ROR1-targeted delivery of OSU-2S, a nonimmunosuppressive FTY720 derivative, exerts potent cytotoxicity in mantle-cell lymphoma in vitro and in vivo

Rajeswaran Mani; Chi-Ling Chiang; Frank W Frissora; Ribai Yan; Xiaokui Mo; Sivasubramanian Baskar; Christoph Rader; Rebecca Klisovic; Mitch A Phelps; Ching-Shih Chen; Robert J Lee; John C Byrd; Robert Baiocchi; L James Lee; Natarajan Muthusamy

doi:10.1016/j.exphem.2015.04.008

ROR1-targeted delivery of OSU-2S, a nonimmunosuppressive FTY720 derivative, exerts potent cytotoxicity in mantle-cell lymphoma in vitro and in vivo

Exp Hematol. 2015 Sep;43(9):770-4.e2. doi: 10.1016/j.exphem.2015.04.008. Epub 2015 Apr 29.

Authors

Affiliations

¹ Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
² Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.
³ Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁴ Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
⁵ Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
⁶ Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁷ Department of Cancer Biology and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL, USA.
⁸ Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
⁹ Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
¹⁰ Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA; Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
¹¹ Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA; Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
¹² Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA; Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
¹³ Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA; Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.
¹⁴ Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA. Electronic address: raj.muthusamy@osumc.edu.

Abstract

Mantle-cell lymphoma (MCL) remains incurable despite numerous therapeutic advances. OSU-2S, a novel nonimmunosuppressive FTY720 (Fingolimod) derivative, exhibits potent cytotoxicity in MCL cell lines and primary cells. OSU-2S increased the surface expression of CD74, a therapeutic antibody target in MCL cells. OSU-2S, in combination with anti-CD74 antibody milatuzumab, enhanced cytotoxicity in MCL. Moreover, MCL tumor antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) targeted immunonanoparticle-carrying OSU-2S (2A2-OSU-2S-ILP)-mediated selective cytotoxicity of MCL in vitro, as well as activity in a xenografted mouse model of MCL in vivo. The newly developed OSU-2S delivery using ROR1-directed immunonanoparticles provide selective targeting of OSU-2S to MCL and other ROR1(+) malignancies, sparing normal B cells.

Published by Elsevier Inc.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antibodies, Monoclonal, Humanized / pharmacology
Antigens, Differentiation, B-Lymphocyte / genetics
Antigens, Differentiation, B-Lymphocyte / metabolism
Antigens, Neoplasm / metabolism
Cytotoxins / pharmacology*
Drug Delivery Systems*
Fingolimod Hydrochloride
Histocompatibility Antigens Class II / genetics
Histocompatibility Antigens Class II / metabolism
Humans
Lymphoma, Mantle-Cell / genetics
Lymphoma, Mantle-Cell / metabolism*
Mice
Mice, Inbred NOD
Propylene Glycols / pharmacology*
Receptor Tyrosine Kinase-like Orphan Receptors / genetics
Receptor Tyrosine Kinase-like Orphan Receptors / metabolism*
Sphingosine / analogs & derivatives*
Sphingosine / pharmacology
Xenograft Model Antitumor Assays

Substances

Antibodies, Monoclonal, Humanized
Antigens, Differentiation, B-Lymphocyte
Antigens, Neoplasm
Cytotoxins
Histocompatibility Antigens Class II
OSU-2S
Propylene Glycols
invariant chain
milatuzumab
ROR1 protein, human
Receptor Tyrosine Kinase-like Orphan Receptors
Fingolimod Hydrochloride
Sphingosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding