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

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

Heterozygosity at Gm Loci Associated with Humoral Immunity to Osteosarcoma

Familial clustering of osteosarcoma suggests the involvement of genetic factors (1, 2), and the demonstration of a high incidence of osteosarcoma-specific antibodies (3, 4), as well as tumor-specific cell-mediated immunity (5) in patients and their relatives, indicates the involvement of immunological factors in the pathogenesis of this disease. Certain Gm allotypes (genetic markers of IgG) have been shown to be associated with a high relative risk of some forms of cancer. For instance, in Caucasians an unusual Gm haplotype--Gm 1,3;5,13,14--has been found to be associated with neuroblastoma (6), and an increased frequency of Gm (2) has been reported in patients with malignant melanoma (7, 8). A recent report has shown an association of the Gm 1,2; 13,15,16,21 phenotype with lung cancer and primary hepatoma in the Japanese (9). To our knowledge, however, the possible role of Gm allotypes in predisposition to osteosarcoma has not been examined. Immune responsiveness to a variety of antigens in both experimental animals and humans has been shown to be controlled either by major histocompatibility complex (MHC)-linked immune response (Ir) genes or by allotype-linked Ir genes (10-13). In some instances an interactive effect of these two unlinked genetic systems has been observed (12). It is possible that MHC-linked or allotype-linked Ir genes may also influence humoral immunity to tumor antigens. In this report we present evidence for complementary Ir genes controlling immune responses to osteosarcoma-associated antigens (OSAA)

The interplay of discourse congruence and lexical association during sentence processing: Evidence from ERPs and eye tracking

Five experiments used ERPs and eye tracking to determine the interplay of word-level and discourse-level information during sentence processing. Subjects read sentences that were locally congruent but whose congruence with discourse context was manipulated. Furthermore, critical words in the local sentence were preceded by a prime word that was associated or not. Violations of discourse congruence had early and lingering effects on ERP and eye-tracking measures. This indicates that discourse representations have a rapid effect on lexical semantic processing even in locally congruous texts. In contrast, effects of association were more malleable: Very early effects of associative priming were only robust when the discourse context was absent or not cohesive. Together these results suggest that the global discourse model quickly influences lexical processing in sentences, and that spreading activation from associative priming does not contribute to natural reading in discourse contexts

Coreference and lexical repetition: Mechanisms of discourse integration

The use of repeated expressions to establish coreference allows an investigation of the relationship between basic processes of word recognition and higher-level language processes that involve the integration of information into a discourse model. In two experiments on reading, we used eye tracking and event-related potentials (ERPs) to examine whether repeated expressions that are coreferential within a local discourse context show the kind of repetition priming that is shown in lists of words. In both experiments, effects of lexical repetition were modulated by effects of local discourse context that arose from manipulations of the linguistic prominence of the antecedent of a coreferentially repeated name. These results are interpreted within the context of discourse prominence theory, which suggests that processes of coreferential interpretation interact with basic mechanisms of memory integration during the construction of a model of discourse