用于增强放射免疫治疗疗效的可点击裂解放射免疫偶联物的临床前评估

Targeted radiotherapy (TRT) with radiolabeled antibodies is hampered by long circulation times, resulting in dose-limiting toxicity. Tagworks developed a novel TRT approach based on its Click-to-Release platform, comprising an internalizing mAb functionalized with a chelator via a click-cleavable trans-cyclooctene (TCO) linker, and a small-molecule trigger (tetrazine). The radiolabeled mAb is administered and allowed to internalize into tumor cells. Then, a non-cell permeable trigger is injected that selectively reacts with the residual circulating mAb, releasing a small fast-clearing radioactive fragment. This approach is envisioned to unlock the treatment benefits of TRT with long-lived potent beta- ( 177 Lu) and alpha ( 225 Ac) radionuclides, minimizing toxicity to the patient's marrow and kidney while delivering a high therapeutic radioactive dose to the tumor. Tagworks' TGW211 program in Phase 0/1 aims at increasing the therapeutic index of radiolabeled trastuzumab (TGW211-DC), targeting HER2+ tumors. In addition, this approach is being applied to mAbs directed to various other targets in a preclinical setting. Chelate-conjugated mAbs were radiolabeled with 111 In or 177 Lu and release of the radiolabeled-DOTA was measured upon reaction with trigger. Binding and internalization were characterized using BT-474 cells. Pharmacokinetics and biodistribution were determined in nude mice +/- BT-474 xenografts. Patient dosimetry with different radionuclides was modelled using clinical data for [ 89 Zr]Zr-trastuzumab using IDAC-Dose 2.1 and OLINDA. The trigger rapidly released 111 In/ 177 Lu-labeled DOTA in PBS and plasma (e.g. 91.8% in 5 min for [ 111 In]In-TGW211-DC). [ 111 In]In-TGW211-DC demonstrated high-affinity in vitro (KD = 8.4 nM), and efficient internalization. In healthy mice, [ 111 In]In-TGW211-DC was highly stable with >20d TCO isomerization half-life, while trigger effectively released the fast-clearing 111 In-fragment in blood. In tumor bearing mice, radioactivity was largely retained inside tumor cells, but cleared from blood by the trigger, reaching maximum tumor-to-blood-ratios (T/B) of 16.3, 24h p.i. and 34.8, 72h p.i. Similar results were obtained for [ 177 Lu]Lu-TGW211-DC. Dosimetry projections indicate maximal healthy tissue dose decrease when trigger is administered 24 hrs post TGW211-DC, reaching up to 92% for 225 Ac and 88% for 177 Lu in marrow. In kidney this resulted in 89% dose decrease for 225 Ac. Finally, this click-cleavable TRT approach could be effectively applied to other internalizing mAb-target combinations. In conclusion, the click-cleavable TRT approach has demonstrated strong platform potential and markedly improved the T/B in mice for TGW211. Moreover, beneficial dosimetry of click-cleavable TRT was projected for TGW211. A First-in-human Phase 0/1 study with HER2+ cancer patients has recently been initiated.