Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia

Laura A. Vitale, Li Zhen He, Lawrence J. Thomas, Jennifer Widger, Jeffrey Weidlick, Andrea Crocker, Thomas O'Neill, James Storey, Martin J. Glennie, Deanna M. Grote, Stephen Maxted Ansell, Henry Marsh, Tibor Keler

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3812-3821
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number14
DOIs
StatePublished - Jul 15 2012

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Human Development
Lymphoma
Leukemia
Monoclonal Antibodies
SCID Mice
T-Lymphocytes
Immunity
Neoplasms
Therapeutics
Lymphocyte Depletion
Macaca fascicularis
Tumor Necrosis Factor Receptors
Macaca
T-Cell Antigen Receptor
Primates
Transgenic Mice
Names
Research Design
Ligands
Antibodies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Vitale, L. A., He, L. Z., Thomas, L. J., Widger, J., Weidlick, J., Crocker, A., ... Keler, T. (2012). Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia. Clinical Cancer Research, 18(14), 3812-3821. https://doi.org/10.1158/1078-0432.CCR-11-3308

Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia. / Vitale, Laura A.; He, Li Zhen; Thomas, Lawrence J.; Widger, Jennifer; Weidlick, Jeffrey; Crocker, Andrea; O'Neill, Thomas; Storey, James; Glennie, Martin J.; Grote, Deanna M.; Ansell, Stephen Maxted; Marsh, Henry; Keler, Tibor.

In: Clinical Cancer Research, Vol. 18, No. 14, 15.07.2012, p. 3812-3821.

Research output: Contribution to journalArticle

Vitale, LA, He, LZ, Thomas, LJ, Widger, J, Weidlick, J, Crocker, A, O'Neill, T, Storey, J, Glennie, MJ, Grote, DM, Ansell, SM, Marsh, H & Keler, T 2012, 'Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia', Clinical Cancer Research, vol. 18, no. 14, pp. 3812-3821. https://doi.org/10.1158/1078-0432.CCR-11-3308
Vitale, Laura A. ; He, Li Zhen ; Thomas, Lawrence J. ; Widger, Jennifer ; Weidlick, Jeffrey ; Crocker, Andrea ; O'Neill, Thomas ; Storey, James ; Glennie, Martin J. ; Grote, Deanna M. ; Ansell, Stephen Maxted ; Marsh, Henry ; Keler, Tibor. / Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 14. pp. 3812-3821.
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AU - Weidlick, Jeffrey

AU - Crocker, Andrea

AU - O'Neill, Thomas

AU - Storey, James

AU - Glennie, Martin J.

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AU - Ansell, Stephen Maxted

AU - Marsh, Henry

AU - Keler, Tibor

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