Elucidating mechanism of action for clinical candidate therapeutic antibodies

Cancer is driven by numerous cellular dysregulations such as increased proliferation, decreased apoptosis, increased vascularization, and evasion of immune surveillance. As such, it is unlikely that inhibiting only one of these disease hallmarks will cause a lasting clinical response. The objective of this work is to modulate intracellular signaling, endothelial expansion, and immune cell activation in human and mouse models of cancer to better inform the development of new antibody therapeutics. The contribution of fourteen growth factors to receptor tyrosine kinase (RTK) driven chemotherapy resistance in nine pancreatic ductal adenocarcinoma and fifteen ovarian cancer cell lines was assessed using phosphorylation of Protein Kinase B (AKT) as a readout for pro-survival signaling via western blot and ELISA. Results revealed redundancy between Insulin-Like Growth Factor Receptor (IGF-1R) and Epidermal Growth Factor Receptor 3 (ErbB3) signaling. In pancreatic cancer cell lines, a tetravalent, bispecific antibody co-targeting IGF-1R and ErbB3 (istiratumab/MM-141) blocked growth factor induced pro-survival signaling and enhanced chemotherapy-induced apoptosis. Istiratumab also improved the in vivo efficacy of gemcitabine and nab-paclitaxel in two cell line-derived xenograft (CDX) models and one patient-derived xenograft (PDX) model of pancreatic cancer. In ovarian cancer cell lines, cell-surface IGF-1R expression correlated significantly with in vitro cisplatin and paclitaxel sensitivity, and istiratumab prevented chemotherapy induced AKT phosphorylation. Furthermore, istiratumab enhanced the in vivo efficacy of paclitaxel, pegylated-liposomal doxorubicin, and cisplatin in an ovarian cancer CDX model. The role of the cytokine Tumor Necrosis Factor (TNF) has been studied within the tumor microenvironment. Firstly, the in vitro human umbilical vein endothelial cell (HUVEC) model of angiogenesis revealed TNF-mediated TNF receptor 1 (TNFR1) activation to be a driver of endothelial tube maintenance. Secondly, an investigation into the driving mechanism of action for a TNFR2-targeting mouse IgG2a (Y9/MM-401) in eight in vivo mouse syngeneic models of cancer showed that cancer cell TNFR2 expression does not drive in vivo efficacy, rather it promotes Fc receptor mediated agonism of tumor infiltrating CD8 positive effector T cells. These data support TNFR2 as a possible therapeutic target for the treatment of cancer

Beyond gender stereotypes in language comprehension: self sex-role descriptions affect the brain’s potentials associated with agreement processing

We recorded Event-Related Potentials to investigate differences in the use of gender information during the processing of reflexive pronouns. Pronouns either matched the gender provided by role nouns (such as “king” or “engineer”) or did not. We compared two types of gender information, definitional information, which is semantic in nature (a mother is female), or stereotypical (a nurse is likely to be female). When they followed definitional role-nouns, gender-mismatching pronouns elicited a P600 effect reflecting a failure in the agreement process. When instead the gender violation occurred after stereotypical role-nouns the Event Related Potential response was biphasic, being positive in parietal electrodes and negative in anterior left electrodes. The use of a correlational approach showed that those participants with more “feminine” or “expressive” self sex-role descriptions showed a P600 response for stereotype violations, suggesting that they experienced the mismatch as an agreement violation; whereas less “expressive” participants showed an Nref effect, indicating more effort spent in linking the pronouns with the possible, although less likely, counter-stereotypical referent

Use of particulate material for the formulation of diagnostic products

Diagnosis is the medical act that identifies the signs and the symptoms of an illness. It is an unavoidable step before the prescription of any medical treatment. Over the last decades, the increasing desire of more precise diagnosis, led to the emergence of new tools: the diagnostic products. These products are used to identify and monitor the cause of disorders to facilitate and specify the diagnosis, and thus, allow an adaptation of the medical treatment. Diagnostic products can be imaging probes, labels for immunoassays, reagents, contrast agents, or radiopharmaceutical products. As a part of diagnostic products, companion diagnostics are specific of a treatment and are mostly used in cancer therapies. They help determining if the patient would profit from a medication, depending on his genotype and possible genetic mutations. Phenotyping cocktails are diagnostic products that are used in phenotyping to obtain additional information, considering the effect of external environmental factors which can also influence the response to a treatment. Diagnostic products permit the personalization of medicine, by adapting the medications to the patient, optimize the treatment, and reduce potential side effects. Despite their great benefit, only a few diagnostic products are developed, limiting the possibility to improve diagnosis and therapeutics. In this manuscript, we present 2 diagnostic products formulated with nanoparticulate and microparticulate material. The first formulation consists in “polymersomes containing quantum dots (QDs) for cellular imaging”. These polymeric vesicles have the capacity to encapsulate highly fluorescent probes like QDs to prevent the toxic effect of the latter without altering their imaging properties. The second diagnostic product is the “CombiCap, a novel drug formulation for the Basel phenotyping cocktail”. This unique formulation is equivalent to the 6 dosage forms composing the Basel cocktail and presents many advantages that facilitate its diagnostic use. Both formulated products are intended for diagnostic purposes. They are safe, reliable, specific, customizable, easy to formulate and easy to use. They bring precise information on the health status of the patient in order to give a better diagnosis, to adapt the medical treatment and to monitor the therapeutic response. The interest for individualized therapies is growing, and therefore, the development of new diagnostic products needs to increase. In the future, the personalization of diagnosis and therapeutics will be a common medical practice

Electrophysiological Evidence for Reversed Lexical Repetition Effects in Language Processing

Effects of word repetition are extremely robust, but can these effects be modulated by discourse context? We examined this in an ERP experiment that tested coreferential processing (when two expressions refer to the same person) with repeated names. ERPs were measured to repeated names and pronoun controls in two conditions: (1) In the prominent condition the repeated name or pronoun coreferred with the subject of the preceding sentence and was therefore prominent in the preceding discourse (e.g., "John went to the store after John/he."); (2) in the nonprominent condition the repeated name or pronoun coreferred with a name that was embedded in a conjoined noun phrase, and was therefore nonprominent (e.g., "John and Mary went to the store after John/he."). Relative to the prominent condition, the nonprominent condition always contained two extra words (e.g., "and Mary"), and the repetition lag was therefore smaller in the prominent condition. Typically, effects of repetition are larger with smaller lags. Nevertheless, the amplitude of the N400 was reduced to a coreferentially repeated name when the antecedent was nonprominent as compared to when it was prominent. No such difference was observed for the pronoun controls. Because the N400 effect reflects difficulties in lexical integration, this shows that the difficulty of achieving coreference with a name increased with the prominence of the referent. This finding is the reverse of repetition lag effects on N400 previously found with word lists, and shows that language context can override general memory mechanisms

“If a lion could speak …”: Online sensitivity to propositional truth-value of unrealistic counterfactual sentences

People can establish whether a sentence is hypothetically true even if what it describes can never be literally true given the laws of the natural world. Two event-related potential (ERP) experiments examined electrophysiological responses to sentences about unrealistic counterfactual worlds that require people to construct novel conceptual combinations and infer their consequences as the sentence unfolds in time (e.g., “If dogs had gills…”). Experiment 1 established that without this premise, described consequences (e.g., “Dobermans would breathe under water …”) elicited larger N400 responses than real-world true sentences. Incorporation of the counterfactual premise in Experiment 2 generated similar N400 effects of propositional truth-value in counterfactual and real-world sentences, suggesting that the counterfactual context eliminated the interpretive problems posed by locally anomalous sentences. This result did not depend on cloze probability of the sentences. In contrast to earlier findings regarding online comprehension of logical operators and counterfactuals, these results show that ongoing processing can be directly impacted by propositional truth-value, even that of unrealistic counterfactuals

An ERP study on L2 syntax processing: When do learners fail?

Event-related brain potentials (ERPs) can reveal online processing differences between native speakers and second language (L2) learners during language comprehension. Using the P600 as a measure of native-likeness, we investigated processing of grammatical gender agreement in highly proficient immersed Romance L2 learners of Dutch. We demonstrate that these late learners consistently fail to show native-like sensitivity to gender violations. This appears to be due to a combination of differences from the gender marking in their L1 and the relatively opaque Dutch gender system. We find that L2 use predicts the effect magnitude of non-finite verb violations, a relatively regular and transparent construction, but not that of gender agreement violations. There were no effects of age of acquisition, length of residence, proficiency or offline gender knowledge. Additionally, a within-subject comparison of stimulus modalities (written vs. auditory) shows that immersed learners may show some of the effects only in the auditory modality; in non-finite verb violations, an early native-like N400 was only present for auditory stimuli. However, modality failed to influence the response to gender. Taken together, the results confirm the persistent problems of Romance learners of Dutch with online gender processing and show that they cannot be overcome by reducing task demands related to the modality of stimulus presentation