The goal of this project is to develop a novel human monoclonal antibody-targeted small interfering RNA (siRNA) therapeutic that has the potential to be first-in-its-kind for treating tumor and metastasis. We have previously identified a panel of rapidly internalizing human single chain antibodies (scFvs) that target clinically represented tumor cell surface antigens. These scFvs were selected from phage antibody display libraries using laser capture microdissection for their ability to bind to tumor cells in situ residing in thir tissue microenvironment, and to mediate efficient intracellular payload delivery to tumor cells. We have in addition identified novel siRNA binding motifs that can be joined with our internalizing scFv and produced as a fusion protein that gains the tumor-targeted intracellular siRNA delivery functions. We propose to develop a novel class of scFv-targeted siRNA therapeutics based on our rapidly internalizing human scFv linked via the novel siRNA binding motif to siRNAs that target genes critical for tumor cell survival.

Public Health Relevance

Small interfering RNA (siRNA) has the potential to be a novel class of therapeutics due to its potent and specific effects on target genes. While siRNA has become an effective research tool, its therapeutic application has been hindered by the lack of an effective technology for targeted systemic delivery in vivo. The goal of this project is to develop novel human antibody-targeted systemic siRNA delivery vehicle that could eventually lead to a new class of therapeutics for treating tumor and cancer metastases. We have previously identified a panel of rapidly internalizing human single chain antibodies (scFvs) that target clinically represented prostate cancer cell surface antigens. These scFvs were selected from phage antibody display libraries using laser capture microdissection for their ability to bind to tumor cells in situ residing in their tissue microenvironment, and to mediate efficient intracellular payload delivery to castration resistant prostate cancer cells. We have in addition identified novel siRNA binding motifs that can be joined with our internalizing scFv and produced as a fusion protein that retains tumor targeting and siRNA binding functions. We propose to develop tumor- targeted systemic siRNA delivery vehicles based on our rapidly internalizing human scFv to modulate genes critical for tumor growth and survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA171315-03
Application #
8702119
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Arya, Suresh
Project Start
2012-08-06
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lee, Nam-Kyung; Zhang, Yafeng; Su, Yang et al. (2018) Cell-type specific potent Wnt signaling blockade by bispecific antibody. Sci Rep 8:766
Lee, Nam-Kyung; Bidlingmaier, Scott; Su, Yang et al. (2018) Modular Construction of Large Non-Immune Human Antibody Phage-Display Libraries from Variable Heavy and Light Chain Gene Cassettes. Methods Mol Biol 1701:61-82
Su, Yang; Bidlingmaier, Scott; Lee, Nam-Kyung et al. (2018) Combine Phage Antibody Display Library Selection on Patient Tissue Specimens with Laser Capture Microdissection to Identify Novel Human Antibodies Targeting Clinically Relevant Tumor Antigens. Methods Mol Biol 1701:331-347
Su, Yang; Liu, Yue; Behrens, Christopher R et al. (2018) Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight 3:
Ha, K D; Bidlingmaier, S M; Su, Y et al. (2017) Identification of Novel Macropinocytosing Human Antibodies by Phage Display and High-Content Analysis. Methods Enzymol 585:91-110
Ha, Kevin D; Bidlingmaier, Scott M; Liu, Bin (2016) Macropinocytosis Exploitation by Cancers and Cancer Therapeutics. Front Physiol 7:381
Sherbenou, Daniel W; Aftab, Blake T; Su, Yang et al. (2016) Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. J Clin Invest 126:4640-4653
Bidlingmaier, Scott; Ha, Kevin; Lee, Nam-Kyung et al. (2016) Proteome-wide Identification of Novel Ceramide-binding Proteins by Yeast Surface cDNA Display and Deep Sequencing. Mol Cell Proteomics 15:1232-45
Sherbenou, Daniel W; Behrens, Christopher R; Su, Yang et al. (2015) The development of potential antibody-based therapies for myeloma. Blood Rev 29:81-91
Bidlingmaier, Scott; Liu, Bin (2015) Identification of Posttranslational Modification-Dependent Protein Interactions Using Yeast Surface Displayed Human Proteome Libraries. Methods Mol Biol 1319:193-202

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