Overexpression of CD47 is frequently observed in various types of human malignancies,inhibiting myeloidmediated elimination of tumor cells and affecting the prognosis of cancer patients.By mapping biomarker expression...Overexpression of CD47 is frequently observed in various types of human malignancies,inhibiting myeloidmediated elimination of tumor cells and affecting the prognosis of cancer patients.By mapping biomarker expression,immuno-positron emission tomography has been increasingly used for patient screening and response monitoring.By immunization alpacas with recombinant human CD47,we prepared a CD47-targeting nanobody C2 and developed[^(68)Ga]Ga-NOTA-C2,followed by an exploration of the diagnostic value in CD47-expressing tumor models including gastric-cancer patient-derived xenograft models.By fusing C2 to an albumin binding domain(ABD),we synthesized ABDC2,which had increased in vivo half-life and improved targeting properties.We further labeled ABDC2 with^(68)Ga/^(89)Zr/177Lu to develop radionuclide theranostic pairs and evaluated the pharmacokinetics and theranostic efficacies of the agents in cell-and patient-derived models.Both C2 and ABDC2 specifically reacted with human CD47 with a high KD value of 23.50 and 84.57 pM,respectively.[^(68)Ga]Ga-NOTA-C2 was developed with high radiochemical purity(99>%,n=4)and visualized CD47 expression in the tumors.In comparison to the rapid renal clearance and short half-life of[^(68)Ga]Ga-NOTA-C2,both[^(68)Ga]Ga-NOTA-ABDC2 and[^(89)Zr]Zr-DFOABDC2 showed prolonged circulation and increased tumor uptake,with the highest uptake of[^(89)Zr]Zr-DFO-ABDC2 occurring at 72 h post-injection.Moreover,[177Lu]Lu-DOTA-ABDC2 radioimmunotherapy suppressed the tumor growth but was associated with toxicity,warranting further optimization of the treatment schedules.Taken together,we reported a series of nanobody-derived CD47-targeted agents,of which[^(68)Ga]Ga-NOTA-C2 and[^(89)Zr]Zr-DFO-ABDC2 are readily translatable.Optimization and translation of CD47-targeted theranostic pair may provide new prospects for CD47-targeted management of solid tumors.展开更多
Serving as targeting ligands,aptamers have shown promise in precision medicine.However,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’clinical translation.To...Serving as targeting ligands,aptamers have shown promise in precision medicine.However,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’clinical translation.To bridge this gap,here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68(^(68)Ga)radiolabeled aptamers.The specificity and binding affinity of a radiolabeled aptamer,named ^(68)Ga[Ga]-NOTA-SGC8,were maintained as proven in vitro.Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity,potential mutation risks,or genotoxicity at high dosage(40 mg/kg).Based on this result,a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles,as well as biosafety,of the radiolabeled SGC8 aptamer in the human body.Taking advantage of the cutting-edge total-body PET,the aptamers’distribution pattern in the human body was acquired in a dynamic fashion.展开更多
基金This work was supported in part by the National Key Research and Development Program of China(Grant Nos.2020YFA0909000 and 2021YFA0910000)the National Natural Science Foundation of China(Grant Nos.82001878 and 82171972)the Shanghai Rising-Star Program(Grant No.20QA1406100).
文摘Overexpression of CD47 is frequently observed in various types of human malignancies,inhibiting myeloidmediated elimination of tumor cells and affecting the prognosis of cancer patients.By mapping biomarker expression,immuno-positron emission tomography has been increasingly used for patient screening and response monitoring.By immunization alpacas with recombinant human CD47,we prepared a CD47-targeting nanobody C2 and developed[^(68)Ga]Ga-NOTA-C2,followed by an exploration of the diagnostic value in CD47-expressing tumor models including gastric-cancer patient-derived xenograft models.By fusing C2 to an albumin binding domain(ABD),we synthesized ABDC2,which had increased in vivo half-life and improved targeting properties.We further labeled ABDC2 with^(68)Ga/^(89)Zr/177Lu to develop radionuclide theranostic pairs and evaluated the pharmacokinetics and theranostic efficacies of the agents in cell-and patient-derived models.Both C2 and ABDC2 specifically reacted with human CD47 with a high KD value of 23.50 and 84.57 pM,respectively.[^(68)Ga]Ga-NOTA-C2 was developed with high radiochemical purity(99>%,n=4)and visualized CD47 expression in the tumors.In comparison to the rapid renal clearance and short half-life of[^(68)Ga]Ga-NOTA-C2,both[^(68)Ga]Ga-NOTA-ABDC2 and[^(89)Zr]Zr-DFOABDC2 showed prolonged circulation and increased tumor uptake,with the highest uptake of[^(89)Zr]Zr-DFO-ABDC2 occurring at 72 h post-injection.Moreover,[177Lu]Lu-DOTA-ABDC2 radioimmunotherapy suppressed the tumor growth but was associated with toxicity,warranting further optimization of the treatment schedules.Taken together,we reported a series of nanobody-derived CD47-targeted agents,of which[^(68)Ga]Ga-NOTA-C2 and[^(89)Zr]Zr-DFO-ABDC2 are readily translatable.Optimization and translation of CD47-targeted theranostic pair may provide new prospects for CD47-targeted management of solid tumors.
基金the National Key Research and Development Program of China(No.2020YFA0909000 and 2020YFA0210800)the National Science Foundation of China(No.22204102,52161160307,91953000,and 2182781)+2 种基金Shanghai Sailing Program,Shanghai Committee of Science and Technology,China(No.21YF1425700)Excellent Academic Leader Programme of Shanghai Health Commission(2022XD033)Core Facility of Basic Medical Sciences in Shanghai Jiao Tong University School of Medicine,and the Innovative Research Team of High-Level Local Universities in Shanghai,China.
文摘Serving as targeting ligands,aptamers have shown promise in precision medicine.However,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’clinical translation.To bridge this gap,here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68(^(68)Ga)radiolabeled aptamers.The specificity and binding affinity of a radiolabeled aptamer,named ^(68)Ga[Ga]-NOTA-SGC8,were maintained as proven in vitro.Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity,potential mutation risks,or genotoxicity at high dosage(40 mg/kg).Based on this result,a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles,as well as biosafety,of the radiolabeled SGC8 aptamer in the human body.Taking advantage of the cutting-edge total-body PET,the aptamers’distribution pattern in the human body was acquired in a dynamic fashion.