Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have sh...Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.展开更多
Integrinα_(v)β_(3)is overexpressed in various tumor cells and angiogenesis.To date,no drug has been proven to target it for therapy.A first-in-human study was designed to investigate the safety,pharmacokinetics,and ...Integrinα_(v)β_(3)is overexpressed in various tumor cells and angiogenesis.To date,no drug has been proven to target it for therapy.A first-in-human study was designed to investigate the safety,pharmacokinetics,and dosimetry of^(177)Lu-AB-3PRGD2,a novel integrinα_(v)β_(3)-targeting radionuclide drug with an albumin-binding motif to optimize the pharmacokinetics.Ten patients(3 men,7 women;aged 45±16 years)with integrinα_(v)β_(3)-avid tumors were recruited to accept^(177)Lu-AB-3PRGD2 injection in a dosage of 1.57±0.08 GBq(42.32±2.11 mCi),followed by serial scans to obtain its dynamic distribution in the body.Safety tests were performed before and every 2 weeks after the treatment for 6-8 weeks.No adverse event over grade 3 was observed.^(177)Lu-AB-3PRGD2 was excreted mainly through the urinary system,with intense radioactivity in the kidneys and bladder.Moderate distribution was found in the liver,spleen,and intestines.The estimated blood half-life was 2.85±2.17 h.The whole-body effective dose was 0.251±0.047 mSv/MBq.The absorbed doses were 0.157±0.032 mGy/MBq in red bone marrow and 0.684±0.132 mGy/MBq in kidneys.This first-in-human study of^(177)Lu-AB-3PRGD2 treatment indicates its promising potential for targeted radionuclide therapy of integrinα_(v)β_(3)-avid tumors.It merits further studies in more patients with escalating doses and multiple treatment courses.展开更多
Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical science.In Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subje...Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical science.In Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subjected to a severe punishment.He was bound to a rock where,each day,an eagle would feast on his liver,which would then miracu-lously regenerate overnight.This myth underscores the liver’s unique regenerative abilities,a feature that is not just le-gendary but also scientifically recognized.展开更多
Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated ...Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).展开更多
基金supported by the National Natural Science Foundation of China(No.82071961)Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare,Key Scientific Research Program for Yong Scholars in Fujian(No.2021ZQNZD016,China)+5 种基金Fujian Natural Science Foundation for Distinguished Young Scholars(No.2022D005,China)Innovation of Science and Technology,Fujian Province(No.2021Y9134,China)National University of Singapore(No.NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine)National Medical Research Council(No.MOH-001388-00,MOH-001041,CG21APR1005,Singapore)Singapore Ministry of Education(No.MOE-000387-00,Singapore)National Research Foundation(No.NRF-000352-00,Singapore).
文摘Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.
基金supported by Chinese Academy of Medical Science Innovation Fund for Medical Sciences(2022-I2M-2-002)the National High-Level Hospital Clinical Research Funding(2022-PUMCH-D-002,China)+2 种基金Clinical and translational medicine research project of the Chinese Academy of Medical Sciences(2022-I2M-C&T-A-008,China)the National Natural Science Foundation of China(82272046)the Fundamental Research Funds for the Central Universities(3332023124,China).
文摘Integrinα_(v)β_(3)is overexpressed in various tumor cells and angiogenesis.To date,no drug has been proven to target it for therapy.A first-in-human study was designed to investigate the safety,pharmacokinetics,and dosimetry of^(177)Lu-AB-3PRGD2,a novel integrinα_(v)β_(3)-targeting radionuclide drug with an albumin-binding motif to optimize the pharmacokinetics.Ten patients(3 men,7 women;aged 45±16 years)with integrinα_(v)β_(3)-avid tumors were recruited to accept^(177)Lu-AB-3PRGD2 injection in a dosage of 1.57±0.08 GBq(42.32±2.11 mCi),followed by serial scans to obtain its dynamic distribution in the body.Safety tests were performed before and every 2 weeks after the treatment for 6-8 weeks.No adverse event over grade 3 was observed.^(177)Lu-AB-3PRGD2 was excreted mainly through the urinary system,with intense radioactivity in the kidneys and bladder.Moderate distribution was found in the liver,spleen,and intestines.The estimated blood half-life was 2.85±2.17 h.The whole-body effective dose was 0.251±0.047 mSv/MBq.The absorbed doses were 0.157±0.032 mGy/MBq in red bone marrow and 0.684±0.132 mGy/MBq in kidneys.This first-in-human study of^(177)Lu-AB-3PRGD2 treatment indicates its promising potential for targeted radionuclide therapy of integrinα_(v)β_(3)-avid tumors.It merits further studies in more patients with escalating doses and multiple treatment courses.
基金supported by the National Natural Science Foundation of China(Nos.82074068,82373912,82300685)the National Key R&D Program of China(No.2023YFD1601400)+3 种基金the Fundamental Research Funds for the Central Universities(No.2632022YC04)Jiangsu Outstanding Youth Fund Project(No.BK20231535)the Natural Science Foundation of Jiangsu Province(No.BK20221052)the Jiangsu Funding Program for Excellent Postdoctoral Talent(No.2022ZB286).
文摘Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical science.In Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subjected to a severe punishment.He was bound to a rock where,each day,an eagle would feast on his liver,which would then miracu-lously regenerate overnight.This myth underscores the liver’s unique regenerative abilities,a feature that is not just le-gendary but also scientifically recognized.
文摘Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).
