免疫诊疗一体化药物[89Zr]Zr-LNTH-2403在非人灵长类动物中通过PET/CT和剂量学评估的质量剂量效应

Leucine-rich repeat-containing protein 15 (LRRC15) is a TGFB-driven cell surface protein overexpressed selectively on highly aggressive mesenchymal stem cell-derived cancers and on cancer-associated fibroblasts of several solid tumors. Herein, we characterized the in vivo biodistribution, dosimetry, pharmacokinetic (PK) profile, and preliminary safety [ 89 Zr]Zr-LNTH-2403 targeting LRRC15 in healthy non-human primates (NHPs) under different administered mass regimens. The humanized monoclonal antibody (mAb) LNTH-2403 (also known as DUNP-19) targeting and internalizing LRRC15 was conjugated to p-SCN-Bn-DFO at a 5 chelator-to-mAb molar ratio for radiolabeling with 89 Zr (t 1/2 =3.3 d). [ 89 Zr]Zr-LNTH-2403 was synthesized with a 174 MBq/mg molar activity and 99% radiochemical purity, as confirmed by iTLC. Three cohorts of two adult male Rhesus Macaques received a single 13 MBq/kg [ 89 Zr]Zr-LNTH-2403 IV bolus at total mAb mass doses of 2, 4, or 8 mg. Serial PET/CT imaging was acquired at 4 time points up to 168 hours post-injection (p.i.). Blood samples were collected at baseline and at each imaging session for PK analysis and CBC and CMP assessments. Volume of interest analyses were performed using the Imalytics Preclinical 3.1. Image-based human dosimetry extrapolations were performed using OLINDA/EXM 1.1 VOI analysis of PET/CT images in the 2 mg cohort demonstrated that [89Zr]Zr-LNTH-2403 exhibited rapid blood-pool distribution, with increasingly prominent adrenal gland uptake, peaking at 27.24 SUV mean at 168 h p.i. Other organs of uptake included the liver, spleen, kidneys, and bone marrow, with peak SUV mean of 7.71, 8.56, 3.98, and 6.56, respectively. Notably, increasing the antibody mass dose to 4 or 8 mg had a significant effect on blood PK and tissue biodistribution, reducing [ 89 Zr]Zr-LNTH-2403 uptake by 3- to 4-fold in the adrenal glands and in the bone marrow, albeit to a lesser extent. The PK profile exhibited a biphasic pattern, with an initial fast distribution half-life of 8.59 hours and a terminal slow half-life of 20.54 hours in the 2 mg cohort. Notably, the slow elimination half-life progressively increased to 33.68 hours at an 8 mg mass dose, evidencing longer antibody circulation. Estimated human-equivalent organ-absorbed doses confirmed that the adrenals received the highest equivalent dose, 2.82 mSv/MBq, followed by the liver, with 1.63 mSv/MBq. The effective whole-body dose was 0.471 mSv/MBq, indicative of acceptable radiation exposure. Blood parameters remained within normal limits. These findings demonstrate a favorable safety and dosimetry profile for [ 89 Zr] Zr-LNTH-2403 in NHPs, supporting its advancement toward first-in-human imaging studies. Importantly, the administered mass of mAb significantly affected the radiotracer's blood and normal organ biodistribution, highlighting the value of preclinical mass-dose optimization in humans.