A Human Anti-CD1a Monoclonal Antibody for Targeted Immunotherapy in Langerhans Cell Histiocytosis and Hematologic Malignancies.

Abstract

Langerhans Cell Histiocytosis (LCH) is characterized by the clonal proliferative of immature Langerhans cells resulting in a disorder with a wide variety of clinical manifestations and outcomes. Current therapies are based on the use of chemotherapeutic and immunosuppressive agents, usually in combination. Treatments are relatively non-specific, associated with significant adverse side effects and are ineffective in a significant number of patients. More effective and less toxic treatments are therefore needed. The selective expression of the nonclassical MHC protein, CD1a, on the lesional Langerhans cells in LCH makes this antigen an excellent immunotherapeutic target. To this end, we have generated a completely human monoclonal antibody (Mab) that specifically binds to a native, external epitope of CD1a using a human spleen phage display library. Epitope binding regions were selected for recognition of external domains of native CD1a and sequences showing specific binding were cloned into a human IgG1 backbone. The anti-CD1a Mab, termed 2113, shows high affinity and specificity for CD1a and is internalized after binding to the surface of CD1a expressing cells. The 2113 Mab also demonstrates significant complement dependent lysis (CDC) and antibody dependent cell cytotoxicity (ADCC) against CD1a expressing cells. No direct antibody mediated apoptosis was observed for 2113 binding to CD1a. A preclinical murine CD1a positive tumor model is being used to test the 2113 Mab for selective localization and tumor cytotoxicity. This Mab should provide an excellent reagent for therapeutic targeting of LCH and CD1a positive hematologic malignancies as well as possibly having application in the treatment of autoimmune disorders, prevention of graft-versus-host disease and augmenting cancer vaccines through direct antigen delivery to Langerhans cells.

The role of Langerhans cells in pathologies of the skin

“…Antibodies against CD1a have been able to substantially reduce skin inflammation . A monoclonal antibody against CD1a has been used in for the treatment of LC histiocytosis and could have application in the treatment of autoimmune disorders.…”