A hybrid protein-polymer nanoworm potentiates apoptosis better than a monoclonal antibody.
B-cell lymphomas continue to occur with a high incidence. The chimeric antibody known as Rituximab (Rituxan) has become a vital therapy for these patients. Rituximab induces cell death via binding and clustering of the CD20 receptor by Fcγ expressing effector cells. Because of the limited mobility of effector cells, it may be advantageous to cluster CD20 directly using multivalent nanostructures. To explore this strategy, this manuscript introduces a nanoparticle that assembles from a fusion between a single chain antibody and a soluble protein polymer. These hybrid proteins express in Escherichia coli and do not require bioconjugation between the antibody and a substrate. Surprisingly a fusion between an anti-CD20 single chain antibody and a soluble protein polymer assemble worm-like nanostructures, which were characterized using light scattering and cryogenic transmission electron microscopy. These nanoworms competitively bind CD20 on two B-cell lymphoma cell lines, exhibit concentration-dependent induction of apoptosis, and induce apoptosis better than Rituximab alone. Similar activity was observed in vivo using a non-Hodgkin lymphoma xenograft model. In comparison to Rituximab, systemic nanoworms significantly slowed tumor growth. These findings suggest that hybrid nanoworms targeted at CD20 may be useful treatments for B-cell related malignancies. Because of the ubiquity of antibody therapeutics, related nanoworms may have uses against other molecular targets.
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California , Los Angeles, California 90033, United States.
Suhaas Rayudu
SR
Aluri
Pu
P
Shi
Joshua A
JA
Gustafson
Wan
W
Wang
Yi-An
YA
Lin
Honggang
H
Cui
Shuanglong
S
Liu
Peter S
PS
Conti
Zibo
Z
Li
Peisheng
P
Hu
Alan L
AL
Epstein
John Andrew
JA
MacKay
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D057127:Single-Chain Antibodies / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013696:Temperature
D011108:Polymers; D057127:Single-Chain Antibodies