Journal
MABS
Volume 6, Issue 3, Pages 739-747Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/mabs.28613
Keywords
CD20 antibody; rituximab; HLA-DR; lysosome-mediated cell death; CrossMab; resistant cancer cell
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Funding
- National Natural Science Foundation of China
- Ministry of Science and Technology of China (973 program project)
- Ministry of Science and Technology of China (863 program project)
- National Key project for New Drug Creation and Manufacture
- Shanghai Commission of Science and Technology
- Shanghai Leading Academic Discipline Protect
- Program for Innovative Research Team in University
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Although rituximab has revolutionized the treatment of hematological malignancies, the acquired resistance is one of the prime obstacles for cancer treatment, and development of novel CD20-targeting antibodies with potent anti-tumor activities and specificities is urgently needed. Emerging evidence has indicated that lysosomes can be considered as an Achilles heel for cancer cells, and might serve as an effective way to kill resistant cancer cells. HLA-DR antibody L243 has been recently reported to elicit potent lysosome-mediated cell death in lymphoma and leukemia cells, suggesting that HLA-DR could be used as a potential target against lymphoma. In this study, we generated a bispecific immunoglobulin G-like antibody targeting both CD20 and HLA-DR (CD20-243 CrossMab) through CrossMab technology. We found that the CrossMab could induce remarkably high levels of complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and anti-proliferative activity. Notably, although HLA-DR is expressed on normal and malignant cells, the CrossMab exhibited highly anti-tumor specificity, showing efficient eradication of hematological malignancies both in vitro and in vivo. Our data indicated that combined targeting of CD20 and HLA-DR could be an effective approach against malignancies, suggesting that CD20-243 CrossMab would be a promising therapeutic agent against lymphoma.
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