The Exon-3-Encoded Domain of IL-15Rα Contributes to IL-15 High-Affinity Binding and Is Crucial for the IL-15 Antagonistic Effect of Soluble IL-15Rα

Bouchaud, Grégory; Garrigue‐Antar, Laure; Solé, Véronique; Quéméner, Agnès; Boublik, Yvan; Mortier, Erwan; Perdreau, Harmonie; Jacques, Yannick; Plet, Ariane

doi:10.1016/j.jmb.2008.07.019

Cited by 43 publications

(44 citation statements)

References 28 publications

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“…The maximal effect on lung metastasis (75% of inhibition) was significantly higher than those induced by IL-2 (45%) or IL-15 (35%). The better in vivo efficiency of RLI versus IL-15 is likely related to its better in vitro efficiency to stimulate IL-15Rα/β/γ-bearing and/or IL-15Rβ/γ-bearing cells as previously reported (29,31). Our pharmacokinetic experiments also indicate that the better efficiency of RLI over IL-15 or IL-2 may also be related to a better serum distribution profile.…”

Section: Discussionsupporting

confidence: 74%

“…Its interest as adjuvant for enhancing the effect of chemotherapeutic agents and adoptive cell therapy on transplanted tumors has been widely established, but its therapeutic potential on its own was found limited, one of the reason being, as described for IL-2, its poor pharmacokinetics in vivo (21,22). Considering the IL-15 transpresentation model, we previously developed the fusion protein RLI, linking human sIL-15Rα-sushi+ domain to human IL-15, and showed its better biological activities than IL-15 in vitro (29,31). The present studies were therefore conducted to evaluate whether RLI would be a better alternative than IL-15 and IL-2 for cancer treatment using two distinct animal models and to measure its bioavailability in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…ILR, RLI, and sushi+ were produced as described previously (29,31 (32), in the presence of anti-IL-15Rβ A41 antibody (66 nmol/L) for Kit225.…”

Section: Cytokines and Reagentsmentioning

confidence: 99%

“…The noncovalent association of sIL-15Rα with IL-15 has been shown to enhance the activity of IL-15 in vitro (29,31) and in vivo (26, 27), and we have recently shown that RLI was more active than the noncovalent association of its two linked moieties (i.e., IL-15 and IL-15Rα-sushi+ domain) to activate in vitro the IL-15Rβ/γ and IL-15Rα/β/γ receptors (29). We therefore compared the maximal activity of RLI with that of a noncovalent association of IL-15 plus IL-15Rα-sushi+ domain in the B16F10 melanoma model (Fig.…”

Section: Rli Is More Efficient Than Ilr and Il-15 For Activating Il-1mentioning

confidence: 99%

“…This fusion protein was shown to exert higher biological activities than IL-15 or even the noncovalent association of IL-15 with the sIL-15Rα in vitro to drive cell proliferation through the IL-15Rβ/γ receptor (29) and in vivo to promote mobilization and expansion of NK cells (30). In the present study, we further investigated the interest of RLI as an antitumoral agent in two mouse models: a syngenic model (lung and liver metastasis of the B16F10 mouse melanoma cells in C57BL/6 mice) and a xenogenic model (tumor growth and metastasis of HCT-116 human colon cancer cells in nude mice).…”

Section: Introductionmentioning

confidence: 99%

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High antitumor activity of RLI, an interleukin-15 (IL-15)–IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer

Bessard

Solé

Bouchaud

et al. 2009

Molecular Cancer Therapeutics

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118

102

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Interleukin (IL)-15 has an important role in tumor immunosurveillance and has a contemplated use in tumor immunotherapy. We have previously engineered the fusion protein RLI, composed of the NH 2 -terminal (amino acids 1-77, sushi+) domain of IL-15 receptor α coupled via a linker to IL-15, and shown that it displayed far better efficacy than IL-15 in vitro. In this report, we investigated in vivo whether RLI would be a better alternative than IL-15 and IL-2 for cancer treatment using two distinct animal models. B16F10 mouse melanoma cells were injected in C57BL/6 mice either i.v. or intrasplenically for lung or liver metastasis, respectively. HCT-116 human colorectal cancer cells were injected in the cecum of nude mice. We show that RLI has a higher efficiency than IL-15 or IL-2 to reduce lung and liver metastasis and enhance survival in the mouse B16F10 melanoma model, a result that was associated with a higher half-life in vivo. We also found that the antitumoral effect of RLI was completely abolished by in vivo depletion of natural killer cells using anti-asialoGM1 antibody. Moreover, RLI was also efficient to reduce by 50% tumor growth and the progression of metastasis of human colon carcinoma cells in an orthotopic nude mouse model. The fusion protein RLI has revealed strong anticancer effect in two different cancer models overcoming the limited effect of IL-15 by increasing its bioavailability and efficiency. These findings hold significant importance for the use of RLI as a potential adjuvant/therapeutic. [Mol Cancer Ther 2009;8(9):2736-45]

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

“…ILR, RLI, and sushi+ were produced as described previously (29,31 (32), in the presence of anti-IL-15Rβ A41 antibody (66 nmol/L) for Kit225.…”

Section: Cytokines and Reagentsmentioning

confidence: 99%

Section: Rli Is More Efficient Than Ilr and Il-15 For Activating Il-1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

High antitumor activity of RLI, an interleukin-15 (IL-15)–IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer

Bessard

Solé

Bouchaud

et al. 2009

Molecular Cancer Therapeutics

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118

102

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Design and characterization of a protein superagonist of IL‐15 fused with IL‐15Rα and a high‐affinity T cell receptor

Stone

Chervin

Schreiber

et al. 2012

Biotechnology Progress

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To avoid high systemic doses, strategies involving antigen-specific delivery of cytokine via linked antibodies or antibody fragments have been employed. Targeting cancer-associated peptides presented by MHC molecules (pepMHC) increases the number of potential target antigens, and takes advantage of cross-presentation on tumor stroma and in draining lymph nodes. Here, we use a soluble, high-affinity single-chain T cell receptor Vα-Vβ (scTv), to deliver cytokines to intracellular tumor-associated antigens presented as pepMHC. Since typical wild-type TCRs exhibit low affinity (Kd =1–100μM or more), we used an engineered TCR, m33, that binds SIY/Kb with nanomolar affinity (Kd =30nM). We generated constructs consisting of m33 scTv fused to murine IL-2, IL-15, or IL-15/IL-15Rα (IL-15 linked to IL-15Rα sushi domain, called “superfusion”). The fusions were purified with good yields, and bound specifically to SIY/Kb with high affinity. Proper cytokine folding and binding were confirmed, and the fusions were capable of stimulating proliferation of cytokine-dependent cells, both when added directly and when presented in trans, bound to cells with the target pepMHC. The m33 superfusion was particularly potent and stable, and represents a promising design for targeted anti-tumor immunomodulation.

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Tumor targeting of the IL‐15 superagonist RLI by an anti‐GD2 antibody strongly enhances its antitumor potency

Vincent

Bessard

Cochonneau

et al. 2013

Intl Journal of Cancer

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Immunocytokines (ICKs) targeting cytokines to the tumor environment using antibodies directed against a tumor-associated antigen often have a higher therapeutic index than the corresponding unconjugated cytokines. Various ICKs displaying significant antitumoral effects in several murine tumor models have already been developed, and some of them, in particular interleukin (IL)-2-based ICKs, are in Phase II clinical trials. Although sharing common biological activities with IL-2 in vitro, IL-15 is now considered as having a better potential in antitumor immunotherapeutical strategies and has been shown to be less toxic than IL-2 in preclinical studies. We previously developed the fusion protein RLI, linking a soluble form of human IL-15Ra-sushi1 domain to human IL-15. RLI showed better biological activities than IL-15 in vitro as well as higher antitumoral effects in vivo in murine and human cancer models. Here, we investigated, in the context of an ICK, the effect of associating RLI with an antibody targeting the GD2 ganglioside, a validated tumoral target expressed on many neurectodermal tumors. Anti-GD2-RLI fully retained the cytokine potential of RLI and the antibody effector functions (antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity). It displayed strong antitumor activities in two syngeneic cancer models in immunocompetent mice (subcutaneous EL4 and metastatic NXS2). Its therapeutic potency was higher than those of RLI and anti-GD2 alone or in combination. We suggest that this is related to its bifunctional (cytokine and antibody) nature.

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The Exon-3-Encoded Domain of IL-15Rα Contributes to IL-15 High-Affinity Binding and Is Crucial for the IL-15 Antagonistic Effect of Soluble IL-15Rα

Cited by 43 publications

References 28 publications

High antitumor activity of RLI, an interleukin-15 (IL-15)–IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer

High antitumor activity of RLI, an interleukin-15 (IL-15)–IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer

Design and characterization of a protein superagonist of IL‐15 fused with IL‐15Rα and a high‐affinity T cell receptor

Tumor targeting of the IL‐15 superagonist RLI by an anti‐GD2 antibody strongly enhances its antitumor potency

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