Development of a recombinant human IL-15·sIL-15Rα/Fc superagonist with improved half-life and its antitumor activity alone or in combination with PD-1 blockade in mouse model

Zhao, Meiqi; Luo, Manyu; Xie, Yueqing; Jiang, Hua; Cagliero, Cédric; Li, Ninghuan; Hao, Yue; Wu, Mingyuan; Hao, Shuai; Sun, Tze-Chien; Yang, Hui; Zhang, Mengxiao; Lin, Tong; Lu, Huili; Zhu, Jianwei

doi:10.1016/j.biopha.2019.108677

Cited by 23 publications

(14 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…showed that the half-lives of the two IL-15/SuIL-15Rα-IgG4 Fc complexes (14.26 h for IL-15/SuIL-15Rα-dFc and 9.16 h for IL-15/SuIL-15Rα-mFc) were significantly extended compared with that of rhIL-15 (0.7 h). The half-life of rhIL-15 was consistent with previous reports (30–40 min) [ 11 , 12 ], while the variation in the half-life values of IL-15 complexes mentioned above may be due to various routes of administration and analysis methods used in different studies. The half-life of IL-15/SuIL-15Rα-mFc was approximately half that of IL-15/SuIL-15Rα-dFc, which may be due to restrictive kidney filtration; specifically, proteins less than 70 kDa are more likely eliminated by kidney filtration [ 32 ].…”

Section: Discussionsupporting

confidence: 91%

“…or 7.7 h (s.c.) [ 31 ], and IL-15·sIL-15Rα/Fc had a half-life of 13.1 h (i.p.) [ 12 ]. In this study, a pharmacokinetic assessment in C57BL/6 J mice (i.v.)…”

Section: Discussionmentioning

confidence: 99%

“…Physiologically, IL-15 transmits signals mainly through the trans-presentation mechanism, in which IL-15 is preassociated with IL-15Rα to form a heterodimer on the surface of monocytes and dendritic cells and then trans-presented to NK and CD8 + T cells expressing IL-15Rβ and γ chains [8]. With this information, several IL-15 superagonists consisting of IL-15 and partial (such as sushi domain, high-affinity IL-15 binding domain of human IL-15Rα) or whole IL-15Rα fused to the Fc domain of IgG1 have been designed and expressed in mammalian cells with enhanced immunostimulatory activity and extended half-lives [9][10][11][12][13]. These IL-15 superagonists exhibited an augmented antitumor effect compared to the IL-15 monomer in multiple studies, which pushed them (mostly ALT-803) into clinical trials to test their efficacy and safety in cancer treatment [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Development of IL-15/IL-15Rα sushi domain-IgG4 Fc complexes in Pichia pastoris with potent activities and prolonged half-lives

Shi

Shao

et al. 2021

Microb Cell Fact

View full text Add to dashboard Cite

Background Interleukin-15 (IL-15) is a critical cytokine for the development, proliferation, and function of natural killer (NK) cells, NKT cells, and CD8+ memory T cells and has become one of the most promising protein molecules for the treatment of cancer and viral diseases. However, there are several limitations in applying IL-15 in therapy, such as its low yield in vitro, limited potency, and short half-life in vivo. To date, there are several recombinant IL-15 agonists based on configurational modifications that are being pursued in the treatment of cancer, such as ALT-803, which are mainly produced from mammalian cells. Results In this study, we designed two different forms of the IL-15 complex, which were formed by the noncovalent assembly of IL-15 with dimeric or monomeric sushi domain of IL-15 receptor α (SuIL-15Rα)-IgG4 Fc fusion protein and designated IL-15/SuIL-15Rα-dFc and IL-15/SuIL-15Rα-mFc, respectively. The two IL-15 complexes were expressed in Pichia pastoris (P. pastoris), and their activities and half-lives were evaluated and compared. Pharmacokinetic analysis showed that IL-15/SuIL-15Rα-dFc had a half-life of 14.26 h while IL-15/SuIL-15Rα-mFc had a half-life of 9.16 h in mice, which were much longer than the 0.7-h half-life of commercial recombinant human IL-15 (rhIL-15). Treatment of mice with intravenous injection of the two IL-15 complexes resulted in significant increases in NK cells, NKT cells, and memory CD8+ T cells, which were not observed after rhIL-15 treatment. Treatment of human peripheral blood mononuclear cells (PBMCs) from healthy donors with the two IL-15 complexes yielded enhanced NK and CD8+ T cell activation and proliferation, which was comparable to the effect of rhIL-15. Conclusions These findings indicate that the IL-15/SuIL-15Rα-dFc and IL-15/SuIL-15Rα-mFc produced in P. pastoris exhibit potent activities and prolonged half-lives and may serve as superagonists for immunotherapy in further research and applications.

show abstract

Section: Discussionsupporting

confidence: 91%

“…or 7.7 h (s.c.) [ 31 ], and IL-15·sIL-15Rα/Fc had a half-life of 13.1 h (i.p.) [ 12 ]. In this study, a pharmacokinetic assessment in C57BL/6 J mice (i.v.)…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development of IL-15/IL-15Rα sushi domain-IgG4 Fc complexes in Pichia pastoris with potent activities and prolonged half-lives

Shi

Shao

et al. 2021

Microb Cell Fact

View full text Add to dashboard Cite

show abstract

“…This efficacy was dramatically reduced in FcRγ −/− mice suggesting that IL-15 increased the ADCC of the anticancer monoclonal antibodies. Both NK cells and macrophages were critical elements of interacting effectors involved in the augmented ADCC and augmented therapeutic responses (71). Following interaction with macrophages there was induction of expression of FcRγIV critical for ADCC by the NK cells (2,74).…”

Section: Il-15 In Combination Therapy With Anticancer Monoclonal Antibodiesmentioning

confidence: 99%

IL-15 in the Combination Immunotherapy of Cancer

et al. 2020

View full text Add to dashboard Cite

We completed clinical trials of rhIL-15 by bolus, subcutaneous, and continuous intravenous infusions (CIV). IL-15 administered by CIV at 2 mcg/kg/day yielded a 38-fold increase in 10-day number of circulating NK cells, a 358-fold increase in CD56 bright NK cells and a 5.8-fold increase in CD8 T cells. However, IL-15 preparations administered as monotherapy were ineffective, due to actions of immunological checkpoints and due to the lack of tumor specific targeting by NK cells. To circumvent checkpoints, trials of IL-15 in combination with other anticancer agents were initiated. Tumor-bearing mice receiving IL-15 with antibodies to CTLA-4 and PD-L1 manifested marked prolongation of survival compared to mice receiving IL-15 with either agent alone. In translation, a phase I trial was initiated involving IL-15 (rhIL-15), nivolumab and ipilimumab in patients with malignancy (NCT03388632). In rhesus macaques CIV IL-15 at 20 µg/kg/day for 10 days led to an 80-fold increase in number of circulating effector memory CD8 T cells. However, administration of γc cytokines such as IL-15 led to paralysis/depression of CD4 T-cells that was mediated through transient expression of SOCS3 that inhibited the STAT5 signaling pathway. This lost CD4 helper role could be restored alternatively by CD40 agonists. In the TRAMP-C2 prostate tumor model the combination of IL-15 with agonistic anti-CD40 produced additive effects in terms of numbers of TRAMP-C2 tumor specific Spas/SCNC/9H tetramer positive CD8 T cells expressed and tumor responses. A clinical trial is being initiated for patients with cancer using an intralesional anti-CD40 in combination with CIV rhIL-15. To translate IL-15-mediated increases in NK cells, we investigated combination therapy of IL-15 with anticancer monoclonal antibodies including rituximab in mouse models of EL-4 lymphoma transfected with human CD20 and with alemtuzumab (CAMPATH-1H) in a xenograft model of adult T cell leukemia (ATL). IL-15 enhanced the ADCC and therapeutic efficacy of both antibodies. These results provided the scientific basis for trials of IL-15 combined with alemtuzumab (anti-CD52) for patients with ATL (NCT02689453), with obinutuzumab (anti-CD20) for patients with CLL (NCT03759184), and with avelumab (anti-PD-L1) in patients with T-cell lymphoma (NCT03905135) and renal cancer (NCT04150562). In the first trial, there was elimination of circulating ATL and CLL leukemic cells in select patients.

show abstract

“…Furthermore, IL-15 is critical in maintenance of CD122 + CD8 + T reg cells (Rifa'i et al, 2008). The combination of IL-15 superagonist with anti-PD-L1 therapy was more effective than either agent alone in murine tumor models (Kowalsky et al, 2018;Knudson et al, 2019;Zhao et al, 2019). Furthermore, Desbois et al (2016) demonstrated that IL-15 trans-signaling with the receptor-linker-IL-15 (RLI) that consists of human IL-15 covalently linked to the human IL-15Rα sushi domain promotes effector/memory CD8 + T cell responses and enhances the antitumor activity of PD-1 antagonists.…”

Section: Il-15 In Combination Therapymentioning

confidence: 99%

Interleukin-15 (dys)regulation of lymphoid homeostasis: Implications for therapy of autoimmunity and cancer

Waldmann

Miljković

Conlon

2019

Journal of Experimental Medicine

View full text Add to dashboard Cite

IL-15, a pleiotropic cytokine, stimulates generation of NK, NK-T, γδ, ILC1, and memory CD8 T cells. IL-15 disorders play pathogenetic roles in organ-specific autoimmune diseases including celiac disease. Diverse approaches are developed to block IL-15 action. IL-15 administered to patients with malignancy yielded dramatic increases in NK numbers and modest increases in CD8 T cells. Due to immunological checkpoints, to achieve major cancer therapeutic efficacy, IL-15 will be used in combination therapy, and combination trials with checkpoint inhibitors, with anti-CD40 to yield tumor-specific CD8 T cells, and with anticancer monoclonal antibodies to increase ADCC and antitumor efficacy, have been initiated.

show abstract

Development of a recombinant human IL-15·sIL-15Rα/Fc superagonist with improved half-life and its antitumor activity alone or in combination with PD-1 blockade in mouse model

Cited by 23 publications

References 37 publications

Development of IL-15/IL-15Rα sushi domain-IgG4 Fc complexes in Pichia pastoris with potent activities and prolonged half-lives

Development of IL-15/IL-15Rα sushi domain-IgG4 Fc complexes in Pichia pastoris with potent activities and prolonged half-lives

IL-15 in the Combination Immunotherapy of Cancer

Interleukin-15 (dys)regulation of lymphoid homeostasis: Implications for therapy of autoimmunity and cancer

Contact Info

Product

Resources

About