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1.
J Immunol ; 191(8): 4174-83, 2013 Oct 15.
Article in English | MEDLINE | ID: mdl-24026078

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.


Subject(s)
Antibodies, Monoclonal/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Neoplasms/therapy , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology , Animals , Cell Proliferation , Humans , Immunoglobulin G/immunology , Immunotherapy , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Transgenic , Neoplasms/immunology , Receptors, Antigen, T-Cell/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/agonists , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics
2.
J Neurosci ; 29(38): 11965-72, 2009 Sep 23.
Article in English | MEDLINE | ID: mdl-19776282

ABSTRACT

Phosphorylation of the NR1 subunit of NMDA receptors (NMDARs) at serine (S) 897 is markedly reduced in schizophrenia patients. However, the role of NR1 S897 phosphorylation in normal synaptic function and adaptive behaviors are unknown. To address these questions, we generated mice in which the NR1 S897 is replaced with alanine (A). This knock-in mutation causes severe impairment in NMDAR synaptic incorporation and NMDAR-mediated synaptic transmission. Furthermore, the phosphomutant animals have reduced AMPA receptor (AMPAR)-mediated synaptic transmission, decreased AMPAR GluR1 subunit in the synapse, and impaired long-term potentiation. Finally, the mutant mice exhibit behavioral deficits in social interaction and sensorimotor gating. Our results suggest that an impairment in NR1 phosphorylation leads to glutamatergic hypofunction that can contribute to behavioral deficits associated with psychiatric disorders.


Subject(s)
Behavior, Animal/physiology , Neuronal Plasticity , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Brain/physiology , Brain/ultrastructure , Gene Knock-In Techniques , In Vitro Techniques , Long-Term Potentiation/genetics , Long-Term Potentiation/physiology , Male , Mice , Mice, Inbred C57BL , Mutation, Missense , Neuronal Plasticity/genetics , Neurons/physiology , Neurons/ultrastructure , Phosphorylation , Receptors, AMPA/metabolism , Schizophrenia/genetics , Social Behavior , Synapses/genetics , Synapses/physiology , Synapses/ultrastructure , Synaptic Transmission/genetics , Synaptic Transmission/physiology
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