Anti-tumor effects of depleting and non-depleting anti-CD27 monoclonal antibodies in immune-competent mice

Sakanishi, Tamami; Yagita, Hideo

doi:10.1016/j.bbrc.2010.02.092

Cited by 36 publications

(28 citation statements)

References 23 publications

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“…Targeting the CD27-costimulation pathway with specific Abs showed considerable promise in a variety of murine model systems (27)(28)(29) and motivated the development of human anti-hCD27…”

Section: Discussionmentioning

confidence: 99%

Agonist Anti-Human CD27 Monoclonal Antibody Induces T Cell Activation and Tumor Immunity in Human CD27–Transgenic Mice

Prostak

Thomas

et al. 2013

The Journal of Immunology

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The CD70/CD27 pathway plays a significant role in the control of immunity and tolerance, and previous studies demonstrated that targeting murine CD27 (mCD27) with agonist mAbs can mediate antitumor efficacy. We sought to exploit the potential of this pathway for immunotherapy by developing 1F5, a fully human IgG1 mAb to human CD27 (hCD27) with agonist activity. We developed transgenic mice expressing hCD27 under control of its native promoter for in vivo testing of the Ab. The expression and regulation of hCD27 in hCD27-transgenic (hCD27-Tg) mice were consistent with the understood biology of CD27 in humans. In vitro, 1F5 effectively induced proliferation and cytokine production from hCD27-Tg–derived T cells when combined with TCR stimulation. Administration of 1F5 to hCD27-Tg mice enhanced Ag-specific CD8+ T cell responses to protein vaccination comparably to an agonist anti-mCD27 mAb. In syngeneic mouse tumor models, 1F5 showed potent antitumor efficacy and induction of protective immunity, which was dependent on CD4+ and CD8+ T cells. The requirement of FcR engagement for the agonistic and antitumor activities of 1F5 was demonstrated using an aglycosylated version of the 1F5 mAb. These data with regard to the targeting of hCD27 are consistent with previous reports on targeting mCD27 and provide a rationale for the clinical development of the 1F5 mAb, for which studies in advanced cancer patients have been initiated under the name CDX-1127.

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“…Targeting the CD27-costimulation pathway with specific Abs showed considerable promise in a variety of murine model systems (27)(28)(29) and motivated the development of human anti-hCD27…”

Section: Discussionmentioning

confidence: 99%

Agonist Anti-Human CD27 Monoclonal Antibody Induces T Cell Activation and Tumor Immunity in Human CD27–Transgenic Mice

Prostak

Thomas

et al. 2013

The Journal of Immunology

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“…Recent studies have documented the potential for anti-CD27 antibodies in mouse lymphoma models (11,13,14). Interestingly, in these studies, the primary mechanism of antitumor activity was through indirect enhancement of the immune responses against the tumor and did not require CD27 expression by the lymphoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…The interaction of CD27 with CD70 plays an important role in the activation, proliferation, and survival of T cells; in clonal B-cell expansion and germinal center formation; and in NK cell cytolytic activity (7)(8)(9)(10). Recent studies show that modulation of this pathway by engineered expression of CD70 or agonist anti-CD27 antibodies can overcome tolerance and circumvent CD40-mediated signaling, leading to antitumor immunity in experimental systems (11)(12)(13)(14). In addition, expression of CD70 on lymphoma and other experimental tumor cell lines has been shown to promote their rejection by both NK and T-cell-dependent mechanisms in immunocompetent mouse tumor models (15,16), and CD27 activation is critical for the appropriate generation of anti-leukemia T-cell response in B-cell precursor acute lymphoblastic leukemia (17).…”

Section: Introductionmentioning

confidence: 99%

Development of a Human Monoclonal Antibody for Potential Therapy of CD27-Expressing Lymphoma and Leukemia

Vitale

Thomas

et al. 2012

Clinical Cancer Research

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Purpose: The TNF receptor superfamily member CD27 is best known for its important role in T-cell immunity but is also recognized as a cell-surface marker on a number of B-and T-cell malignancies. In this article, we describe a novel human monoclonal antibody (mAb) specific for CD27 with properties that suggest a potential utility against malignancies that express CD27.Experimental Design: The fully human mAb 1F5 was generated using human Ig transgenic mice and characterized by analytical and functional assays in vitro. Severe combined immunodeficient (SCID) mice inoculated with human CD27-expressing lymphoma cells were administered 1F5 to investigate direct antitumor effects. A pilot study of 1F5 was conducted in non-human primates to assess toxicity.Results: 1F5 binds with high affinity and specificity to human and macaque CD27 and competes with ligand binding. 1F5 activates T cells only in combination with T-cell receptor stimulation and does not induce proliferation of primary CD27-expressing tumor cells. 1F5 significantly enhanced the survival of SCID mice bearing Raji or Daudi tumors, which may be mediated through direct effector mechanisms such as antibody-dependent cellular cytotoxicity. Importantly, administration of up to 10 mg/kg of 1F5 to cynomolgus monkeys was well tolerated without evidence of significant toxicity or depletion of circulating lymphocytes.Conclusions: Collectively, the data suggest that the human mAb 1F5, which has recently entered clinical development under the name CDX-1127, may provide direct antitumor activity against CD27-expressing lymphoma or leukemia, independent of its potential to enhance immunity through its agonistic properties.

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“…Help" vaccine combined with either a control mAb or a CD27 agonist mAb that stimulates CD27 function in the absence of CD70 binding (25). CD27 agonism significantly increased the magnitude of the CD8 þ T-cell response to "No Help" vaccination as monitored in the blood, throughout the entire kinetics of the primary response (Fig.…”

Section: Cd4mentioning

confidence: 94%

“…24), CTLA-4 (9D9), and PD-1 (RMP1-14) or agonistic mAb to CD27 (RM27-3E5; ref. 25) were injected i.p. at 100 mg per mouse in 100 mL HBSS on each day of primary vaccination and in case of FR70 mAb also at day 9.…”

Section: Antibody Treatmentsmentioning

confidence: 99%

CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination

et al. 2016

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Anti-tumor effects of depleting and non-depleting anti-CD27 monoclonal antibodies in immune-competent mice

Cited by 36 publications

References 23 publications

Agonist Anti-Human CD27 Monoclonal Antibody Induces T Cell Activation and Tumor Immunity in Human CD27–Transgenic Mice

Agonist Anti-Human CD27 Monoclonal Antibody Induces T Cell Activation and Tumor Immunity in Human CD27–Transgenic Mice

Development of a Human Monoclonal Antibody for Potential Therapy of CD27-Expressing Lymphoma and Leukemia

CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination

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