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Prolongation of sickle cell survival by dimethyl adipimidate is compromised by immune sensitization
Abstract:
The effect of dimethyl adipimidate (DMA), an amino-reactive crosslinking reagent with demonstrated antisickling properties in vitro, on the survival of 51Cr-labeled autologous sickle cells was evaluated in five adult males with sickle cell anemia. The survival of cells pretreated with 5 mmol/L DMA (pH 7.4), normal (t1/2 28-33 days) in four subjects and near-normal (t1/2 20 days) in the fifth, was considerably longer than that usually observed in sickle cell disease. In fact, the effect of DMA on the survival of sickle cells in vivo equals or exceeds that of any other agent tested to date. In three subjects, the survival of a second infusion of DMA-treated red cells was much shorter (t1/2 1.8, 3, 4.5 days) than in the initial study. An antibody was detected in the serum of these subjects that was directed to DMA-treated red cells. Modification of the immunogenicity of treated cells will be required before further consideration of DMA for use in the therapy of sickle cell anemia.
Insights
Dimethyl adipimidate (DMA) extended sickle cell survival in vivo, showing promise for sickle cell anemia therapy. However, subsequent infusions led to shorter survival due to antibody formation against DMA-treated red blood cells.
Area of Science:
- Hematology
- Biochemistry
- Immunology
Background:
- Sickle cell anemia is a genetic blood disorder characterized by abnormal hemoglobin.
- Red blood cell (RBC) survival is significantly reduced in sickle cell disease.
- Novel therapeutic agents are needed to improve RBC lifespan and patient outcomes.
Purpose of the Study:
- To evaluate the in vivo effect of dimethyl adipimidate (DMA) on the survival of autologous sickle cells.
- To assess the potential of DMA as a therapeutic agent for sickle cell anemia.
Main Methods:
- Five adult males with sickle cell anemia were enrolled.
- 51Cr-labeled autologous RBCs were pretreated with 5 mmol/L dimethyl adipimidate (DMA) at pH 7.4.
- RBC survival was measured, and antibody formation against DMA-treated RBCs was assessed.
Main Results:
- Initial DMA treatment of RBCs resulted in normal to near-normal survival times (t1/2 20-33 days) in four out of five subjects.
- DMA's effect on sickle cell survival in vivo was comparable to or better than other agents tested.
- A second infusion of DMA-treated RBCs showed significantly shorter survival (t1/2 1.8-4.5 days) in three subjects.
- Antibodies directed against DMA-treated RBCs were detected in the serum of subjects with shortened survival.
Conclusions:
- Dimethyl adipimidate (DMA) demonstrates significant potential in prolonging sickle cell survival in vivo.
- The development of antibodies against DMA-modified RBCs poses a challenge for repeated therapeutic administration.
- Further modification to reduce the immunogenicity of DMA-treated cells is necessary for its clinical application in sickle cell anemia therapy.