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

Menée in vitro, à l'aide de xénogreffes et sur des singes cynomolgus, cette étude évalue l'activité d'un anticorps monoclonal appelé CDX-1127 dans les leucémies et lymphomes CD27+

Résumé en anglais

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 report, 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 immunodeficiency (SCID) mice inoculated with human CD27-expressing lymphoma cells were administered 1F5 to investigate direct anti-tumor 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 (ADCC). 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 anti-tumor activity against CD27 expressing lymphoma or leukemia, independent of its potential to enhance immunity through its agonistic properties.