(174ae) Engineered Somatostatin Receptor 2 Monoclonal Antibody to Target and Treat Neuroendocrine Tumors

Neuroendocrine tumors (NETs) overexpress somatostatin receptor (SSTRs) critical for tumor growth and progression. The surface overexpressed SSTR2 presents a promising target for therapeutic intervention. This study evaluates the efficacy of a novel humanized anti-SSTR2 monoclonal antibody (mAb) to target and treat NETs. We first engineered our previously developed SSTR2 mAb and constructed chimeric and humanized mAbs to enhance the stability in circulation and extend its half-life. The engineered SSTR2 mAbs showed high NET-targeting and specificity in flow cytometry, confocal microscopy, and in vivo imaging. Then we constructed antibody-drug conjugate (ADC) by linking potent cytotoxic agent DM1 to the engineered mAbs, which demonstrated high cytotoxicity to various NET subtypes (lung, pancreas, and thyroid). Furthermore, in vivo evaluation showed that the engineered SSTR2 moderated ADC therapies exhibit high tumor targeting specificity, robust serum stability, minimal organ toxicity, and anti-tumor activity in mouse models bearing human NET xenografts. Our study revealed that the engineered anti-SSTR2 mAb can target and deliver highly potent payload for NETs treatment.