Abstract
Background:
A GMP-compliant process for manufacturing a medicinal cellbased product, known as Mreg_UKR, containing human regulatory macrophages (Mreg) has been established. Mreg_UKR is currently being investigated in a Phase-I/II trial as a means to safely reduce maintenance immunosuppression in kidney transplant recipients. Partway into this study, manufacturing failure occurred in 3 ...
Abstract
Background:
A GMP-compliant process for manufacturing a medicinal cellbased product, known as Mreg_UKR, containing human regulatory macrophages (Mreg) has been established. Mreg_UKR is currently being investigated in a Phase-I/II trial as a means to safely reduce maintenance immunosuppression in kidney transplant recipients. Partway into this study, manufacturing failure occurred in 3 independent batches. These failures could not be attributed to procedural errors or donor-related factors. Therefore, a root-cause analysis was undertaken, including characterising current and previous lots of pooled, heat-inactivated, recalcified plasma-derived, male-only human AB serum that were used in the manufacturing process.
Methods:
Single Ag bead arrays and CDC-crossmatches were performed by an accredited laboratory.
Results:
Throughout process-development and clinical production, 3 separate charges of serum from the same supplier were used. Under researchconditions, all 3 sera supported normal development of Mregs from monocytes.To test whether an tibodies in the sera could explain idiosyncratic manufacturing failures, the 3 sera were screened by single-antigen bead array for anti-HLA. All 3 charges contained HLA Clas s I- and II-reactive antibodies at above- threshold levels. To test whether these antibodies fixed complement, mixed- and B cell-crossmatches were performed using cells from a DR4-positive donor. Despite the presence of anti-DR4 antibody, no complement-dependent cytotoxicity was observed. A low concentration of anti-HLA antibody in our AB serum is the most likely explanation for this discrepancy; however, we cannot formally exclude false-positive signals from the bead array or false-negative results from crossmatching.
Conclusion:
The unexpected presence of anti-HLA antibodies in certain commercially available human AB sera argues for substituting human AB serum with platelet lysate or serum -free medium wherever feasible.
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