The formation of anti-infliximab Abs during treatment with infliximab is associated with a loss of clinical response, the appearance of infusion reactions and discontinuation of treatment.

Murine models of Plasmodium falciparum malaria may become crucial tools in drug discovery. Here we show that non-myelodepleted NOD-scid IL2R␥ null mice engrafted with human erythrocytes support an infectious burden up to tenfold higher than that supported by engrafted NOD-scid ␤2microglobulin null mice. The new model was validated for drug discovery and was used to assess the therapeutic efficacy of 4-pyridones, selective inhibitors of P. falciparum cytochrome bc 1 .Malaria is caused by the erythrocytic stages of protozoan parasites of the genus Plasmodium. Among the species pathogenic for humans, Plasmodium falciparum is responsible for 300 to 500 million cases of malaria and over a million deaths annually, particularly in developing countries. The development of new antimalarial medicines and vaccines is a key part of the global strategy for malaria eradication (6).P. falciparum almost exclusively infects human erythrocytes (hE). As a result, candidate drugs and vaccines in early stages of preclinical development are usually tested in vivo by measuring their therapeutic efficacy against rodent-adapted plasmodial species and by assessing the antiparasitic response of non-human immune systems, respectively (11). To overcome the host specificity issue, two conceptually different murine models of erythrocytic stages of P. falciparum malaria have been developed. The first one requires chemical in vivo depletion of phagocytic cells from immunodeficient mice engrafted with hE in order to allow the growth of P. falciparum after intraperitoneal (i.p.) infection (2, 8). However, its variable kinetics of parasitemia and, particularly, the use of toxic reagents, which might affect the efficacy of antimalarials or effector cells, have limited its use in drug discovery (5). Recently, a new P. falciparum murine model that does not require in vivo myeloablative treatment of mice and is suitable for drug discovery was described (1). In this new model, NOD-scid mice genetically deficient in beta-2 microglobulin (␤2 m tm1Unc , abbreviated as ␤2 m null ) engrafted with hE (HM-␤2 m null ) are infected intravenously with P. falciparum strains selected in vivo for their competence to grow reproducibly in hE-engrafted immunodeficient mice (1).The NOD-scid ␤2 m null mouse strain retains residual NK cell activity as well as other innate immune functions and shows a high incidence of early thymic lymphomas, which dramatically diminish their life span (4). These characteristics may be a serious problem for addressing long-term pharmacokinetic/ pharmacodynamic (PK/PD) studies because of the relatively low total parasite burden per mouse achievable (1) and the short life span of NOD-scid ␤2 m null mice (4). Interestingly, NOD-scid strains carrying a null mutation of the interleukin 2 (IL-2) receptor ␥ chain (IL2R␥ tm1Wjll , abbreviated as IL2R␥ null ) have been developed (10). These murine strains lack fully mature NK cells and show additional defects in their innate immune system that explain their greater ability to support the engraftme...

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Reduction in apoptosis has been associated with tumor metastases and response to chemotherapy in breast cancer. We examine the influence of apoptosis status and the expression of antiapoptotic proteins Bcl-2 and Bcl-x L on metastatic progression and response to therapy in an experimental model of breast cancer. We used human breast cancer cells (MDA-MB 435, MDA-MB 468 and MCF-7) to induce orthotopic xenograft tumors in nude mice. The overexpression of Bcl-2 or Bcl-x L influenced tumorigenicity, 468 transfectants being less tumorigenic than control (p < 0.0001). Lung metastasis appeared at day 120 in animals injected with 435/Bcl-2 or 435/Bcl-x L and they showed higher metastatic activity than control 435/Neo tumors (p ‫؍‬ 0.02). In contrast, mice with 468 tumors were followed for 1 year after tumor excision, but they did not develop metastatic foci. The vast catalog of cancer cell genotypes is manifested in the wide range of alterations to cell physiology that dictate malignant growth. Moreover, the growth of tumor cell populations is determined not only by the rate of cell proliferation but also by the rate of cell death. The progression of tumors until they metastasize to distant sites and withstand the action of therapy results from cumulative changes that render tumor cells more motile and invasive as well as resistant to apoptosis. 1 Gene products controlling the balance between cell death and survival arise from an expanding family of genes, of which Bcl-2 was the first to be clearly associated with apoptosis inhibition. 2,3 Several independent signal transduction pathways leading to cell death converge in a final common effector mechanism in which Bcl-2 acts as a dominant repressor. 4 This protein, which localizes to the mitochondrial membrane, nuclear envelope and endoplasmic reticulum, 5 and Bcl-x L , a member of the Bcl-2 gene family, exert their antiapoptotic function by preventing the release of cytochrome c from mitochondria to the cytosol. 6,7 The antiapoptotic activity of these proteins may be dependent upon their interaction with other death-promoting proteins. 8 -10 Reduction in apoptosis has been associated with the development of fibrocystic changes in the breast and with an increased risk of cancer. 11 The imbalance between cell survival and apoptosis could be crucial in the progression of breast cancer, allowing the accumulation of genetic alterations. 12 High levels of Bcl-2 and Bcl-x L are frequently found in tumors, where they may have distinct biologic roles in cell survival, tumor development and drug resistance. 13 Most breast cancer cells overexpress Bcl-x L and Bcl-2, which raises the question as to which is more crucial for their survival.We identified loss of apoptosis and Bcl-2 overexpression in T 1 ductal breast carcinomas and this phenotype was associated with the likelihood of lymph node metastasis in patients 14 and with accumulated oncogene alterations. 15 Increased levels of Bcl-x L expression were found in a subset of primary human breast carcinomas, mainly in undifferent...

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ATI of RMC-treated, CT-P13-treated or RMC to CT-P13 switched patients show full cross-reactivity with CT-P13 and SB2. Findings suggest that immunodominant epitopes in the reference and CT-P13 drugs are equally present in SB2. Data support full interchangeability between biosimilars in regard to immunogenicity.

Anti-IFX antibodies of Remicade-treated patients cross-react with either Inflectra or Remsima. Although additional epitopes may be present in the biosimilar, results suggest that epitopes influencing the immune response to IFX are also present in the biosimilar. Antibody-positive patients treated with Remicade should not be switched to the biosimilar, since antibodies will interact with the new drug and potentially lead to loss of response. This finding supports the utility for therapeutic drug monitoring before a switching strategy is considered.

The increasing incidence of breast cancer brain metastasis in patients with otherwise well-controlled systemic cancer is a key challenge in cancer research. It is necessary to understand the properties of brain-tropic tumor cells to identify patients at risk for brain metastasis. Here we attempt to identify functional phenotypes that might enhance brain metastasis. To obtain an accurate classification of brain metastasis proteins, we mapped organ-specific brain metastasis gene expression signatures onto an experimental protein-protein interaction network based on brain metastatic cells. Thirty-seven proteins were differentially expressed between brain metastases and non-brain metastases. Analysis of metastatic tissues, the use of bioinformatic approaches, and the characterization of protein expression in tumors with or without metastasis identified candidate markers. A multivariate analysis based on stepwise logistic regression revealed GRP94, FN14, and inhibin as the best combination to discriminate between brain and non-brain metastases (ROC AUC = 0.85, 95% CI = 0.73 to 0.96 for the combination of the three proteins). These markers substantially improve the discrimination of brain metastasis compared with ErbB-2 alone (AUC = 0.76, 95% CI = 0.60 to 0.93). Furthermore, GRP94 was a better negative marker (LR = 0.16) than ErbB-2 (LR = 0.42). We conclude that, in breast carcinomas, certain proteins associated with the endoplasmic reticulum stress phenotype are candidate markers of brain metastasis.