Chronic lymphocytic leukemia or CLL, one of the most common forms of leukemia in Europe and North America, is a disorder of morphologically mature but immunologically less mature lymphocytes. It is manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues. [1]
While advances in molecular biology have enhanced the general understanding of the pathophysiology of chronic lymphocytic leukemia, together with the discovery and development of new therapeutic agents, have made management of the disease more effective than in the past, CLL is generally not curable. To date, treatment ranges from periodic observation with treatment of infectious, hemorrhagic, or immunologic complications, to a variety of therapeutic options that may include steroids, alkylating agents, purine analogs, combination chemotherapy, monoclonal antibodies, and transplant options. [1][2]
Data from the American Cancer Society shows that, each year, in the United States, 15,720 new patients will be diagnosed with the disease and an estimated 4,600 patients will die. [3] Hence, there is critical need of new, effective, and safe therapies.
A potential new approach
The recently identified IgM-receptor FcµR is expressed on CD19+B cells, CD4+/CD8+ T cells, and CD56+/CD3- NK cells and overexpressed in chronic lymphocytic leukemia. It also mediates the rapid internalization and lysosomal shuttling of IgM via its Fc fragment (Fcµ).
Current research shows that the aggregation of FcμR with IgM leads to rapid internalization of IgM (>80% internalized within 5 minutes). On the other hand, mAb bound FcμR is not internalized. Hence. overexpression on CLL cells and rapid internalization of FcμR represents a potential of selectively delivering a cytotoxic agent into malignant cells. [4]
To exploit this internalization and trafficking pathway for targeted drug delivery, researchers at the Hematology Branch, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, in cooperation with the Molecular Discovery Program at the National Cancer Institute, the Institut de Génomique Fonctionnelle, at the Université Montpellier and the Department of Cancer Biology at The Scripps Research Institute in Florida, developed a novel strategy for targeted cytotoxic therapy of chronic lymphocytic leukemia. Study results were published in the October 24, 2014 issue of Cancer Research, published by the American Association for Cancer Research (AACR)
The team of scientists, including Berengere Vire, Martin Skarzynski, Joshua Thomas, Christopher Nelson, Alexandre David, Georg Aue, Terrence Burke, Christoph Rader and Adrian Wiestner, engineered a scaffold derived from the CH2-CH3-CH4 IgM constant regions with a C-terminal selenocysteine. This allowed covalent conjugation with the cytotoxic agent monomethylauristatin F (MMAF), an anti-mitotic agent that inhibits cell division by blocking the polymerization of tubulin, to the protein scaffold (Fcµ) [4][5]
Resistance to standard chemotherapy
This Fcµ-drug conjugate was selectively toxic for FcµR expressing cell lines in vitro and for chronic lymphocytic leukemia cells but not autologous normal T-cells ex vivo.
In this study, the researchers observed that the cytotoxic activity of the Fcµ-drug conjugate was maintained in chronic lymphocytic leukemia cells carrying a 17p deletion, which predicts resistance to standard chemotherapy.
Next, the scientists tested the possible therapeutic application of the Fcµ-drug conjugate in immunodeficient NSG mice engrafted with peripheral blood cells from leukemia patients.
Three intravenous injections of the Fcµ-drug conjugate over a 10-day period were well tolerated and selectively killed the human chronic lymphocytic leukemia cells but not the co-engrafted autologous human T-cells.
Potent and specific therapeutic activity
Based on these unique properties of FcµR and the results of their initial test, the researchers concluded that FcµR-targeted drug delivery showed potent and specific therapeutic activity in chronic lymphocytic leukemia.
Based on their study, the researchers provided proof-of-concept for FcµR as a valuable therapeutic target in chronic lymphocytic leukemia and for IgM-based antibody drug conjugates as a new targeting platform.
