Anti-Cancer Immune Priming with Beta-Radioligand Therapy and Isoform-Selective Targeting of 4Ig-B7-H3
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Radioligand therapy (RLT), a re-emerging oncologic strategy using molecularly-targeted therapeutic radioisotopes, clinically reduces tumor burden and enhances survival for select patients with otherwise unresponsive advanced prostate cancer and neuroendocrine tumors. Developing new approaches to next generation targets and a better understanding of systemic immune effects could broaden the impact of RLT. Aside from contributions to immune checkpoint, B7-H3 ( CD276 ) is an attractive oncologic target because of its widespread and high differential expression across a variety of solid tumors compared to normal tissues. However, B7-H3 has two isoforms: a 4Ig-B7-H3 isoform, the dominant transmembrane protein expressed on tumors and tumor immune microenvironments (TIME), and a 2Ig-B7-H3 isoform, a soluble ectodomain protein, representing a circulating, and in the context of RLT, significant shed (decoy) antigen. To enhance tumor-specific binding and circumvent confounding soluble 2Ig-B7-H3, a novel IgG2a monoclonal antibody (MIL33B) was generated with high affinity for 4Ig-B7-H3 (72 picomolar) and 8- to 18-fold selectivity over soluble 2Ig-B7-H3. Live cell fluorescence microscopy using AF594-labeled MIL33B demonstrated strong membranous localization and target specificity. PET-CT imaging with 89 Zr-labeled MIL33B confirmed robust tumor-selective target binding in vivo in murine xenograft (HeLa cervical) and syngeneic tumor models (4T1 breast, B16F10 melanoma, and CT26 colorectal) expressing human 4Ig-B7-H3. As a single dose beta-emitting systemic RLT therapeutic, 90 Y-labeled MIL33B (100 μCi) produced 53% long-term survival in a 4Ig-B7-H3-dependent manner in an otherwise fatal established CT26 colorectal tumor model. Immunologic analysis showed that 90 Y-MIL33B RLT functioned as an immune priming event, engaging downstream CD8 + T-cell activation and inducing immunological memory in vivo , thus illustrating the potential of systemic beta-RLT to target both primary and metastatic sites. Thus, MIL33B showcases a strategy to selectively target 4Ig-B7-H3 for beta-RLT, warranting further investigation as an immune priming tactic alone or in combination for cancer therapy.
Statement of significance
Modest antigen expression levels, even if target tissue-selective, combined with ectodomain shedding (soluble decoy antigens) can generally hinder targeted diagnostic and therapeutic strategies, but are especially challenging for radioligand therapy, PET imaging, and in vivo diagnostics wherein high specific activity radioisotopes necessitate use of low masses of biocarrier. Binding, absorption and non-specific tissue deposition of radiolabeled biocarriers by decoy antigens can significantly misdirect systemic radiation, reducing therapeutic efficacy. An antibody development process with a focus aimed at on-target affinity for folded proteins on live cells resulted in a novel picomolar affinity antibody selectively targeting membranous 4Ig-B7-H3 over soluble decoy 2Ig-B7-H3. This antibody shows promise as a transformative systemic beta-radioligand therapy platform for immune priming applications in oncology, and potentially in cardiology, rheumatology, and autoimmunity.
