Due to increase of immunotherapy in oncology, it is essential to have a biological characterization of tumors. Knowing which antigens are expressed both on the surface of the tumor cell and at tumor microenvironment in order to predict the tretment response different therapeutic antibodies, has become a need. ImmunoPET is a non-invasive diagnostic imaging tool that combines the high specificity of antibodies against antigens with the high sensitivity, resolution and quantification capacity of PET imaging. With ImmunoPET we obtain a virtual biopsy of tumors, it has a big present and future in preclinical-clinical research, being already a reality in predicting and monitoring the response to treatments with monoclonal antibodies, allowing a selection of patients and therapies reaching a personalized medicine contributing to improve clinical decisions.
Con el auge de la inmunoterapia en oncología es fundamental tener una caracterización biológica de los tumores. Conocer que antígenos se expresan tanto en la superficie de la célula tumoral como en el microambiente del tumor para poder predecir la respuesta al tratamiento de los diferentes anticuerpos terapéuticos, se ha convertido en una necesidad. La immunoPET es una herramienta de diagnóstico por imagen, no invasiva, que aúna la elevada especificidad de los anticuerpos frente a los antígenos con la elevada sensibilidad, resolución y capacidad de cuantificación de la imagen PET. Con la ImmunoPET obtenemos una biopsia virtual del tumor con un amplísimo presente y futuro en investigación preclínica-clínica, siendo ya una realidad en la predicción y monitorización de la respuesta a los tratamientos con anticuerpos monoclonales, permitiendo una selección de pacientes y terapias alcanzando una autentica medicina personalizada contribuyendo a mejorar las decisiones clínicas.
ImmunoPET is a molecular imaging technique that combines the excellent properties of specificity and affinity of the antibodies for their corresponding antigen with an elevated sensitivity and capacity of quantification of positron emission tomography (PET) images (Fig. 1). Although there are already tracers based on antibodies for single photon emission computed tomography (SPECT) imaging2–4, the advantages in terms of quality of the image, spatial resolution and quantification of the PET has led the development of new tracers to be mainly focused on PET. The concept of immunoPET was already used a few decades ago5,6 but its development has accelerated in recent years due to the approval of therapeutic antibodies for immunotherapy in many types of cancer. The improvement in the obtainment of PET isotopes such as zirconium-89 (89Zr), copper-64 (64Cu) and idodine-124 (124I) and better nuclear reactions and greater purity have also contributed to the development of immunoPET7.
The characterization of tumors at a molecular level is of extraordinary importance. The standard method for the quantification of biomarkers is biopsy and posterior immunohistochemistry, which is an invasive method that sometimes cannot be repeated over time and is also subject to the heterogeneity of the tumors and possibly not obtaining a sample representative of all the tumoral biology8. ImmunoPET can provide similar information to that of immunohistochemistry with a method that is non-invasive, in vivo, in 3 dimensions and of the whole body in the form of a “virtual biopsy”, obtaining an image of tumoral expression of the antigen9. In addition, patients must be monitored for making clinical decisions as to whether to continue therapy or not and, more specifically, in relation to the new immunotherapy treatments for which it is very important to rely on immunoPET images longitudinally along the treatment.
The aim of this review was to describe the most important targets for immunoPET in oncology as well as briefly detail the different types of antibodies and isotopes available and their applications.
AntibodiesAntibodies are glycoproteins, which, in their most common form (IgG), contain two polypeptides chains of different heavy (H) and light (L) sizes of approximately 55 and 28kDa, respectively, forming a Y-shaped heterotetramer of approximately 150kDa. The modular structure of the antibodies has allowed the design of different formats with different molecular weights, maintaining their binding capacity and specificity to the antigen, by the engineering of either proteins or derivatives of a special class of antibodies which only possess heavy chains present naturally in camelids and some shark species. All these antibody fragments can be labeled with different isotopes for generating immunoPET probes. Below, a brief description of the formats most commonly used is provided10,11 (Fig. 2).
Different types of antibodies with their molecular weights. Note the difference in size depending on the type of fragment. A: whole antibody with its Fab y Fc fragment antibody (Fab) and crystallizable fragment (cF); B. single chain fragment variable (scFV); C. minibody; D Fab Fab; E: diabody; F. scFv; G: nanobody.
The approval of the regulatory agencies of multiple therapeutic antibodies for use in different types of cancer has led to the monoclonal antibodies used for therapy being investigated as PET imaging probes labeled with radioisotopes with a half-life of several days. In fact, there is a very active investigation in preclinical models and with increasingly more attention on the clinical application of these immunoPET probes with antibodies12,13. Recently, bispecific and even trispecific antibodies have been developed for recognizing more than one antigen. These multispecific antibodies can also be used as immunoPET probes14.
The limitations of the use of whole antibodies are their large size (around 150kDa), which does not allow them to be eliminated renally and they remain circulating for a long time. This induces the subsequent need for radioisotopes with an adequate half-life of 68Ge is 270 days according to the half-life of the antibody in order to label this type of molecular and make a PET image. This elevated period of the radioactive isotope and the long biological half-life of elimination of the antibody makes the tumor/background less optimal. Moreover, elimination via the liver hinders the visualization of hepatic tumors and metastases3,10,13.
NanobodiesTo obtain antibodies with a much shorter elimination half-life and thereby be able to have better tumor/background relationships in the immunoPET images, nanobodies have been used. These are the minimum sequences of a single domain (14 kDA) able to recognize a determined antigen and are derived from heavy chains and produced naturally by camelids (camels, llamas and alpacas) and by sharks. Despite being the smallest antibody fragments known to date, nanobodies have binding affinities to the antigen within the same range as conventional antibodies. In addition, nanobodies have naturally acquired important adaptations which make them very attractive molecules in biomedicine for both therapy and for in vivo diagnostic applications. Their small size and complementary determining regions allow them to bind to active enzyme sites and internal regions of surface proteins which are often less accessible to the larger conventional molecules15. The low molecular weight allows nanobodies to better penetrate into solid tumors and have a very rapid renal elimination, being cleared from the bloodstream within a few hours or even minutes. Some clinical trials are already using this format of antibodies for immunoPET. The organs less susceptible to being visualized by immmunoPET are the kidneys precisely due to the physiological elimination of the nanobodies11,16–19.
Antibody FragmentsMany types of antibodies have been engineered for becoming immunoPET probes. In general, these fragments lack the crystallizable fragment region and are smaller in size than whole antibodies but conserve their characteristics of specificity versus the antigen. The single chain fragment variables (scFv) have a molecular size of ≈30 kDa in which the very heavy and very light domains are covalently bound by short flexible peptides. Diabodies (60kDa) consist in scFv dimers that are formed by shortening the flexible peptide and opening the scFv, producing a crossover with another scFv in a non-covalent manner. These are minibodies which are essentially a scFv with a CH3 of the human IgG1 and a size of ≈75 KDa, which avoid accumulation in the kidney by having a molecular weight greater than 60kDa, among other aspects. All of these fragment antibodies are characterized by having more rapid elimination from the bloodstream compared with complete antibodies3,12,20,21.
Bispecific and trispecific antibodiesThese are antibodies with the capacity of specifically and simultaneously binding two or three different antigens or two epitopes of a same antigen. This characteristic confers these antibodies certain functional advantages compared to monoclonal antibodies such as, for example, the capacity of interfering with multiple targets, bringing two targets closer, and overall, transporting pharmaceuticals, immunoPET probes or nanoparticles to the target tissue22,23.
Radioactive IsotopesGamma emitting isotopes such as 131I, 111In and 99mTc have been used to label antibodies, but the characteristics of the positron emitting isotopes provide better image quality. In addition to providing the possibility of their quantification, different chelators have been used to provide greater stability and affinity to the antibodies, improving their pharmacokinetic characteristics. Below we discuss the most promising PET isotopes for immunoPET.
Zirconium-89 (89Zr)This is the most widely used isotope in immunoPET with a half-life of 78.4h it is what best matches the biological half-life of the complete antibodies. It is produced in a cyclotron by different nuclear reactions which will not be discussed in this review. What can be said is that cyclotrons have considerably improved in the last years and have facilitated their production and distribution with a purity of 99.9%. The energy of the positron is very favorable for PET imaging. The chelator most commonly used is deferoxamine (DFO or Df). However, in the PET studies with [89Zr]-DFO-antibody, a small quantity of free 89Zr always deposits in bones, which may be a problem for the diagnosis of primary tumors and bone metastases. As a chelator, DOTA has shown to reduce bone uptake; however, the chemical reaction necessary is much larger and complex. Nonetheless, bone uptake is negligible in patients and is more manifested in preclinical investigation. This radioisotope is usually used with antibodies which, after binding to their antigen, internalize in the cell and 89Zr remains residualized.
Copper-64 (64Cu)With a half-life of 12.7h, in optimal conditions 64Cu can react with several chelator agents (NOTA, DOTA derivatives). It is obtained in a cyclotron and the possibility of a theragnostic pair with 67Cu, a negative beta emitter, is very interesting. There are no unspecific copper deposits in tissues and the elimination of 64Cu is mainly hepatobiliary, and thus, these organs, the intestine and nearby organs such as the pancreas can limit their application in the immunoPET imaging in tumors of these organs. However, their low positron energy compared to other PET isotopes would provide immunoPET with better resolution and high quality images1,24.
Yttrium-86 (86Y)This isotope is produced in a cyclotron and has a half-life of 14.7h. Together with the well know negative beta emitter 90Y, it is also applied in theragnosis. Among others, EDTA, DOTA, and DTPA can be used a chelator agents.
Iodine-124 (124I)Iodine isotopes are the most well known and used in the field of diagnosis and therapy in thyroid cancer. Its therapeutic pair, 131I, is well known. 124I was one of the first isotopes used in immunoPET. It has a half-life of 4.18 days and is produced in a cyclotron. It does not need chelators, it is not a radiometal as the other isotopes and it does not accumulate in bones. However, its metabolism and elimination make it inadequate for stomach and genitourinary cancers.
Fluor-18 (18F)The physical characteristics of this radionuclide make it ideal for PET imaging. It has a half-life of 68Ge is 270 days of 110min and it is interesting for the labeling of antibody fragments and nanobodies with short biological half-lives, which allow making the images the same day. It is produced in a cyclotron and its use is widely extended. However, 18F is not often used in immunoPET due to the difficult conditions of radiolabeling with antibodies with low performance. New strategies of chelation with aluminum are under investigation.
Galium-68 (68Ga)With a very short half-life of 1.1h 68Ga is an attractive isotope, since on being produced in a 68Germanium/68Galium generator, its in situ obtention is very affordable. The half-life of 68Ge is 270 days and, thus, the generator can be eluted for almost 1year. The chelator most commonly used with 68GA is NOTA and its derivative, since DOTA is more unstable.
Other radiometalsThere are also new isotopes that are candidates for immunoPET that may be chelated by different strategies. Here, we will only mention scandium-44 (44Sc), which has a half-life of 3h and is obtained in a cyclotron or generator, manganese-52 (52Mn, T1/2=5.5 days), terbium-152 (152Tb, T1/2=17h), bromodeoxyuridine-76 (76Br, T1/2=16h), lanthanum-132 (132 La, T1/2=.5h) and niobium-90 (90Nb, T1/2=14.6h)3.
ImmunoPET in OncologyImmunoPET imaging provides a high specificity versus the tumoral antigens and a high sensitivity in both the detection of primary tumors and affected lymph nodes and distant metastasis1,5,6,8,10,12,13,25–27. It can complement immunohistochemistry and even substitute it when lesions are not accessible, and it is very useful for often avoiding follow-up with more invasive studies such as biopsies. ImmunoPET can help in the selection of responder patients who are candidates to treatments with a specific antibody or act as an essential tool in theragnosis with a corresponding radioactive beta emitter pair. The tumors can also be classified taking into account the expression of their surface antigens to personalize therapies with specific antibodies against them1,10 (Fig. 3).
![A: PET image with the LEM 2/15 antibody labeled with zirconium [89Zr]-DFO-LEM 2/15 of a mouse with a subcutaneous implant of glioblastoma cells that express MT1-MMP (red arrow) and a subcutaneous implant of cells that do not express MT1-MMP as a control (yellow arrow). B: Immunohistochemistry with the specific LEM 2/15 antibody versus MT1-MMP showing elevated expression of the antigen.](https://static.elsevier.es/multimedia/22538089/0000004100000005/v2_202210270529/S2253808922000817/v2_202210270529/en/main.assets/gr3.jpeg?xkr=j8Dj6vFLUrri2HsCGpqSicTlFKjsygnuC6WYiCqXTFdQDIuEnkHAkv/eC26zBIopw80QKC3b/osJ7XEWQJjzADiMVDASBF3Sfsr+SpClhzddXP1+CDRKTHAOmilOyikV6A9S8Ko6awPim43H2Pza7U+UCx63iksW0k5+h7LWVRBBjSV7tn1fwhEomYyEvnwd3PXlIcy7/RTWfl2T7JFjDOexSMAeEkoLG5+WCzf6Wq07x+jmma5o6rNTRl+BikLzH8gpMETJojsENMA8R2lSvuh57BvfsuG22/rMyrnF6ipOLnBU39g5UwRoE4uWm/mqq0c5eOpkHJbYs+zW0HLxfw==)
A: PET image with the LEM 2/15 antibody labeled with zirconium [89Zr]-DFO-LEM 2/15 of a mouse with a subcutaneous implant of glioblastoma cells that express MT1-MMP (red arrow) and a subcutaneous implant of cells that do not express MT1-MMP as a control (yellow arrow). B: Immunohistochemistry with the specific LEM 2/15 antibody versus MT1-MMP showing elevated expression of the antigen.
Below, a brief review of some of the applications of immunoPET in oncology in both preclinical and clinical investigation is provided.
At present, there are numerous therapeutic antibodies of epidermal growth factor receptors (EGFR), such as cetuximab, panitumumab, nimotuzumab as well as tyrosine kinase receptors such as erlotinib. All of these antibodies are susceptible to becoming converted into immunoPET probes, coupling a therapeutic antibody to a PET isotope. Clinical studies have already shown that immunoPET with [89Zr]-Df-cetuximab can effectively visualize the expression of EGFR and predict response to treatment with cetuximab in colorectal cancer as well as in head and neck and lung cancer28–33. [89Zr]-Df nimotuzumab has shown to be effective in monitoring therapy in epidermoid carcinomas and gliomas34.
Following the approval of therapeutic antibodies, such as tratuzumab, trastuzumab emtansine and pertuzumab, against the EGFR HER2/ErbB2, the development of immunoPET probes such as [89Zr]-Df-trastuzumab has demonstrated its value in the detection of breast cancer and its metastases not detected by other means35. Clinical studies with [64]Cu-DOTA trastuzumab36 have also been carried out. The Federal Drug Administration has also approved [89Zr]-Df-Pertuzumab for detecting metastasis of breast and even brain cancer37. Fragment antibodies and nanobodies have also been used to detect HER2. [68Ga]-DOTA-Fab trastuzumab is an example already used in patients38 as well as nanobodies labeled with 68Ga/18F for studying patients with HER2 positive breast cancer39,40. Visualization of the heterogeneity of HER2 expression by immunoPET is a clear example of the application of immunoPET that allows selecting patients that express HER2 for applying targeted therapies with antibodies. The same strategies have been developed with HER 3/ErbB3 labeling the respective patritumab and lumretuzumab antibodies with [64Cu]-DOTA and 89Zr-DFO, as well as fragment antibodies and nanobodies41.
Antibodies versus the receptor of the vascular endothelial growth factor (VEGF) have been approved for multiple indications (such as bevacizumab). The immunoPET probe [89Zr]-Df-bevacizumab has already been used in breast, neuroendocrine, renal, and lung cancer and glioblastoma in different clinical trials. ImmunoPET would be useful for visualizing the changes in VEGF expression before and after targeted therapies. It has been suggested that antiangiogenic therapies induce the apoptosis of endothelial cells and normalize the hyperpermeability of the tumor vasculature, which, in turn, could cause a reduction in the uptake of these immunoPET probes, being a factor to take into account when interpreting these images41,42.
Specific antibodies against differential clusters have been developed, including CD20, CD38, CD 146 and CD105. The most known is rituximab, a specific antibody versus CD20. Studies have demonstrated the efficacy of 64Cu, 124I and 89Zr incorporated in rituximab for the diagnosis and follow-up of lymphomas, with the latter already been used in patients. Rituximab labeled with 68Ga and its therapeutic pair 177Lu have also been used in radioimmunotherapy (RIT) in lymphomas43. The strategy of the theragnostic combination of the imaging isotope and its therapeutic beta emitter pair will be commented later since it is common for many immunoPET probes. CD38 is expressed in multiple myeloma and in other solid tumors. [89]Zr-Df-daratumumab has been preclinically used for the visualization of multiple myeloma43 and has also been used with its respective strategy of RIT 90Y-DOTA biotin in myeloma and in non-Hodgkin lymphoma. Antibodies against CD146have also been developed as an alternative in patients with lung carcinoma resistant to bavacizumab labeled with 64Cu NOTA YY146. This probe has also been labeled with 89Zr in metastatic lung cancer and melanoma44. Another target is endoglin or CD105 which is a transforming growth factor beta (TGF-b), against this receptor, ImmunoPET probes have also been developed using different strategies labeled with 89Zr, 64Cu or 68Ga NOTA TRC105 for the detection and monitoring of breast cancer45.
The CA19.9 antigen is an established biomarker for many types of cancer such as adenocarcinoma, and lung, breast and some epithelial carcinomas. The probe used for the detection of this antigen by immunoPET in a patient with metastasis of pancreatic carcinoma is [89Zr]-Df-5B1 and pretargeting strategies with 5B1-TCO and Tz-PEG11-Al-18F-NOTA or 64Cu NOTA-PEG7-TZ have also been used46. The CA-125 antigen is also a biomarker in gynecological cancers, and overall, immunoPET probes with 64Cu and 89Zr have been developed versus the monoclonal antibody B43.13 for the indication of ovarian cancer in which recurrence and the appearance of new lymph nodes have been detected. In this indication, bispecific antibodies have also been used, which, on one hand, bind to the antigen that recognizes the immunoPET probe and, on the other hand, carry the therapeutic antibody recognizing its own antigen, as in the case of 89Zr-DFO-REGN4018 with which a clinical trial is currently ongoing47.
There are also prostate-specific markers (PSMA) using immunoPET, such as for example, 89Zr-IAB2M that is currently being used in a clinical trial. One of its advantages is that it does not accumulate in salivary glands as occurs with the remaining PSMA probes and avoids problems of xerostomy48. As with the remaining immunoPET probes, their possibilities for performing pretargeting and identifying the associated pair for RIT is under investigation.
ImmunoPET of the Immune SystemImmunotherapy is becoming one of the most powerful tools in the treatment against cancer. In cancer patients it is very complicated to predict who will respond and evaluate the efficacy of the treatments. Generically, immunoPET is useful for visualizing immune response after therapies with antibodies12,27,49,50. Radiotracers are being developed for the imaging of interleukins and specific cells of the immune system, such as B lymphocytes, natural killer cells, macrophages, myeloid cells and T lymphocytes. Imaging of the immune checkpoints, OX 40, interferon gamma, and granzyme B, among others, can also be carried out.
T lymphocytes can be visualized labeling their clusters of CD3, CD4, CD8, CD2 and CD7 differentiation. There are anti-CD3 antibodies labeled with 89Zr in colorectal cancer and tumor infiltrating lymphocytes that infiltrate tumors can also be observed. For non-invasive detection of CD8+ there are already radiopharmaceuticals, such as [89Zr]-Df-IAB22M2C, currently in the clinical phase for solid tumors51. Anti-CD4 and anti-CD8 diabodies have also been developed for in vivo detection of the intratumoral expression of CD8 after immune therapy with anti-CD-137 or anti-PDL1 labeled with 64Cu52. Nanobodies versus CD8 are also able to predict the response to anti-CTLA-4 treatment.
Some very promising tools that are under development are immunoPET probes that directly label CTLA-4 ([89Zr]-DfH11-PEG and [64Cu]-DOTA-ipilimumab)53 and PD1, a characteristic marker of exhausted T cells. Pembrolizumab and nivolumab are inhibitors of PD1 and have been used for developing immunoPET probes labeled with different isotopes such as 89Zr and 64Cu for preclinical investigation, and some of these probes have been used in patients in different clinical trials54. Another immunoPET probe has been developed and used in patients. [89Zr]-Df-atezolizumab provides biological information of the extremely heterogeneous status of PD-L1 expression, which allows solving failures which immunohistochemistry sometimes has when predicting response55. Beyond imaging of PD-L1 expression, immunoPET can provide information on the dysregulation of PD-L1 after radiotherapy or after targeted therapy, being able to predict resistance to drugs and, ultimately, selecting patients who will best respond to immunotherapy.
Another T cell marker that is emerging strongly is OX40, also known as CD134, and it belongs to the family of tumoral necrosis factors. It has been labeled with 64Cu in preclinical trials ([64]Cu-DOTA-AbOX40) with very good results in models of lymphoma56. Interferon gamma, granzyme B and the interleukin-2 receptor are antigens that have also been used for the development of immunoPET probes labeled with 89Zr in investigation.
Anti-CEA and anti- carbonic anhydrase CAIX antibodies are markers of hypoxia with [89Zr]-Df-girentuximab and [124I]-cG250 in patients with renal and colorectal carcinoma57. Another interesting biomarker are the proteases, specifically the extracellular matrix metalloproteinases, which are expressed in very aggressive tumors and confer the tumoral cell the capacity to metastasize. Their expression can be detected with a specific antibody (LEM2/15) and with all the immunoPET strategies: [89Zr]-DFO for whole antibodies and [68Ga]-DOTA for fragments and peptides10,58 (Figs. 4 and 5).
![PET image of a mouse with [68Ga]-DOTA-AF7p-1 with subcutaneous implants of pancreas carcinoma cells in the dorsal region. (A) 3D representation of the PET image; (B) Uptake showing heterogeneity in the expression of the antigen independently of tumor size; (C) coronal slice and (D) axial slice.](https://static.elsevier.es/multimedia/22538089/0000004100000005/v2_202210270529/S2253808922000817/v2_202210270529/en/main.assets/gr5.jpeg?xkr=DiM7LhpgnZ0afu5jJ9Xo8bcAO+tyyYw3HuYlTDg2dRm4t8qNRHpPxxI7ooeQoHQLxWIT2EGyln1TygnRIQ04Q2nIHfSggbzi7MQu69/yZiyZySRH4/sLj8zBgNBcomTLT4FtSoM0AYWl1G93Ddi8gdGBxamgOIQ3Y3cZlCXfVo9jN7gni+DV9Gp8crw86qvTfAxzmVJL/Fv5Yu611/SJnF0PsVONtD/mKANWOj6GvfNOBj0Hu5l04/r3bHXPKOCMMPmpuvOYsqbkafue72OkdlwpX8FSimGZzaLRxhmOpwITPYBefpZ+ThGqhKoS85w19EY4dAl/6Coam8OJgSheOw==)
PET image of a mouse with [68Ga]-DOTA-AF7p-1 with subcutaneous implants of pancreas carcinoma cells in the dorsal region. (A) 3D representation of the PET image; (B) Uptake showing heterogeneity in the expression of the antigen independently of tumor size; (C) coronal slice and (D) axial slice.
To end, two concepts which have appeared along this review will be discussed: pretargeting or prelabeling. One of the most important disadvantages of the use of antibodies is their long circulating half-life due to their great molecular weight producing an elevated circulating background and diminishing the tumor/background relationship, which is of such importance when performing imaging studies. The pretargeting approach consists in first introducing the antibody conjugated with a click molecule, leaving it to biodistribute and reach its target, the antigen, and after, injecting a molecular labeled with a radioisotope which covalently binds to the click molecule. Once inside the organism, a biorthogonal chemical reaction is produced with the consequent visualization of the antigen in question4. In addition, this approach is also useful to use isotopes with a shorter half-life, and, in the case of therapy, have less radio labeled antibody circulating, thereby reducing the secondary effects by radiation.
Radioimmunotherapy (RIT) is no more than labeling the antibody with its radioisotope pair (Beta negative, Aalpha or Auger electron emitter) to treat tumors once a specificity for the antigen on behalf of the immunoPET imaging probe has been demonstrated. This would be the clearest expression of theragnosis: define the presence and localization of the antigen by immunoPET; for example, labeled with 68Ga, and perform RIT with its beta emitter analog 177Lutetium4,5,41 (Fig. 6).
Simple scheme of prelabeling by click chemistry (biorthogonal reaction) in which antibodies are injected with a click molecule (blue) in the first injection. In the second injection the isotope is injected with its click (red) complementing, in this case, 68Ga DOTA., and in the third injection the theragnostic pair is injected also with the click molecule (red) 177 Lu.
ImmunoPET has a promising future in the management of oncological patients and is already in use. The continuing advances in the development of therapeutic antibodies and the sophistication of the immunoPET imaging strategies will help both advances to go hand in hand. Previous non-invasive knowledge of antigen expression by imaging is clearly useful for the validation of new therapeutic antibodies. In addition, the utility of monitoring of Antobody therapy by PET imaging without the need to perform repeated biopsies is a great advantage, since immunoPET provides a perfect description of tumoral heterogeneity in 3 dimensions and in the whole body, and can also provide information of the tumoral biology in a non-invasive and repeatable manner over time, allowing the selection and therapy monitoring of patients.
Thanks to Jorge L, Martinez-Torrecuadrada and Miguel A Morcillo for his invaluable support and critical review of this manuscript. To all the Molecular Unit staff at CNIO and the Biomedical Applications at CIEMAT. To RENIM consortia (Spanish Network of Nanotechnology and Molecular Imaging) granted by Madrid Community, Spain S2017/BMD-3867 RENIM-CM) and BBVA Foundation for his help to the project: Radioinmunotheragnostics for metastatic lung cancer with pretargeted clickable Ab fragments. Ayudas fundación BBVA a equipos de investigación científica 2019.
