Abstract
We developed a potentially novel and robust antibody discovery methodology, termed selection of phage-displayed accessible recombinant targeted antibodies (SPARTA). This combines an in vitro screening step of a naive human antibody library against known tumor targets, with in vivo selections based on tumor-homing capabilities of a preenriched antibody pool. This unique approach overcomes several rate-limiting challenges to generate human antibodies amenable to rapid translation into medical applications. As a proof of concept, we evaluated SPARTA on 2 well-established tumor cell surface targets, EphA5 and GRP78. We evaluated antibodies that showed tumor-targeting selectivity as a representative panel of antibody-drug conjugates (ADCs) and were highly efficacious. Our results validate a discovery platform to identify and validate monoclonal antibodies with favorable tumor-targeting attributes. This approach may also extend to other diseases with known cell surface targets and affected tissues easily isolated for in vivo selection.
Keywords:
Cancer; Therapeutics.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology*
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Neoplasm / immunology*
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Antibodies, Neoplasm / isolation & purification
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Antibodies, Neoplasm / therapeutic use
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Antibody Affinity
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Antibody Specificity
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Antigens, Neoplasm / immunology*
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Bacteriophages
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Breast Neoplasms / immunology*
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Breast Neoplasms / therapy
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Cell Line, Tumor
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Cell Surface Display Techniques
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Cell Survival
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Endoplasmic Reticulum Chaperone BiP
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Female
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Heat-Shock Proteins / immunology*
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High-Throughput Screening Assays
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Humans
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Immunoglobulin Variable Region / immunology
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Immunotherapy
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Lung Neoplasms / immunology*
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Lung Neoplasms / therapy
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Mice
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Plasmids
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Proof of Concept Study
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Receptor, EphA5 / immunology*
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Recombinant Proteins
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Saccharomyces cerevisiae
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Antibodies, Neoplasm
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Antigens, Neoplasm
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Endoplasmic Reticulum Chaperone BiP
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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Immunoglobulin Variable Region
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Recombinant Proteins
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EPHA5 protein, human
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Receptor, EphA5