Some aerospace applications of estimation theory

Electrical Engineering, Mathematics and Computer Scienc

The antibody-drug conjugate target landscape across a broad range of tumour types

Background: Antibody-drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Because ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours. Materials and methods: PubMed and ClinicalTrials. gov were searched for ADCs that are or were evaluated in clinical trials. Gene expression profiles of 18 055 patient-derived tumour samples representing 60 tumour (sub)types and 3520 healthy tissue samples were collected from the public domain. Next, we applied Functional Genomic mRNA-profiling to predict per tumour type the overexpression rate at the protein level of ADC targets with healthy tissue samples as a reference. Results: We identified 87 ADCs directed against 59 unique targets. A predicted overexpression rate of >= 10% of samples for multiple ADC targets was observed for high-incidence tumour types like breast cancer (n = 31 with n = 23 in triple negative breast cancer), colorectal cancer (n = 18), lung adenocarcinoma (n = 18), squamous cell lung cancer (n = 16) and prostate cancer (n = 5). In rare tumour types we observed, amongst others, a predicted overexpression rate of 55% of samples for CD22 and 55% for ENPP3 in adrenocortical carcinomas, 81% for CD74 and 81% for FGFR3 in osteosarcomas, and 95% for c-MET in uveal melanomas. Conclusion: This study provides a data-driven prioritization of clinically available ADCs directed against 59 unique targets across 60 tumour (sub)types. This comprehensive ADC target landscape can guide clinicians and drug developers which ADC is of potential interest for further evaluation in which tumour (sub)type

Glypican 3 Overexpression across a Broad Spectrum of Tumor Types Discovered with Functional Genomic mRNA Profiling of a Large Cancer Database

Glypican 3 (GPC3), a membrane-bound heparan sulfate proteoglycan, is overexpressed in ∼70% to 80% of hepatocellular carcinomas (HCCs), but uncommonly expressed in healthy tissues. This raised interest in GPC3 as drug target, and several GPC3-targeting drugs are in clinical development. We therefore predicted GPC3 protein overexpression across tumors and validated these predictions. Functional genomic mRNA profiling was applied to expression profiles of 18,055 patient-derived tumor samples to predict GPC3 overexpression at the protein level in 60 tumor types and subtypes using healthy tissues as reference. For validation, predictions were compared with i) immunohistochemical (IHC) staining of a breast cancer tissue microarray and ii) literature data reporting IHC GPC3 overexpression in various solid, hematological, and pediatric tumors. The percentage of samples with predicted GPC3 overexpression was 77% for HCCs (n = 364), 45% for squamous cell lung cancers (n = 405), and 19% for head and neck squamous cell cancers (n = 344). Breast cancer tissue microarray analysis showed GPC3 expression ranging from 12% to 17% in subgroups based on ER and HER2 receptor status. In 28 out 34 tumor types for which functional genomic mRNA data could be compared with IHC there was a relative difference of ≤10%. This study provides a data-driven prioritization of tumor types and subtypes for future research with GPC3 targeting therapies

Theranostics Using Antibodies and Antibody-Related Therapeutics

In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment. In addition, these drugs are relatively easy to radiolabel. Noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibody-related therapeutics. Molecular antibody imaging can potentially elucidate drug target expression, tracer uptake in the tumor, tumor saturation, and heterogeneity for these parameters within the tumor. These data can support drug development and may aid in patient stratification and monitoring of the treatment response. Selecting a radionuclide for theranostic purposes generally starts by matching the serum half-life of the mAb or antibody-related therapeutic and the physical half-life of the radionuclide. Furthermore, PET imaging allows better quantification than the SPECT technique. This information has increased interest in theranostics using PET radionuclides with a relatively long physical half-life, such as Zr-89. In this review, we provide an overview of ongoing research on mAbs and antibody-related theranostics in preclinical and clinical oncologic settings. We identified 24 antibodies or antibody-related therapeutics labeled with PET radionuclides for theranostic purposes in patients. For this approach to become integrated in standard care, further standardization with respect to the procedures involved is required