Nanobody clinical transformation new field: tumor imaging diagnosis
The IgG of most mammalian antibodies contains two heavy chains and two light chains. Scientists have discovered heavy chain-only IgG (HCAb) in sharks and camels, and further developed single-domain antibodies (sdAb), called nano Antibody or VHH, molecular weight is only 15KD. Nanobodies have the advantages of low molecular weight, simple humanization, high affinity, high stability, microbial expression, low immunogenicity, strong penetrating power, and good solubility. They have attracted much attention in disease diagnosis and treatment. 1. Commonly used targets for nanobody development At present, the targets of nanobodies are mainly extracellular targets (ligands, receptors, transmembrane proteins) of tumor cells and immune cells, such as EGFR1 (HER1)/EGFR2 (HER2)/ VEGFR2/c-Met/CXCR7 etc.
Common tumor microenvironment nanobody development targets[3]
2. Nanobodies are used for tumor imaging diagnosis 1. PET (Positron Emission Computed Tomography) In PET imaging, isotope-labeled antibodies or antibody fragments are used to label drug targets in vivo, with good specificity. Nanobodies have good tissue penetration due to their small molecular weight, and have been used to evaluate the distribution of drug targets in patients and to study the tumor microenvironment. The 68/67Ga or 89Zr labeled EGFR antibody 7D12 is the first Nanobody used in PET and shows a good tumor background. In 2016, 68Ga-labeled HER Nanobody was used to evaluate HER2 expression in breast cancer [5], and two phase II clinical trials have been carried out since then. Myeloid suppressor cells (MDSCs) in the tumor microenvironment are one of the important immunotherapy resistance factors. In the mouse model, 89Zr-labeled Nanobodies were used for PET analysis of the distribution of CD8+ T cells and CD11b+ MDSCs before and after PD-1 blocking treatment [6].
2. SPECT (single photon emission computed tomography)
SPECT imaging uses gamma-emitting radioisotopes and uses 99mTc-labeled nanobodies to detect the distribution of drug targets in the clinic as a medication guide. In 2019, a joint study by the Department of Nuclear Medicine of Shanghai First People's Hospital and King's College London used 99mTc-labeled PD-L1 single domain antibody to evaluate the expression of PD-L1 in patients with non-small cell lung cancer, providing a basis for immune checkpoint antibody therapy.
PD-L1 expression in primary tumors, lymph nodes and bone metastases [7]
3. NIR fluorescence
Both PET and SPECT expose patients to radiation, and the attenuation speed of isotope requires imaging detection immediately after injection, so non-isotopic diagnostic methods are urgently needed in clinical practice. Infrared fluorescence detection, as a non-isotopic diagnostic method, began to study target expression, guide surgical resection according to imaging area, and study tumor microenvironment.
Image-guided surgical resection based on IRDye800CW labeled HER2 Nanobody [8]
4. Ultrasound-based molecular imaging
Ultrasound is an important branch of molecular imaging, and nanobeads can be used as ultrasound contrast agents. Nanobeads carry tumor-specific antibodies to assist in the diagnosis of tumors. The large molecular weight of conventional antibodies limits the number of target sites. Studies have begun to use Nanobodies for ultrasound molecular diagnosis in mouse models. For example, using nanobeads carrying anti-PMSA nanoantibodies for prostate cancer imaging in a xenograft mouse model. 3. Summary In addition to its natural advantages as a therapeutic antibody, nanobodies also have unique advantages as an imaging diagnostic antibody. For example, it is easier to penetrate into the tumor core than conventional antibodies, and it is more convenient and complete to evaluate the expression of primary and metastatic targets. Level, the expression level of drug-resistant molecules, the number of suppressive immune cells in the microenvironment, etc. Therefore, the development of companion diagnostic reagents for imaging diagnosis based on Nanobodies can better return to the clinic and benefit thousands of patients!
Common tumor microenvironment nanobody development targets[3]
2. Nanobodies are used for tumor imaging diagnosis 1. PET (Positron Emission Computed Tomography) In PET imaging, isotope-labeled antibodies or antibody fragments are used to label drug targets in vivo, with good specificity. Nanobodies have good tissue penetration due to their small molecular weight, and have been used to evaluate the distribution of drug targets in patients and to study the tumor microenvironment. The 68/67Ga or 89Zr labeled EGFR antibody 7D12 is the first Nanobody used in PET and shows a good tumor background. In 2016, 68Ga-labeled HER Nanobody was used to evaluate HER2 expression in breast cancer [5], and two phase II clinical trials have been carried out since then. Myeloid suppressor cells (MDSCs) in the tumor microenvironment are one of the important immunotherapy resistance factors. In the mouse model, 89Zr-labeled Nanobodies were used for PET analysis of the distribution of CD8+ T cells and CD11b+ MDSCs before and after PD-1 blocking treatment [6].
2. SPECT (single photon emission computed tomography)
SPECT imaging uses gamma-emitting radioisotopes and uses 99mTc-labeled nanobodies to detect the distribution of drug targets in the clinic as a medication guide. In 2019, a joint study by the Department of Nuclear Medicine of Shanghai First People's Hospital and King's College London used 99mTc-labeled PD-L1 single domain antibody to evaluate the expression of PD-L1 in patients with non-small cell lung cancer, providing a basis for immune checkpoint antibody therapy.
PD-L1 expression in primary tumors, lymph nodes and bone metastases [7]
3. NIR fluorescence
Both PET and SPECT expose patients to radiation, and the attenuation speed of isotope requires imaging detection immediately after injection, so non-isotopic diagnostic methods are urgently needed in clinical practice. Infrared fluorescence detection, as a non-isotopic diagnostic method, began to study target expression, guide surgical resection according to imaging area, and study tumor microenvironment.
Image-guided surgical resection based on IRDye800CW labeled HER2 Nanobody [8]
4. Ultrasound-based molecular imaging
Ultrasound is an important branch of molecular imaging, and nanobeads can be used as ultrasound contrast agents. Nanobeads carry tumor-specific antibodies to assist in the diagnosis of tumors. The large molecular weight of conventional antibodies limits the number of target sites. Studies have begun to use Nanobodies for ultrasound molecular diagnosis in mouse models. For example, using nanobeads carrying anti-PMSA nanoantibodies for prostate cancer imaging in a xenograft mouse model. 3. Summary In addition to its natural advantages as a therapeutic antibody, nanobodies also have unique advantages as an imaging diagnostic antibody. For example, it is easier to penetrate into the tumor core than conventional antibodies, and it is more convenient and complete to evaluate the expression of primary and metastatic targets. Level, the expression level of drug-resistant molecules, the number of suppressive immune cells in the microenvironment, etc. Therefore, the development of companion diagnostic reagents for imaging diagnosis based on Nanobodies can better return to the clinic and benefit thousands of patients!
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