Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive antitumor activity. Patients with tumors expressing PD-L1 are most likely to respond to ...this treatment. The aim of our study was to develop a noninvasive imaging technique to determine tumor PD-L1 expression in vivo. This could allow selection of patients that are most likely to benefit from anti-PD-1/PD-L1 treatment and to monitor PD-L1 expression during therapy. The monoclonal antibody PD-L1.3.1 was radiolabeled with Indium-111 ((111)In) and characterized using PD-L1-expressing MDA-MB-231 cells. Subsequently, the optimal antibody dose and time point for imaging was determined in mice with MDA-MB-231 xenografts. Finally, SPECT/CT imaging was performed in xenograft models with different PD-L1 expression levels and tumor sections were analyzed for PD-L1 expression using IHC. The optimal antibody dose of (111)In-PD-L1.3.1 (Kd = 1 nmol/L) for SPECT/CT imaging was ≤1 μg. Highest tumor-to-normal tissue contrast was obtained at days 3 and 7 after injection. (111)In-PD-L1.3.1 SPECT/CT showed efficient accumulation in high PD-L1-expressing tumors (MDA-MB-231 and SK-Br-3), whereas no specific uptake was observed in tumors with low or no detectable levels of PD-L1 (SUM149, BT474, and MCF-7). SPECT/CT and autoradiography showed a very heterogeneous distribution of (111)In-PD-L1.3.1 within the tumor. In conclusion, this is the first study showing the feasibility of noninvasive in vivo imaging of PD-L1 expression in tumors. (111)In-PD-L1.3.1 showed efficient and specific uptake in PD-L1 expressing xenografts. This technique may enable patient selection for PD-1 and PD-L1-targeted therapy.
During the process of bone regeneration, a multitude of morphogenetic signaling factors regulate cellular behavior and ultimately tissue response. These factors are presented to cells under strong ...spatial and temporal control, which stresses the relevance of controlled delivery of multiple growth factors for bone tissue regeneration. This demand for biomimetic delivery has prompted the development of a novel generation of biomaterials that is capable of delivering multiple growth factors in a controlled manner. Therefore, the current study has exploited the strong capacity of colloidal gels solely made of oppositely charged gelatin nanospheres to obtain controlled release of angiogenic and osteogenic growth factors. The release kinetics of dual delivery of osteogenic bone morphogenetic protein-2 (BMP-2) and angiogenic basic fibroblast growth factor (bFGF) were investigated in vitro by radiolabeling the respective growth factors and monitoring their release in vitro. Furthermore, the effect of single or dual delivery of BMP-2 and bFGF on bone regeneration was evaluated in vivo using a rat femoral condyle defect model. The in vitro results confirmed that the delivery kinetics of BMP-2 and/or bFGF are more dependent on the degree of crosslinking than on the type of gelatin. Sequential release characterized by rapid release of angiogenic bFGF and more sustained release of BMP-2 was obtained by loading bFGF onto cationic nanospheres of low crosslinking density and BMP-2 onto anionic nanospheres of high crosslinking density. The in vivo study demonstrated the biocompatibility and biodegradability of bare colloidal gelatin gels, and did not show any adverse effects on the process of bone healing after 4week of implantation since the volumes of new bone formation were comparable to empty control defects. An obvious stimulatory effect on bone regeneration was observed for the colloidal gels loaded with BMP-2, whereas bFGF-loaded colloidal gelatin gels did not influence the rate of bone regeneration. In contrast, the combined delivery of BMP-2 and bFGF resulted into an inhibitory effect on osteogenesis under the current experimental conditions. Summarizing, the current study proved that nanostructured colloidal gelatin gels are suitable carriers for programmed and sustained release of multiple therapeutic proteins for tissue regeneration.
By loading different growth factors in sub-populations of gelatin nanospheres (NS) respectively, colloidal gels comprising oppositely charged gelatin nanospheres showed strong capacity to obtain sequential release of dual growth factors. Display omitted
Abstract Colloidal gels have recently emerged as a promising new class of materials for regenerative medicine by employing micro- and nanospheres as building blocks to assemble into integral ...scaffolds. To this end, physically crosslinked particulate networks are formed that are injectable yet cohesive. By varying the physicochemical properties of different particle populations, the suitability of colloidal gels for programmed delivery of multiple therapeutic proteins is superior over conventional monolithic gels that lack this strong capacity for controlled drug release. Colloidal gels made of biodegradable polymer micro- or nanospheres have been widely investigated over the past few years, but a direct comparison between micro- vs. nanostructured colloidal gels has not been made yet. Therefore, the current study has compared the viscoelastic properties and capacity for drug release of colloidal gels made of oppositely charged gelatin microspheres vs. nanospheres. Viscoelastic properties of the colloidal gelatin gels were characterized by rheology and simple injectability tests, and in vitro release of two selected osteogenic proteins (i.e. bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP)) from the colloidal gelatin gels was evaluated using radiolabeled BMP-2 and ALP. Nanostructured colloidal gelatin gels displayed superior viscoelastic properties over microsphere-based gels in terms of elasticity, injectability, structural integrity, and self-healing behavior upon severe network destruction. In contrast, microstructured colloidal gelatin gels exhibited poor gel strength and integrity, unfavorable injectability, and did not recover after shearing, resulting from the poor gel cohesion due to insufficiently strong interparticle forces. Regarding the capacity for drug delivery, sustained growth factor (BMP-2) release was obtained for both micro- and nanosphere-based gels, the kinetics of which were mainly depending on the particle size of gelatin spheres with the same crosslinking density. Therefore, the optimal gelatin carrier for drug delivery in terms of particle size and crosslinking density still needs to be established for specific clinical indications that require either short-term or long-term release. It can be concluded that nanostructured colloidal gelatin gels show great potential for sustained delivery of therapeutic proteins, whereas microstructured colloidal gelatin gels are not sufficiently cohesive as injectables for biomedical applications.
Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody ...fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-limiting nephrotoxicity. An overview of renal handling of radiolabeled peptides and resulting nephrotoxicity is presented, and strategies to reduce nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of competitive inhibitors of reabsorption also interferes with the interaction of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clinical PRRT. Furthermore, nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT.
Radioiodinated pharmaceuticals are convenient tracers for clinical and research investigations because of the relatively long half‐lives of radioactive iodine isotopes (i.e., 123I, 124I, and 131I) ...and the ease of their chemical insertion. Their application in radionuclide imaging and therapy may, however, be hampered by poor in vivo stability of the C–I bond. After an overview of the use of iodine in biology and nuclear medicine, we present here a survey of the catabolic pathways for iodinated xenobiotics, including their biodistribution, accumulation, and biostability. We summarize successful rational improvements in the biostability and conclude with general guidelines for the design of stable radioiodinated pharmaceuticals. It appears to be necessary to consider the whole molecule, rather than the radioiodinated fragment alone. Iodine radionuclides are generally retained in vivo on sp2 carbon atoms in iodoarenes and iodovinyl moieties, but not in iodinated heterocycles or on sp3 carbon atoms. Iodoarene substituents also have an influence, with increased in vivo deiodination in the cases of iodophenols and iodoanilines, whereas methoxylation and difluorination improve biostability.
Radioiodinated pharmaceuticals are convenient tracers for clinical and research investigations. Their application may, however, be hampered by poor in vivo stability of the C–I bond. We present here a survey of the catabolic pathways for iodinated xenobiotics, summarizing general guidelines for the design of biologically stable radioiodinated pharmaceuticals.
Monoclonal antibody G250 (mAbG250) recognizes a determinant on carbonic anhydrase IX (CAIX). CAIX is expressed by virtually all renal cell carcinomas of the clear cell type (ccRCC), but expression in ...normal tissues is restricted. The homogeneous CAIX expression in ccRCC and excellent targeting capability of mAbG250 in animal models led to the initiation of the clinical evaluation of mAbG250 in (metastatic) RCC (mRCC) patients. Clinical studies confirmed the outstanding targeting ability of mAbG250 and cG250 PET imaging, as diagnostic modality holds great promise for the future, both in detecting localized and advanced disease. Confirmation of the results obtained in the non-randomized clinical trials with unmodified cG250 is needed to substantiate the value of cG250 treatment in mRCC. cG250-Based radio immuno-therapy (RIT) holds promise for treatment of patients with small-volume disease, and adjuvant treatment with unmodified cG250 may be of value in selected cases. In the upcoming years, ongoing clinical trials should provide evidence for these assumptions. Lastly, whether cG250-based RIT can be combined with tyrosine kinase inhibitors, which constitutes the current standard treatment for mRCC, needs to be established.
Nuclear medicine imaging procedures play an important role in the assessment of inflammatory diseases. With the advent of 3-dimensional anatomic imaging, there has been a tendency to replace ...traditional planar scintigraphy by CT or MRI. Furthermore, scintigraphic techniques may have to be combined with other imaging modalities to achieve high sensitivity and specificity, and some may require time-consuming labeling procedures. On the other hand, new developments such as combined SPECT/CT increase the diagnostic power of scintigraphy. Also, the advent of PET had a considerable impact on the use of nuclear medicine imaging techniques. In this review, we aim to provide nuclear medicine specialists and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the assessment of patients with osteomyelitis, infected vascular prostheses, metastatic infectious disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease, sarcoidosis, and fever of unknown origin.
Abstract Context The clinical management of patients with renal cell carcinoma (RCC) remains difficult, and the development of new diagnostic, prognostic, and therapeutic tools is still required. ...Objective To review the current knowledge on the RCC-associated antigen carbonic anhydrase IX (CAIX) and provide evidence for how this antigen may aid in the clinical management of RCC. Evidence acquisition Clinical papers describing diagnostic, prognostic, and/or therapeutic applications of CAIX in RCC were selected from the Pubmed database. The search was manually augmented by reviewing the reference lists of articles. Evidence synthesis Expression of CAIX is regulated by the Von Hippel Lindau (VHL) protein (pVHL). Because of the invariable VHL mutational loss in clear-cell RCC (ccRCC) patients, CAIX expression is ubiquitous in ccRCC. Determination of CAIX expression in nephrectomy specimens of RCC patients improves prognostic accuracy; high CAIX expression appears to correlate with a favourable prognosis and a greater likelihood of response to systemic treatment for metastatic disease. Therefore, CAIX expression might be used to stratify metastatic ccRCC (mRCC) patients for systemic treatment. When incorporated into the RCC nomogram, CAIX expression seems to improve diagnostic accuracy for primary RCC as well as mRCC patients, but further evidence is required. Clinical studies with the CAIX-specific monoclonal antibody (mAb) cG250 have provided unequivocal evidence that ccRCC lesions can be imaged with radiolabeled cG250. Results are awaited of a large, randomised trial that aims to establish the value of cG250 imaging for primary RCC. The outcome of another large, placebo-controlled study is awaited to establish the usefulness of CAIX-targeted therapy in the adjuvant setting. Therapeutic trials with high-dose radiolabeled cG250 and CAIX-loaded dendritic cells in mRCC patients are still in phase 1 or 2. Conclusions CAIX improves diagnostic accuracy and is an attractive target for imaging of and therapy for ccRCC.
The success of cellular therapies will depend in part on accurate delivery of cells to target organs. In dendritic cell therapy, in particular, delivery and subsequent migration of cells to regional ...lymph nodes is essential for effective stimulation of the immune system. We show here that in vivo magnetic resonance tracking of magnetically labeled cells is feasible in humans for detecting very low numbers of dendritic cells in conjunction with detailed anatomical information. Autologous dendritic cells were labeled with a clinical superparamagnetic iron oxide formulation or (111)In-oxine and were co-injected intranodally in melanoma patients under ultrasound guidance. In contrast to scintigraphic imaging, magnetic resonance imaging (MRI) allowed assessment of the accuracy of dendritic cell delivery and of inter- and intra-nodal cell migration patterns. MRI cell tracking using iron oxides appears clinically safe and well suited to monitor cellular therapy in humans.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Simlukafusp alfa (FAP-IL2v, RO6874281/RG7461) is an immunocytokine comprising an antibody against fibroblast activation protein α (FAP) and an IL-2 variant with a retained affinity for IL-2Rβγ > IL-2 ...Rβγ and abolished binding to IL-2 Rα. Here, we investigated the immunostimulatory properties of FAP-IL2v and its combination with programmed cell death protein 1 (PD-1) checkpoint inhibition, CD40 agonism, T cell bispecific and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. The binding and immunostimulatory properties of FAP-IL2v were investigated
and compared with FAP-IL2wt. Tumor targeting was investigated in tumor-bearing mice and in a rhesus monkey. The ability of FAP-IL2v to potentiate the efficacy of different immunotherapies was investigated in different xenograft and syngeneic murine tumor models. FAP-IL2v bound IL-2 Rβγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4+/CD8+ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory T cells (Tregs). T cells activated by FAP-IL2v were less sensitive to Fas-mediated apoptosis than those activated by FAP-IL2wt. Imaging studies demonstrated improved tumor targeting of FAP-IL2v compared to FAP-IL2wt. Furthermore, FAP-IL2v significantly enhanced the
and
activity of therapeutic antibodies that mediate antibody-dependent or T cell-dependent cellular cytotoxicity (TDCC) and of programmed death-ligand 1 (PD-L1) checkpoint inhibition. The triple combination of FAP-IL2v with an anti-PD-L1 antibody and an agonistic CD40 antibody was most efficacious. These data indicate that FAP-IL2v is a potent immunocytokine that potentiates the efficacy of different T- and NK-cell-based cancer immunotherapies.
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