The objective of this proposal is to establish the molecular identities of a panel of internalizing mesothelioma cell surface antigens that are bound by a panel of novel internalizing human single chain antibodies (scFvs) that target both epithelioid and sarcomatoid (a particularly recalcitrant form) mesothelioma. The proposed study is built upon our recent work where we have selected a combinatorial human antibody library on live mesothelioma cells and identified a panel of internalizing scFvs that bind to all subtypes of mesothelioma cells in situ with no binding to normal mesothelium, and mediate efficient intracellular delivery of small molecule payloads to both epithelioid and sarcomatoid mesothelioma cells in vitro. We hypothesize that these scFvs define novel mesothelioma antigens that have significantly greater specificity, subtype coverage and therapeutic potential than currently known antigens. Identification of these novel mesothelioma antigens would (1) allow further engineering of the lead antibodies to improve affinity, specificity, pharmacokinetics and biodistribution, (2) allow development of additional antibodies targeting non-overlapping epitopes of the same antigen, which is often required for diagnostic assay development, (3) enhance our understanding of tumor behaviors that involve the cell membrane, which may lead to identification of additional novel targets for further therapeutic development, and (4) provide a sound rationale for clinical trial design such as pre-screening of patients based on target expression. We are uniquely positioned to accomplish this goal as we have developed and adapted effective methods to identify tumor antigens targeted by scFvs. Key to this proposal is our newly developed novel antigen identification strategies based on eukaryotic cell surface display of the human proteome. In addition, we have established functional collaborations with Drs. Burlingame and Chalkley and their National Mass Spectrometry Facility at UCSF to identify tumor antigens that are difficult to identify by expression cloning methods such as post-translationally modified antigens. We propose to use the methods and strategies that we have developed and adapted to systematically identify mesothelioma cell surface antigens targeted by our panel of internalizing human scFvs.

Public Health Relevance

The objective of this proposal is to establish the molecular identities of a panel of mesothelioma cell surface antigens that are bound by a panel of novel internalizing human single chain antibodies that target both epithelioid and sarcomatoid (a particularly recalcitrant form) mesothelioma. Given that mesothelioma is a major occupation-related illness with no treatment to date, and little is known about mesothelioma cell surface antigens expressed by all subtypes of the disease, identification of mesothelioma antigens targeted by our panel of internalizing antibodies addresses a critical need and is likely to have a significant impact on the development of antibody-based therapeutics and diagnostics against mesothelioma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129491-04
Application #
8403611
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2010-03-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$307,352
Indirect Cost
$103,113
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ha, Kevin D; Bidlingmaier, Scott M; Liu, Bin (2016) Macropinocytosis Exploitation by Cancers and Cancer Therapeutics. Front Physiol 7:381
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; 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; Liu, Bin (2015) Utilizing Yeast Surface Human Proteome Display Libraries to Identify Small Molecule-Protein Interactions. Methods Mol Biol 1319:203-14
Bidlingmaier, Scott; Su, Yang; Liu, Bin (2015) Combining Phage and Yeast Cell Surface Antibody Display to Identify Novel Cell Type-Selective Internalizing Human Monoclonal Antibodies. Methods Mol Biol 1319:51-63
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 Novel Protein-Ligand Interactions by Exon Microarray Analysis of Yeast Surface Displayed cDNA Library Selection Outputs. Methods Mol Biol 1319:179-92
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
Ha, Kevin D; Bidlingmaier, Scott M; Zhang, Yafeng et al. (2014) High-content analysis of antibody phage-display library selection outputs identifies tumor selective macropinocytosis-dependent rapidly internalizing antibodies. Mol Cell Proteomics 13:3320-31
Behrens, Christopher R; Liu, Bin (2014) Methods for site-specific drug conjugation to antibodies. MAbs 6:46-53

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