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Immuno-targeting the multifunctional CD38 using nanobody
Ting Li1, Shali Qi2, Mandy Unger3
1School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
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.
Insights
Researchers developed nanobodies targeting CD38, a protein highly expressed in multiple myeloma (MM). These nanobodies led to an effective immunotoxin for treating MM cells, showing promise for new therapies and diagnostics.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- CD38 is a cell surface antigen and signaling enzyme overexpressed in hematologic malignancies like multiple myeloma (MM).
- CD38's role in calcium signaling and its high expression in MM make it a promising therapeutic target.
Purpose of the Study:
- To generate high-affinity nanobodies against CD38 for targeted immunotherapy.
- To develop novel tools for quantifying CD38 expression and create effective anti-MM agents.
Main Methods:
- Generation and affinity assessment of nanobodies against CD38.
- Crystal structure determination of CD38-nanobody complexes to identify epitopes.
- Engineering of chromobodies for CD38 expression analysis.
- Construction and in vitro testing of a CD38-targeted immunotoxin (nanobody-PE38).
Main Results:
- High-affinity nanobodies targeting three distinct CD38 epitopes were developed.
- Chromobodies enabled efficient quantification of CD38 expression, confirming higher levels in MM cells.
- The nanobody-PE38 immunotoxin demonstrated potent and selective cytotoxicity against MM cells (EC50 ~10^-11 M).
- Retinoid acid treatment enhanced CD38 expression and immunotoxin efficacy.
Conclusions:
- Nanobodies are effective tools for targeting CD38 in multiple myeloma.
- The developed immunotoxin shows significant potential for MM therapy.
- CD38-targeted strategies, including immunotoxins and expression modulation, offer promising avenues for clinical application and diagnostics.
