantly lower levels of antidonor IgG (Figure 5). No antidonor IgM response was detected in either the control or M reg-treated group (data not shown). Therefore, there is no evidence that intravenous injection of allogeneic mouse M regs caused humoral sensitization.

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.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.

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