Development and Characterization of Nanobody-Derived CD47 Theranostic Pairs in Solid Tumors
You Zhang,
Di Zhang,
Shuxian An,
Qiufang Liu,
Chenyi Liang,
Juan Li,
Ping Liu,
Changfeng Wu,
Gang Huang,
Weijun Wei,
Jianjun Liu
Affiliations
You Zhang
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Di Zhang
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Shuxian An
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Qiufang Liu
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center,
Fudan University, Shanghai 200030, China.
Chenyi Liang
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Juan Li
Institute of Cancer and Basic Medicine, Chinese Academy of Sciences,
The Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China.
Ping Liu
School of Biomedical Engineering and Med-X Research Institute,
Shanghai Jiao Tong University, Shanghai 200030, China.
Changfeng Wu
Department of Biomedical Engineering,
Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
Gang Huang
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Weijun Wei
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Jianjun Liu
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Overexpression of CD47 is frequently observed in various types of human malignancies, inhibiting myeloid-mediated 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 [68Ga]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 68Ga/89Zr/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. [68Ga]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 [68Ga]Ga-NOTA-C2, both [68Ga]Ga-NOTA-ABDC2 and [89Zr]Zr-DFO-ABDC2 showed prolonged circulation and increased tumor uptake, with the highest uptake of [89Zr]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 [68Ga]Ga-NOTA-C2 and [89Zr]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.
