Development and Characterization of B7-H3-Targeted Radioimmunotherapies For The Treatment of Solid Tumors

<p>Radioimmunotherapy involves the selective targeting of therapeutic radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Radioimmunotherapy has been successful in treating hematologic cancers, such as non-Hodgkin’s Lymphoma. However, treatment of solid tumors by radioimmunotherapy remains a challenge, driven in part by a lack of high affinity antibodies against highly tumor-selective surface antigens. Herein, we characterize novelanti-B7-H3 immuno-conjugates for PET imaging and RIT of solid tumors in preclinical models.</p> <p>Human B7-H3 (CD276) protein is highly expressed on solid tumor cell surfaces and endovascular surfaces in a wide variety of cancers (colon, breast, pancreatic, prostate, head and neck, glioblastoma, ovarian, and non-squamous cell lung cancer), and is low or absent in normal tissues, an ideal RIT target. First, we developed in-house a high affinity (picomolar) dual species (human, mouse) anti-B7-H3 antibody (MIL33B), validated through biolayer interferometry and ELISA. AF594-labeled MIL33B showed membrane-associated staining of tumor cells natively expressing or induced to overexpress B7-H3, displacement by unlabeled MIL33B, and no staining in knockout cell lines and isotype control, confirming specificity. MIL33B labeled with ⁸⁹Zr (⁸⁹Zr-DFO-MIL33B) for PET/CT imaging demonstrated high retention in multiple syngeneic tumor models transfected with human B7-H3 compared to vector controls or tumors imaged with isotype control antibody (⁸⁹Zr-DFO-IgG2a) and in immunodeficient tumor models with high B7-H3 tumor expression compared to B7-H3 KO tumors.</p> <p>Next, a single intravenous administration of MIL33B labeled with Yttrium-90 (⁹⁰Y-DOTA-MIL33B; 100 mCi), a therapeutic beta-emitter, induced complete tumor regression and long-term survival of greater than 50% of mice harboring established syngeneic subcutaneous CT26 tumors, a radio-resistant colorectal cell type transfected with human B7-H3 (CT26 hB7-H3) compared to with tumors transfected with vector control (CT26 vector). Mice whose tumors regressed in response to ⁹⁰Y-DOTA-MIL33B treatment developed immunologic memory and <em>in vivo </em>depletion assays demonstrated that CD8b+ cells were necessary to confer the therapeutic effects of ⁹⁰Y-DOTA-MIL33B. These results point to the promise of ⁹⁰Y-DOTA-MIL33B radioimmunotherapy as a treatment for solid tumors and as a potential immune modulator.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2022

Authors dc:creator

• Glazer, Sarah
• <p>0000-0001-9384-1287</p>

Contributors dc:contributor

• David Piwnica-Worms, M.D., Ph.D.
• Scott Evans, M.D.
• Jeffrey Molldrem, M.D.

• solid tumors
• radioimmunotherapy
• theranostics
• PET
• B7-H3
• antibody
• beta-emitters
• Cancer Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1174

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2231