纳米抗体与特化连接子文库的协同整合：一种新型放射性核素药物偶联物（RDC）平台，为具有最佳成药性和治疗指数的下一代放射治疗药物铺平道路

Background: Radionuclide drug conjugates (RDCs) represent a promising approach in oncology, yet their development is hindered by the scarcity of targeting moieties possessing both high affinity and favorable pharmacokinetics, leading to intense competition for validated targets. To address this, we have developed a novel and differentiated RDC platform utilizing readily available nanobodies as targeting vectors. This platform incorporates our intelligent Ligase-Dependent Conjugation (iLDC) technology and a proprietary linker, which collectively enhance pharmacokinetic profiles and biodistribution. The platform's efficacy is validated by GR9001, a ⁶⁴Cu/¹⁷⁷Lu-labeled anti-PSMA nanobody-based RDC, which has demonstrated superior tumor targeting and biodistribution, potent therapeutic efficacy, and a promising safety profile in both preclinical and first-in-human studies. Results: In preclinical studies, 64 Cu-GQ9001 exhibits an enhanced pharmacokinetic profile, along with excellent biodistribution characterized by significantly higher tumor accumulation and retention and minimized kidney uptake. Meanwhile, 177 Lu-GQ9001 also demonstrates superior antitumor activity and shows great potential to overcome resistance to Pluvicto®. In mCRPC patients, 177 Lu-GQ9001 was well tolerated, and no severe adverse events were observed. SPECT images revealed an optimal circulation half-life of 177 Lu-GQ9001 in the blood, with high, increasing tumor uptake and low, rapidly clearing normal tissue uptake. Compared with published data for other PSMA-targeted radioligands (e.g., PSMA-617), 177 Lu-GQ9001 exhibited significantly higher normalized absorbed doses in tumor lesions and similar absorbed doses in normal organs. Consequently, this profile resulted in substantially superior tumor-to-background (T/B) ratios. Furthermore, 177 Lu-GQ9001 showed superior efficacy at lower doses, with a significant reduction in PSA levels. Conclusion: By leveraging GQ's nanobody-based RDC platform, a potential best-in-class anti-PSMA RDC has been developed that demonstrates a comprehensively superior profile to Pluvicto®-including optimized half-life, enhanced tumor uptake, excellent safety, and potent efficacy in CDX models and mCRPC patients-thereby establishing a transformative paradigm that expands the promise of nanobody-based therapeutics beyond existing modalities to novel tumor targets.