Abstract
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.
Highlights
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies that represents approximately 4% of all cancers
Our results indicated that CD20–243 CrossMab induces significantly high levels of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and cell death in NHL, and has potent anti-tumor capacities against both pathways and provide transformed cells with higher growth B-lymphoma cells and rituximab-resistant (RR) B-lymphoma and survival potential.[11,12,16]
A targeted therapeutic agent inhibiting one crucial pathway in a tumor may not completely shut off a hallmark capability, allowing some cancer cells to survive with residual function until they or their progeny eventually adapt to the selective pressure imposed by the therapy being applied
Summary
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies that represents approximately 4% of all cancers. These data show the urgent need to design bispecific antibody with potent anti-tumor activities against NHL
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