Characterization of BDG8: An antibody-human IL-2 complex that selectively activates the effector arm of the immune system. Journal of Clinical Oncology

Timothy Wyant, Inbar Amit, Itay Levin, Natali Levitan, Noam Grossman, Olga Bluvshtein, Ruet Barak, Guy Nimrod, Sharon Fischman, Marek Strajbl, Yehezkel Sasson, Michael Zehnin, Yanay Ofran

Research output: Contribution to journalMeeting Abstractpeer-review


e15004Background: Interleukin 2 is a 15.4 kDa type I cytokine of the four helix bundle structure. IL-2 signaling has two opposite effects, it can enhance immune response by activation of effector cells and regulate immune response by activation proliferation of regulatory T cells (Tregs). IL-2 mediates its effect by binding to two forms of IL-2 receptor: i) trimeric receptors made of IL-2Rα (CD25), IL-2Rβ (CD122), and a common IL-2Rγ (γc, CD132) chains or ii) a dimeric receptor of only the IL-2Rβ and IL-2Rγ subunits. In Tregs, activation of the trimeric receptor is associated with FoxP3 mediated transcription leading to the production of suppression factors. Tregs express higher levels of the αβγ trimeric IL-2 receptor than effector cells. However binding of IL-2 to the βγ dimer is associated with activation of effector cells expressing relatively high levels of the βγ dimer and express low levels of trimer. High dose IL-2 therapy is used in melanoma and metastatic renal cell carcinoma with response rates 10%-15%. While efficacious, this approach has several disadvantages: 1) IL-2 dependent adverse effects such as Vascular Leak Syndrome (VLS) excluding many patients from being considered 2) The short half-life of IL-2 requires frequent administration, resulting in repeated spikes in the level of circulating IL-2. 3) Administered IL-2 is not selective and enhances a non-desired activation of Tregs. Methods: Antibodies were computational designed to bind to a specific epitope on Il-2 allowing for the binding to the CD122/CD132 complex and exclude the CD122/CD132/CD25 complex. Results: Here we show that we specifically designed and tested a humanized antibody (BD8) that: i) binds tightly the human IL-2 (hIL-2) and ii) the antibody- hIL-2 complex preferentially to bind the IL-2Rβ sub-unit and blocks the IL-2Rα subunit. We show administering the BD8 Ab-IL-2 complex to C57BL/6 mice has a profound effect on activation of MP CD8+, NK and NKT effector cells with minimal effect on Tregs. In mice the antibody-hIL-2 complex serum half -life is much longer then the half-life of hIL-2. In the B16-F10 Melanoma model, BD8-hIL2 resulted in robust effect compared to hIL-2 alone. Conclusions: BD8 is a computationally designed antibody specifically binds to IL-2 inducing the activation of effector cells without stimulating Tregs and demonstrates efficacy in animal cancer models.
Original languageEnglish
Article numbere15004
Pages (from-to)e15004-e15004
JournalJournal of Clinical Oncology
Issue number15_suppl
StatePublished - 25 May 2020

Bibliographical note

doi: 10.1200/JCO.2020.38.15_suppl.e15004


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