Abstract
CD38, as a cell surface antigen is highly expressed in several hematologic malignancies including multiple myeloma (MM) and has been proven to be a good target for immunotherapy of the disease. CD38 is also a signaling enzyme responsible for the metabolism of two novel calcium messenger molecules. To be able to target this multifunctional protein, we generated a series of nanobodies against CD38 with high affinities. Crystal structures of the complexes of CD38 with the nanobodies were solved, identifying three separate epitopes on the carboxyl domain. Chromobodies, engineered by tagging the nanobody with fluorescence proteins, provide fast, simple and versatile tools for quantifying CD38 expression. Results confirmed that CD38 was highly expressed in malignant MM cells compared with normal white blood cells. The immunotoxin constructed by splicing the nanobody with a bacterial toxin, PE38 shows highly selective cytotoxicity against patient-derived MM cells as well as the cell lines, with half maximal effective concentration reaching as low as 10−11 molar. The effectiveness of the immunotoxin can be further increased by stimulating CD38 expression using retinoid acid. These results set the stage for the development of clinical therapeutics as well as diagnostic screening for myeloma.
Highlights
CD38, as a cell surface antigen is highly expressed in several hematologic malignancies including multiple myeloma (MM) and has been proven to be a good target for immunotherapy of the disease
CD38 is a novel protein serving multiple functions. Is it the dominant signaling enzyme in mammalian cells for mediating the mobilization of multiple intracellular calcium stores[2], but it functions as a surface antigen interacting with specific receptors, such as CD44,5 and CD316
Its expression level on activated T cells is an indicator of AIDS progression[28] and has been found to be highly expressed on myeloma cells[29]
Summary
CD38, as a cell surface antigen is highly expressed in several hematologic malignancies including multiple myeloma (MM) and has been proven to be a good target for immunotherapy of the disease. Decades of research documents that it is a novel multifunctional molecule, serving as a differentiation antigen on cell surface, and, most surprisingly, as the dominant signaling enzyme responsible for the metabolism of two intracellular calcium messenger molecules, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) (reviewed in Lee[1]). It is well-established that the C-terminal domain possesses all the catalytic activities of the enzyme. They are much smaller and more stable than conventional full-length antibodies but retain equivalent antigen-binding capacity[15]
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