Marked enhancement of antigen‐specific T‐cell responses by IL‐7‐fused nonlytic, but not lytic, Fc as a genetic adjuvant

Nam, Hyo Jung; Song, Mi-Young; Choi, Donghoon; Yang, Se-Hwan; Jin, Hyun-Tak; Sung, Young‐Chul

doi:10.1002/eji.200939271

Cited by 27 publications

(27 citation statements)

References 36 publications

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“…S2). In our previous study, the serum IL7 level was comparable in mice treated with either IL7-Fc or rIL7 immediately after intraperitoneal injection, and the in vivo IL7-Fc level declined more slowly than rIL7 due to the prolonged circulating half-life by Fc fusion (27). In contrast, in this study, the serum IL7 level was initially undetectable (Supplementary Fig.…”

Section: Discussioncontrasting

confidence: 47%

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Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells

Choi

Kang

Seo

et al. 2016

Clinical Cancer Research

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Purpose: The induction of tissue-localized virus-specific CD8 T-cell response is essential for the development of an effective therapeutic vaccine against genital diseases, such as cervical cancer and genital herpes. Here, we aimed to elucidate the immunologic role of IL7 in the induction of mucosal cellular immunity.Experimental Design: IL7 was engineered through Fc fusion to enhance mucosal delivery across the genital epithelial barrier. The immunomodulatory role of IL7 was evaluated by monitoring the kinetics of various immune cells and measuring the expression of chemokines and cytokines after intravaginal administration of Fcfused IL7 (IL7-Fc). The antitumor effects of intramuscular human papillomavirus (HPV) DNA vaccine or topical IL7-Fc alone or in a combinational regimen on mice survival were compared using a orthotopic cervical cancer model. Results:Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNg, TNFa, IL6, and IL1b), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, gd T cells, and dendritic cells. Importantly, in this murine cervical cancer model, topical administration of IL7-Fc after intramuscular HPV DNA vaccination increases the number of HPV-specific CD8 T cells in the genital mucosa, but not in the spleen, leading to stronger antitumor activity than the HPV DNA vaccine alone.Conclusions: Our findings provide an important insight into the immunomodulatory role of IL7-Fc via topical application and the design of therapeutic vaccine regimen that induces effective genital-mucosal CD8 T-cell responses. Clin Cancer Res; 22(23); 5898-908. Ó2016 AACR.

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Section: Discussioncontrasting

confidence: 47%

“…The codon-optimized human IL7 (27) and G-CSF gene were individually fused with a hybrid Fc-fragment, which contains the upper CH2 domain of IgD, and the last CH2 and CH3 domains of IgG4 (28). The schematic structure of Fc-fused IL7 is presented in Supplementary Fig.…”

Section: Preparation and Treatmentmentioning

confidence: 99%

Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells

Choi

Kang

Seo

et al. 2016

Clinical Cancer Research

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“…It should also be noted that the IL-7-Fc fusion protein we analyzed has mutations that preclude binding to FcgR and C1q, supporting the notion that Fc enhances IL-7 potency in vivo independently of these Fcbinding proteins. 29 Taken together, these data indicate that the Fc, via the actions of FcRn, accounts for approximately 80% of the in vivo T-cell mitogenic effect of IL-7/M25 treatment.…”

Section: Discussionmentioning

confidence: 61%

“…IL-7-Fc is a recombinant protein of hIL-7 fused to a mutant, nonlytic form of murine Fcg2a (L235E, E318A, K320A, K322A) and was prepared as previously described. 29 Anti-IL-7 mAbs have been described previously. 13,30 Fab fragments of M25 (M25 Fab ) were generated by using papain (Worthington Biochemical), and the IL-7 neutralizing capacity of M25 Fab was standardized to M25 by in vitro T-cell survival assay.…”

Section: Abs and Cytokinesmentioning

confidence: 99%

“…29 In order to achieve a fair comparison between IL-7/M25 and IL-7-Fc, the relative activity of IL-7-Fc and IL-7 was determined by an in vitro T-cell survival assay (data not shown). The in vivo potency of the fusion protein was then compared with a functionally equivalent dose of IL-7, either as free cytokine or as bound to M25, by measuring the induced proliferation of CD8…”

Section: Il-7-fc Fusion Protein Exhibits Enhanced In Vivo Potencymentioning

confidence: 99%

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IL-7/anti–IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R

Martin

Leeuwen

et al. 2013

Blood

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Key Points• IL-7/antibody complexes are potent because they prolong IL-7 availability in vivo by decreasing specific and nonspecific consumption.Interleukin-7 (IL-7) is essential to T-cell survival as well as homeostatic proliferation, and clinical trials that exploit the mitogenic effects of IL-7 have achieved success in treating human diseases. In mice, the in vivo potency of IL-7 improves dramatically when it is administered as a complex with the anti-IL-7 neutralizing monoclonal antibody clone M25. However, the mechanism whereby M25 augments IL-7 potency is unknown. We have analyzed the discrete contributions of the antibody constant (Fc) and IL-7-binding (Fab) domains to the mechanism. By engaging the neonatal Fc receptor the Fc domain extends the in vivo lifespan of IL-7/M25 complexes and accounts for the majority of their activity. Unexpectedly, the IL-7-neutralizing Fab domain provides an additional, albeit smaller, contribution, possibly by serving as a cytokine depot. This study is the first to demonstrate that the neutralizing aspect of the monoclonal antibody is directly involved in enhancing the potency of a cytokine with a single form of receptor. Lessons from the mechanism of IL-7/M25 complexes inform the design of nextgeneration cytokine therapeutics. (Blood. 2013;121(22):4484-4492)

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Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy

Kim

Choi³

et al. 2020

Clin & Trans Imm

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Objectives Emerging oncotherapeutic strategies require the induction of an immunostimulatory tumor microenvironment (TME) containing numerous tumor‐reactive CD8+ T cells. Interleukin‐7 (IL‐7), a T‐cell homeostatic cytokine, induces an antitumor response; however, the detailed mechanisms underlying the contributions of the IL‐7 to TME remain unclear. Here, we aimed to investigate the mechanism underlying the induction of antitumor response by hybrid Fc‐fused long‐acting recombinant human IL‐7 (rhIL‐7‐hyFc) through regulation of both adaptive and innate immune cells in the TME. Methods We evaluated rhIL‐7‐hyFc‐mediated antitumor responses in murine syngeneic tumor models. We analysed the cellular and molecular features of tumor‐infiltrating lymphocytes (TILs) and changes in the TME after rhIL‐7‐hyFc treatment. Furthermore, we evaluated the antitumor efficacy of rhIL‐7‐hyFc combined with chemotherapy and checkpoint inhibitors (CPIs). Results Systemic delivery of rhIL‐7‐hyFc induced significant therapeutic benefits by expanding CD8+ T cells with enhanced tumor tropism. In tumors, rhIL‐7‐hyFc increased both tumor‐reactive and bystander CD8+ TILs, all of which displayed enhanced effector functions but less exhausted phenotypes. Moreover, rhIL‐7‐hyFc suppressed the generation of immunosuppressive myeloid cells in the bone marrow of tumor‐bearing mice, resulting in the immunostimulatory TME. Combination therapy with chemotherapy and CPIs, rhIL‐7‐hyFc elicited a strong antitumor response and even under a T lymphopenic condition by restoring CD8+ T cells. When combined with chemotherapy and CPIs, rhIL‐7‐hyFc administration enhanced antitumor response under intact andlymphopenic conditions by restoring CD8+ T cells. Conclusion Taken together, these data demonstrate that rhIL‐7‐hyFc induces antitumor responses by generating T‐cell‐inflamed TME and provide a preclinical proof of concept of immunotherapy with rhIL‐7‐hyFc to enhance therapeutic responses in the clinic.

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Marked enhancement of antigen‐specific T‐cell responses by IL‐7‐fused nonlytic, but not lytic, Fc as a genetic adjuvant

Cited by 27 publications

References 36 publications

Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells

Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells

IL-7/anti–IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R

Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy

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