Comparison of elapegademase and pegademase in ADA-deficient patients and mice

Abstract

The absence of adenosine deaminase (ADA) causes severe combined immune deficiency (SCID), which has been treated with PEGylated bovineextracted ADA (ADAGEN). ADAGEN was recently replaced by a PEGylated recombinant bovine ADA, expressed in Escherichia coli (elapegademase, ELA-ADA). Limited information on ELA-ADA is available. ADA enzymatic activity of ELA-ADA and ADAGEN was assessed in vitro at diverse dilutions. ADA activity and immune reconstitution in an ADA-SCID patient treated with ELA-ADA were compared with age-matched patients previously treated with ADAGEN. ADA activity and thymus reconstitution were evaluated in ADA-deficient mice following ELA-ADA or ADAGEN administered from 7 days postpartum. In vitro, ADA activity of ELA-ADA and ADAGEN were similar at all dilutions. In an ADA-SCID patient, ELA-ADA treatment led to a marked increase in trough plasma ADA activity, which was 20% higher than in a patient previously treated with ADAGEN. A marked increase in T cell numbers and generation of naive T cells was evident following 3 months of ELA-ADA treatment, while T cell numbers increased following 4 months in 3 patients previously treated with ADAGEN. T cell proliferations stimulation normalized and thymus shadow became evident following ELA-ADA treatment. ADA activity was significantly increased in the blood of ADA-deficient mice following ELA-ADA compared to ADAGEN, while both treatments improved the mice weights, the weight, number of cells in their thymus and thymocyte subpopulations. ELA-ADA has similar in-vitro and possibly better in-vivo activity than ADAGEN. Future studies will determine whether ELA-ADA results in improved long-term immune reconstitution.

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

“…While we have highlighted many successful examples of LAPFs ( Table 1 20 , 46 , 56 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 ), challenges still remain in many areas of their application. Improved technologies still need to solve the potential issues of current strategies.…”

An appraisal of the Wilson & Jungner criteria in the context of genomic-based newborn screening for inborn errors of immunity

“…The definitive treatment for adenosine deaminase (ADA)-deficiency SCID is either HSCT or GT; however, pegylated ADA enzyme replacement therapy is also available for the management of this condition. [34][35][36][37] Enzyme replacement therapy is effective in achieving adequate detoxification and restoration of immunologic function, and can be used as an interim, bridging measure until curative therapy can be instituted. 37 Cytokine therapies.…”

The Use of Induced Pluripotent Stem Cells to Study the Effects of Adenosine Deaminase Deficiency on Human Neutrophil Development

“…These mutations were previously shown to cause near-absent ADA activity (36). ADA-iPSC-1 generated using retroviruses expressing OCT4, SOX2, KLF4, and MYC, with pluripotency determined by expression of pluripotency markers and teratoma formation as previously described (37). ADA-iPSC-2 was generated at the Centre for Commercialization of Regenerative Medicine, Toronto, Canada, using non-integrative Sendai virus.…”