IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor α subunit CD25

Létourneau, Sven; Leeuwen, Ester M. M. van; Krieg, Carsten; Martin, Chris; Pantaleo, Giuseppe; Sprent, Jonathan; Surh, Charles D.; Boyman, Onur

doi:10.1073/pnas.0909384107

Cited by 186 publications

(228 citation statements)

References 46 publications

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“…Conversely, CD122 high effector cells, including (MP) CD8 + and NK cells, responded very efficiently to IL-2 via their dimeric βγ IL-2Rs, present at very high levels on these cells. This situation led us to explore CD122-specific IL-2/mAb CD122 complexes, for which the anti-IL-2 mAb is thought to cover up the CD25-binding epitope of IL-2, thus impeding interaction with CD25 (7,11,23). Accordingly, IL-2/mAb CD122 complexes caused efficient activation of IL-2Rβγ high effector cells, but not IL-2Rαβγ low/int pulmonary endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-IL-2 mAbs CD122 (such as anti-hIL-2 mAb MAB602 or anti-mouse IL-2 mAb S4B6) are thought to obscure the CD25-binding epitope of IL-2 (7,11,23). Thereby, anti-IL-2 mAbs CD122 direct IL-2 to CD122 high cells, while interfering with CD25-dependent binding of IL-2 to IL-2Rαβγ low/int lung endothelial cells and, thus, preventing pulmonary VLS.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, anti-IL-2 mAbs CD25 (such as anti-hIL-2 mAb 5344 or anti-mouse IL-2 mAb JES6-1) are believed to cover up the CD122-binding epitope of IL-2 (7,11,23). In favor of this hypothesis, IL-2/mAb CD25 complexes behave similarly to hIL-2 mutein BAY50-4798, containing a single mutation at amino acid 88 of hIL-2, which interacts with the CD122-binding epitope of IL-2.…”

Section: Discussionmentioning

confidence: 99%

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Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells

Krieg

Létourneau

Pantaleo

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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331

340

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IL-2 immunotherapy is an attractive treatment option for certain metastatic cancers. However, administration of IL-2 to patients can lead, by ill-defined mechanisms, to toxic adverse effects including severe pulmonary edema. Here, we show that IL-2–induced pulmonary edema is caused by direct interaction of IL-2 with functional IL-2 receptors (IL-2R) on lung endothelial cells in vivo. Treatment of mice with high-dose IL-2 led to efficient expansion of effector immune cells expressing high levels of IL-2Rβγ, including CD8 + T cells and natural killer cells, which resulted in a considerable antitumor response against s.c. and pulmonary B16 melanoma nodules. However, high-dose IL-2 treatment also affected immune cell lineage marker-negative CD31 + pulmonary endothelial cells via binding to functional αβγ IL-2Rs, expressed at low to intermediate levels on these cells, thus causing pulmonary edema. Notably, IL-2–mediated pulmonary edema was abrogated by a blocking antibody to IL-2Rα (CD25), genetic disruption of CD25, or the use of IL-2Rβγ–directed IL-2/anti-IL-2 antibody complexes, thereby interfering with IL-2 binding to IL-2Rαβγ + pulmonary endothelial cells. Moreover, IL-2/anti-IL-2 antibody complexes led to vigorous activation of IL-2Rβγ + effector immune cells, which generated a dramatic antitumor response. Thus, IL-2/anti-IL-2 antibody complexes might improve current strategies of IL-2–based tumor immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells

Krieg

Létourneau

Pantaleo

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

331

340

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“…Potentiation of the biological activity of cytokines by antibody anti-cytokines has been described for IL-2, IL-3, IL-6, IFN-␥, and TNF. [41][42][43][44][45] This phenomenon has been associated with formation of stable complexes between cytokines and their respective antibodies that optimize the immune response. 41 It is probable that decreased parasite load after using anti-MIF antibody may be associated with formation of complexes between anti-MIF and endogenous MIF that potentiated the MIF effect.…”

Section: Discussionmentioning

confidence: 99%

“…[41][42][43][44][45] This phenomenon has been associated with formation of stable complexes between cytokines and their respective antibodies that optimize the immune response. 41 It is probable that decreased parasite load after using anti-MIF antibody may be associated with formation of complexes between anti-MIF and endogenous MIF that potentiated the MIF effect. A protector activity of MIF has been proposed in several models of infection owing to its proinflammatory activity in cells infected with bacteria 29,46 and protozoa.…”

Section: Discussionmentioning

confidence: 99%

Effect of Macrophage Migration Inhibitory Factor (MIF) in Human Placental Explants Infected with Toxoplasma gondii Depends on Gestational Age

Gomes¹,

Silva²,

Silva³

et al. 2011

The American Journal of Pathology

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Because macrophage migration inhibitory factor (MIF) is a key cytokine in pregnancy and has a role in inflammatory response and pathogen defense, the objective of the present study was to investigate the effects of MIF in first-and third-trimester human placental explants infected with Toxoplasma gondii. Explants were treated with recombinant MIF, IL-12, interferon-␥, transforming growth factor-␤1, or IL-10, followed by infection with T. gondii RH strain tachyzoites. Supernatants of cultured explants were assessed for MIF production. Explants were processed for morphologic analysis, immunohistochemistry, and real-time PCR analysis. Comparison of infected and stimulated explants versus noninfected control explants demonstrated a significant increase in MIF release in first-trimester but not third-trimester explants. Tissue parasitism was higher in third-than in first-trimester explants. Moreover, T. gondii DNA content was lower in first-trimester explants treated with MIF compared with untreated explants. However, in third-trimester explants, MIF stimulus decreased T. gondii DNA content only at the highest concentration of the cytokine. In addition, high expression of MIF receptor was observed in first-trimester placental explants, whereas MIF receptor expression was low in third-trimester explants. In conclusion, MIF was up-regulated and demonstrated to be important for control of T. gondii infection in first-trimester explants, whereas lack of MIF up-regulation in third-trimester placentas may be involved in higher susceptibility to infection at this gestational age.

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Engineered Cytokines for Cancer and Autoimmune Disease Immunotherapy

Uricoli

Birnbaum

et al. 2021

Adv Healthcare Materials

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Cytokine signaling is critical to a range of biological processes including cell development, tissue repair, aging, and immunity. In addition to acting as key signal mediators of the immune system, cytokines can also serve as potent immunotherapies with more than 20 recombinant products currently Food and Drug Administration (FDA)‐approved to treat conditions including hepatitis, multiple sclerosis, arthritis, and various cancers. Yet despite their biological importance and clinical utility, cytokine immunotherapies suffer from intrinsic challenges that limit their therapeutic potential including poor circulation, systemic toxicity, and low tissue‐ or cell‐specificity. In the past decade in particular, methods have been devised to engineer cytokines in order to overcome such challenges and here, the myriad strategies are reviewed that may be employed in order to improve the therapeutic potential of cytokine and chemokine immunotherapies with applications in cancer and autoimmune disease therapy, as well as tissue engineering and regenerative medicine. For clarity, these strategies are collected and presented as they vary across size scales, ranging from single amino acid substitutions, to larger protein‐polymer conjugates, nano/micrometer‐scale particles, and macroscale implants. Together, this work aims to provide readers with a timely view of the field of cytokine engineering with an emphasis on early‐stage therapeutic approaches.

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IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor α subunit CD25

Cited by 186 publications

References 46 publications

Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells

Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells

Effect of Macrophage Migration Inhibitory Factor (MIF) in Human Placental Explants Infected with Toxoplasma gondii Depends on Gestational Age

Engineered Cytokines for Cancer and Autoimmune Disease Immunotherapy

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