Abstract
Monoclonal antibody therapy has offered treatment benefits. Nonetheless, a lack of efficacy still exists, partially because monovalent binding of antibodies to specific receptors fails to translate into an active response. Here, we report a pretargeting-postassembly approach that exploits the selective Watson-Crick base pairing properties of oligonucleotides and multivalently tethers receptor-prebound antibodies to albumin at the cell surface. We demonstrate that this two-step self-assembling strategy allows sequential actions of receptor binding and clustering that broadens and strengthens the functions of antibodies. We show that anti-CD20 obinutuzumab (OBN) modified with one morpholino oligonucleotide (OBN-MORF1) maintains the feature of naked OBN antibody upon CD20 binding, and results in actin redistribution, homotypic adhesion, and lysosome-mediated cell death. Consecutive treatment with albumin grafted with multiple copies of a complementary morpholino oligonucleotide (HSA-(MORF2)x) hybridizes with surface-attached OBN-MORF1, manipulates CD20 clustering, and engages additional signals to induce calcium influx and caspase-related apoptosis. With the two types of different mechanisms collaborating in one system, the simple design exerted a notable survival extension of mice bearing disseminated B-cell lymphomas.
Original language | English |
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Pages (from-to) | 11422-11432 |
Number of pages | 11 |
Journal | ACS Nano |
Volume | 13 |
Issue number | 10 |
DOIs | |
State | Published - Oct 22 2019 |
Externally published | Yes |
Funding
The research was supported in part by NIH grant RO1 GM95606 (to J.K.) from the National Institute of General Medical Sciences, Experimental Therapeutics Program of the Huntsman Cancer Institute, and The University of Utah Research Foundation. We acknowledge support of funds in conjunction with grant P30 CS042014 awarded to Huntsman Cancer Institute.
Funders | Funder number |
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University of Utah Research Foundation | P30 CS042014 |
National Institutes of Health | RO1 GM95606 |
National Institutes of Health | |
National Cancer Institute | P30CA042014 |
National Cancer Institute | |
National Institute of General Medical Sciences | |
Huntsman Cancer Institute |
Keywords
- antibody assembly
- human serum albumin
- morpholino oligonucleotide
- multivalency
- receptor clustering