B7-H4-targeted radiotheranostics enable precise imaging and potent therapy across solid tumor models.

Abstract

B7-H4 is an emerging immunoregulatory checkpoint broadly overexpressed across solid tumors and minimally present in normal tissues, making it an attractive candidate for targeted imaging and therapy. Here, we develop and evaluate a B7-H4-directed radiotheranostic antibody labeled with [⁸⁹Zr] for PET imaging and with either [¹⁷⁷Lu] or [²²⁵Ac] for β- or α-particle therapy, respectively. [⁸⁹Zr]-immunoPET enabled quantitative, whole-body visualization of B7-H4 expression and reliably distinguished high, intermediate, and negative-expressing tumors. Radiotherapy with [¹⁷⁷Lu]- or [²²⁵Ac]-conjugated antibody exhibited potent, antigen-dependent antitumor activity, including complete and durable regressions in B7-H4-high expressing xenografts after a single administration, while having a minimal effect on B7-H4-negative tumors. Both therapeutic constructs were well tolerated, causing only transient, reversible myelosuppression without sustained hepatic, renal, or histopathologic toxicity. These findings identify B7-H4 as a promising target for integrated imaging and radionuclide therapy and provide a preclinical foundation for the future development of B7-H4-directed radiotheranostic strategies.