title: Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice.
abstract: 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.
authors.affiliation: Celldex Therapeutics, Inc., Phillipsburg, NJ 08865;
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: He
authors.forename: Naseem
authors.initials: N
authors.lastname: Prostak
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Thomas
authors.forename: Laura
authors.initials: L
authors.lastname: Vitale
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weidlick
authors.forename: Andrea
authors.initials: A
authors.lastname: Crocker
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Pilsmaker
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Round
authors.forename: Alison
authors.initials: A
authors.lastname: Tutt
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
authors.forename: Henry
authors.initials: H
authors.lastname: Marsh
authors.forename: Tibor
authors.initials: T
authors.lastname: Keler
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007167:Immunotherapy; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000819:agonists / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D011948:Receptors, Antigen, T-Cell; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7