Rada Dehghan, Arezoo Beig Parikhani, Reza Ahangari Cohan, Mohammad Ali Shokrgozar, Esmat Mirabzadeh, Soheila Ajdary, Sirous Zeinali, Hajarossadat Ghaderi, Yeganeh Talebkhan* and Mahdi Behdani* Pages 868 - 876 ( 9 )
Background: Interleukin 2 (IL-2) is a vital cytokine in the induction of T and NK cell responses, the proliferation of CD8+ T cells, and the effective treatment of human cancers such as melanoma and renal cell carcinoma. However, widespread use of this cytokine is limited due to its short half-life, severe toxicity, lack of specific tumor targeting, and activation of Treg cells mediated by high-affinity interleukin-2 receptors.
Objective: In this study, a tumor-targeting LIV-1 VHH-mutIL2 immunocytokine with reduced CD25 (α chain of the high-affinity IL-2 receptor) binding activity was developed to improve IL-2 half-life by decreasing its renal infiltration in comparison with wild and mutant IL-2 molecules.
Methods: The recombinant immunocytokine was designed and expressed. The biological activity of the purified fusion protein was investigated in in vitro and in vivo experiments.
Results: The fusion protein represented specific binding to MCF7 (the breast cancer cell line) and more efficient cytotoxicity than wild-type IL-2 and mutant IL-2. The PK parameters of the recombinant immunocytokine were also improved in comparison to the IL-2 molecules.
Conclusion: The observed results showed that LIV1-mIL2 immunocytokine could be considered as an effective agent in the LIV-1-targeted treatment of cancers due to its longer half-life and stronger cytotoxicity.
Immunotherapy, interleukin-2, immunocytokine, LIV-1, nanobody, pharmacokinetics.