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

• Published in: Clinical cancer research Vol. 18; no. 14; pp. 3812 - 3821
• Main Authors: VITALE, Laura A, HE, Li-Zhen, ANSELL, Stephen M, MARSH, Henry, KELER, Tibor, THOMAS, Lawrence J, WIDGET, Jennifer, WEIDLICK, Jeffrey, CROCKER, Andrea, O'NEILL, Thomas, STOREY, James, GLENNIE, Martin J, GROTE, Deanna M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2012
• Subjects: Animals; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity - immunology; Antineoplastic agents; Biological and medical sciences; Cell Proliferation; Hematologic and hematopoietic diseases; Humans; Leukemia - drug therapy; Leukemia - immunology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma - drug therapy; Lymphoma - immunology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, SCID; Mice, Transgenic; Neoplasms - drug therapy; Neoplasms - immunology; Pharmacology. Drug treatments; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 7 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 7 - immunology; Human; Treatment; Lymphoproliferative syndrome; Leukemia; Development; Malignant hemopathy; Monoclonal antibody; Lymphoid neoplasm; Gene expression; Lymphoma; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-3308

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. 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. 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. 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.