Using therapeutic antibodies that need to cross the blood-brain barrier (BBB) to treat neurological disease is a difficult challenge. We have shown that bispecific antibodies with optimized binding to the transferrin receptor (TfR) that target β-secretase (BACE1) can cross the BBB and reduce brain amyloid-β (Aβ) in mice. Can TfR enhance antibody uptake in the primate brain? We describe two humanized TfR/BACE1 bispecific antibody variants. Using a human TfR knock-in mouse, we observed that anti-TfR/BACE1 antibodies could cross the BBB and reduce brain Aβ in a TfR affinity-dependent fashion. Intravenous dosing of monkeys with anti-TfR/BACE1 antibodies also reduced Aβ both in cerebral spinal fluid and in brain tissue, and the degree of reduction correlated with the brain concentration of anti-TfR/BACE1 antibody. These results demonstrate that the TfR bispecific antibody platform can robustly and safely deliver therapeutic antibody across the BBB in the primate brain.
Through the recent conduct of the ToGA trial, HER2 has shown to be predictive for the treatment with trastuzumab in advanced gastric and gastro-oesophageal cancer. When it comes to the prognostic properties the situation is different. Despite the fact that it is more than 20 years ago since the first studies demonstrating an association between a positive HER2 status and poor prognosis were published the issue is still controversial. In this current systematic review a large number of studies on HER2 and gastric cancer have been reviewed. The studies included in this review should fulfill the following two criteria. First criterion: The number of patients in each study should be ≥ 100, and the HER2 status should have been determined either by immunohistochemistry (IHC) or in situ hybridization (ISH). Second criterion: The selected articles should include an analysis of the association between the HER2 status and survival or relevant clinicopathological characteristics. Forty-two publications with a total of 12,749 patients fulfilled the two criteria and were reviewed in detail. The majority of the publications (71%) showed that a HER2-postive status measured either by IHC or ISH was associated with poor survival and/or clinicopathological characteristics, such as serosal invasion, lymph node metastases, disease stage, or distant metastases. Based on the current analysis a clear trend towards a potential role for HER2 as a negative prognostics factor in gastric cancer was shown, suggesting that HER2 overexpression and/or amplification is a molecular abnormality that might be linked to the development of gastric cancer.
Over the last couple of decades, molecular diagnostics have played an increasing role in drug development. Especially within oncology, more and more drugs are being developed together with a predictive biomarker assay using the drug-diagnostic codevelopment model. Not only do these assays support the development process but also the use of the drugs after regulatory approval as an important treatment decision tool. When these predictive biomarker assays are linked to a specific drug, they are called companion diagnostics. Furthermore, these assays are also considered an important element in the realization of precision medicine. Today, 21 different drugs have obtained US FDA approval together with a companion diagnostic assay, and the requirement for testing is part of their regulatory labeling. More than half of these drugs are for treatment of non-small cell lung cancer (NSCLC). With the approval of the different programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitors, for the treatment of advanced stage NSCLC, a new class of predictive biomarker assays-complementary diagnostics-has emerged. Until now, 3 immune checkpoint inhibitors have obtained regulatory approval for treatment of NSCLC, and they all have a biomarker assay linked to their use. However, only for pembrolizumab, the PD-L1 immunohistochemical (IHC) 22C3 pharmDx assay has status as a companion diagnostic. For nivolumab and atezolizumab, the assays PD-L1 IHC 22C3 pharmDx and Ventana PD-L1 (SP142) have status as complementary diagnostics, which means that there are no requirements for testing included in the labeling for these drugs. Here, the authors discuss the clinical performance of the different IHC PD-L1 expression assays including the selection of the clinical cutoff values.
Abstract. Efflux transporters of the ATP-binding cassette superfamily including breast cancer resistance protein (Bcrp/Abcg2), P-glycoprotein (P-gp/Abcb1) and multidrug resistance-associated proteins (Mrp's/ Abcc's) are expressed in the blood-brain barrier (BBB). The aim of this study was to investigate if a bovine endothelial/rat astrocyte in vitro BBB co-culture model displayed polarized transport of known efflux transporter substrates. The co-culture model displayed low mannitol permeabilities of 0.95±0.1·10 H-etoposide revealed polarized transport favouring the brain-to-blood direction for all substrates. Steady state efflux ratios of 2.5±0.2 for digoxin, 4.4±0.5 for estrone-3-sulphate and 2.4±0.1 for etoposide were observed. These were reduced to 1.1±0.08, 1.4±0.2 and 1.5±0.1, by addition of verapamil (digoxin), Ko143 (estrone-3-sulphate) or zosuquidar+reversan (etoposide), respectively. Brain-toblood permeability of all substrates was investigated in the presence of the efflux transporter inhibitors verapamil, Ko143, zosuquidar, reversan and MK 571 alone or in combinations. Digoxin was mainly transported via P-gp, estrone-3-sulphate via Bcrp and Mrp's and etoposide via P-gp and Mrp's. The expression of P-gp, Bcrp and Mrp-1 was confirmed using immunocytochemistry. The findings indicate that P-gp, Bcrp and at least one isoform of Mrp are functionally expressed in our bovine/rat co-culture model and that the model is suitable for investigations of small molecule transport.KEY WORDS: blood-brain barrier; breast cancer resistance protein; multidrug resistance-associated protein; p-glycoprotein; polarized small molecule transport.
The variability of pharmacotherapy can be of a significant magnitude, and the main reason for this is often diseases heterogeneity. Patients who have similar diagnoses very often respond differently to the same pharmacological intervention, with great variability in both efficacy and safety outcome. Despite having discussed personalized medicine for more than a decade, we still see that most drug prescriptions for severe chronic diseases are largely based on 'trial and error' and not on solid biomarker data. However, with the advance of molecular diagnostics and a subsequent increased understanding of disease mechanisms, things are slowly changing. Within the last few years, we have seen an increasing number of predictive biomarker assays being developed to guide the use of targeted cancer drugs. This type of assay is called companion diagnostics and is developed in parallel to the drug using the drug-diagnostic co-development model. The development of companion diagnostics is a relatively new discipline and in this review, different aspects will be discussed including clinical and regulatory issues.Furthermore, examples of drugs, such as the ALK and PD-1/PD-L1 inhibitors, that have been approved recently together with a companion or complimentary diagnostic will be given.
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