A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors.

BACKGROUND: Ertumaxomab (ertu) is a bispecific, trifunctional antibody targeting Her2/neu, CD3 and the Fcγ-receptors I, IIa, and III forming a tri-cell complex between tumor cell, T cell and accessory cells. METHODS: Patients (pts) with Her2/neu (1+/SISH positive, 2+ and 3+) expressing tumors progressing after standard therapy were treated to investigate safety, tolerability and preliminary efficacy. In this study, ertu was applied i.v. in 2 cycles following a predefined dose escalating scheme. Each cycle consisted of five ascending doses (10-500 µg) applied weekly within 28 days with a 21 day treatment-free interval. If 2 pts experienced a dose limiting toxicity (DLT) at a given dose level, the maximum tolerated dose (MTD) had been exceeded. RESULTS: Fourteen heavily pretreated pts (e.g. breast, rectal, gastric cancer) were enrolled in the four main cohorts. Three (21 %) pts had to be replaced. Two serious adverse events (SAE) with possible relation to the investigational drug were seen, both fully reversible. A DLT was not detected. Consequently, the MTD could not be determined. All adverse events (AE) were transient and completely reversible. Most frequent AEs were fatigue (14/14), pain (13/14), cephalgia (12/14), chills (11/14), nausea (8/14), fever (7/14), emesis (7/14) and diarrhea (5/14). Single doses up to 300 µg were well tolerated (total dose up to 800 µg per cycle). We observed one partial remission and two disease stabilizations after first treatment cycle. CONCLUSIONS: Single doses up to 300 µg could be safely administered in an escalating dose scheme. Immunological responses and clinical activity warrant further evaluation in patients with Her2 over expressing tumors. TRIAL REGISTRATION: EudraCT number: 2011-003201-14; ClinicalTrials.gov identifier: NCT01569412.

La vida en pareja con el síndrome de Down / Living as a couple with Down’s syndrome

La mejora de las condiciones de vida de las personas con síndrome de Down ha supuesto enormes oportunidades para normalizar sus vidas y gozar de proyectos acordes a sus expectativas e ilusiones. La inserción escolar y laboral, la participación comunitaria y la vida independiente son los escenarios que les han permitido estudiar, trabajar, tener amigos, pareja y, en ocasiones, su propia casa. La emancipación de sus familias es todavía excepcional, pero supone un hito que culmina un proyecto de vida elegido voluntariamente. La tendencia más habitual es que vivan indefinidamente con sus padres hasta que estos fallezcan y luego vayan a vivir con otro familiar o a una institución. Para muchos es impensable vivir solos, que formen parejas o que tengan relaciones sexuales. Pero ¿qué quieren las personas con síndrome de Down? Como miembros de nuestra realidad, desean lo mismo que todos los jóvenes: tener un trabajo, una pareja, una casa y poder vivir juntos. En algunos casos estos deseos han recibido el apoyo de las familias que, con ciertas dosis de riesgo y valentía, les han ofrecido la oportunidad de que se constituyan como una unidad familiar propia y gocen de una vida normalizada con los apoyos necesarios. Este artículo se nutre de la experiencia real y cotidiana de 14 años apoyando los procesos de emancipación de estas personas que han iniciado su convivencia como pareja y familia (AU)

The improvement in the living conditions of individuals with Down’s syndrome has opened enormous opportunities to lead a normal life and take advantages of projects in keeping with their expectations and hopes. The integration into schools and workplaces, participation in the community, and an independent life are the scenarios that have enabled them to study, work, have friends, a partner and, occasionally, their own home. The emancipation from their families is still exceptional, but is a challenge that culminates in a voluntarily chosen life project. The most usual tendency is that they live indefinitely with their families until these die and then go on living with another family member or in an institution. For many of them it is unthinkable to live alone, form a partnership or have sexual relationships. But, what do individuals with Down’s syndrome want? As members of our reality, they want the same as other young people: to have a job, a partner, a home and to be able to live together. In some cases these wishes have received the support of the families, who with a certain amount of risk and bravery, have offered them the opportunity to form their own family unit and enjoy a normal life with the necessary support. This article is drawn from the real and daily experience of 14 years of supporting the emancipation process of these individuals who have started to live together as a couple and a family(AU)

Ciudadanos de pleno derecho / Full citizens

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Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer.

Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein that is frequently overexpressed in a variety of carcinomas. This pan-carcinoma antigen has served as the target for a plethora of immunotherapies. Innovative therapeutic approaches include the use of trifunctional antibodies (trAbs) that recruit and activate different types of immune effector cells at the tumour site. The trAb catumaxomab has dual specificity for EpCAM and CD3. In patients with malignant ascites, catumaxomab significantly increased the paracentesis-free interval, corroborating the high efficacy of this therapeutic antibody. Here, we characterised the monoclonal antibody (mAb) HO-3, that is, the EpCAM-binding arm of catumaxomab. Peptide mapping indicated that HO-3 recognises a discontinuous epitope, having three binding sites in the extracellular region of EpCAM. Studies with glycosylation-deficient mutants showed that mAb HO-3 recognised EpCAM independently of its glycosylation status. High-affinity binding was not only detected for mAb HO-3, but also for the monovalent EpCAM-binding arm of catumaxomab with an excellent K(D) of 5.6 x 10(-10) M. Furthermore, trAb catumaxomab was at least a 1000-fold more effective in eliciting the eradication of tumour cells by effector peripheral blood mononuclear cells compared with mAb HO-3. These findings suggest the great therapeutic potential of trAbs and clearly speak in favour of EpCAM-directed cancer immunotherapies.

EpCAM an immunotherapeutic target for gastrointestinal malignancy: current experience and future challenges.

Despite advances in surgery and adjuvant regimes, gastrointestinal malignancy remains a major cause of neoplastic mortality. Immunotherapy is an emerging and now successful treatment modality for numerous cancers that relies on the manipulation of the immune system and its effector functions to eradicate tumour cells. The discovery that the pan-epithelial homotypic cell adhesion molecule EpCAM is differentially expressed on gastrointestinal tumours has made this a viable target for immunotherapy. Clinical trials using naked anti EpCAM antibody, immunoconjugates, anti-idiotypic and dendritic cell vaccines have met variable success. The murine IgG2a Edrecolomab was shown to reduce mortality and morbidity at a level slightly lower than treatment with 5FU and Levamisole when administered to patients with advanced colorectal carcinoma in a large randomised controlled trial. Fully human and trifunctional antibodies that specifically recruit CD3-positive lymphocytes are now being tested clinically in the treatment of minimal residual disease and ascites. Although clinical trials are in their infancy, the future may bring forth an EpCAM mediated approach for the effective activation and harnessing of the immune system to destroy a pathological aberrance that has otherwise largely escaped its attention.

Increased chondroitin sulphate proteoglycan expression (B5 immunoreactivity) in metastases of uveal melanoma.

BACKGROUND: Metastatic uveal melanoma has a poor prognosis and limited therapeutic options. Proteoglycans are involved in tumor cell invasion and metastatic behavior. The mAbB5 stains a chondroitin sulphate proteoglycan (CSPG) on cutaneous melanoma cells. Here, we compare the B5-staining of CSPG in primaries and metastases of uveal melanoma. MATERIAL AND METHODS: Immunohistopathological staining was performed in 15 cutaneous and 39 uveal melanoma samples. A score for intracellular and surface staining was established. B5 staining was compared in primaries and metastases of uveal melanoma using Student's t-test. RESULTS: Eight of 11 (73%) uveal melanoma metastases were positive for B5-staining whereas only 5 of 28 (18%) primary uveal melanoma samples were B5-positive (P < 0.001). Nine of 15 cutaneous melanoma samples (60%) were B5-positive without significant difference between primary and metastatic lesions. Surface staining was found both on uveal melanoma metastases and cutaneous melanomas. CONCLUSIONS: CSPG was expressed significantly more often in metastases than in primaries of uveal melanoma. It potentially may be one factor associated with metastatic spread. Further studies are needed to determine its use as prognostic factor. The mAbB5 may also be a promising tool for immunotherapy due to its strong staining of CSPG on the surface of cutaneous and metastatic uveal melanoma cells.

Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody.

Bispecific antibodies (bsAbs) can efficiently mediate tumor cell killing by redirecting preactivated or costimulated T cells to disseminated tumor cells, especially in a minimal residual disease situation. This study demonstrates that the trifunctional bsAb BiLu is able to kill tumor cells very efficiently without any additional costimulation of effector cells in vitro and in vivo. Remarkably, this bsAb also induces a long-lasting protective immunity against the targeted syngeneic mouse tumors (B16 melanoma and A20 B-cell lymphoma, respectively). A strong correlation was observed between the induction of a humoral immune response with tumor-reactive antibodies and the survival of mice. This humoral response was at least in part tumor specific as shown in the A20 model by the detection of induced anti-idiotype antibodies. Both the survival of mice and antitumor titers were significantly diminished when F(ab')(2) fragments of the same bsAb were applied, demonstrating the importance of the Fc region in this process. With the use of T-cell depletion, a contribution of a cellular antitumor response could be demonstrated. These results reveal the necessity of the Fc region of the bsAb with its potent immunoglobulin subclass combination mouse immunoglobulin G2a (IgG2a) and rat IgG2b. The antigen-presenting system seems to be crucial for achieving an efficient tumor cell killing and induction of long-lasting antitumor immunity. Hereby, the recruitment and activation of accessory cells by the intact bsAb is essential.

Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes.

The renin-angiotensin system (RAS) is the most important regulatory system of electrolyte homeostasis and blood pressure. We report here the development of transgenic rats carrying the human angiotensinogen TGR-(hAOGEN) and human renin TGR(hREN) genes. The plasma levels and tissue distribution of the transcription and translation products from both genes are described. A unique species specificity of the enzyme kinetics was observed. The human RAS components in the transgenic rats did not interact with the endogenous rat RAS in vivo. Instead, infusions of exogenous human RAS components specifically interacted with human transgene translation products. Thus, infusion of human renin in TGR(hAOGEN) led to an increase of angiotensin II and an elevation of blood pressure, which could not be antagonized by the human-specific renin enzyme inhibitor Ro 42-5892. Rat renin also elevated blood pressure and angiotensin II in TGR(hAOGEN); however, this effect was not antagonized by the human renin inhibitor. Compared to mice, rats offer the advantage of chronic instrumentation and repetitive, sophisticated, hemodynamic, and endocrinological investigations. Thus, transgenic rat models with human-specific enzyme kinetics permit primate-specific analyses in non-primate in vivo and in vitro experimental systems.

Factors affecting plasma levels of ketoconazole during long-term treatment.

In the present study we intended to obtain information on the evolution of near-peak blood levels during long-term treatment. 56 patients with an indication for systemic treatment of nail or skin mycoses obtained a daily dose of 200 mg ketoconazole. They were periodically checked for blood level of ketoconazole, clinical and mycological status and enzyme values. The average blood level was 2.8 +/- 1.3 micrograms/ml plasma. The blood level was not influenced by the length of the treatment. A correlation between blood level and weight or sex was not observed, whereas a significant negative correlation occurred between blood level and age (age group 15-30 years: 3.9 +/- 1.3 micrograms/ml; 46-60 years: 2.4 +/- 0.9 micrograms/ml).

The inhibitory effects of prednisone, 16-methylen-prednisolone, and ACTH on con-A induced lymphokines (interferon-y) as measured by the chemiluminescence-activity of blood monocytes.

When lymphocytes are stimulated with mitogens or antigens they are enhanced via a cascade of lymphokines to produce interferon-y (IFN-y). IFN-y augments the H2O2 secretion of human monocytes which indirectly can be measured by chemiluminescence. We tested prednisone, 16-methylen-prednisolone and ACTH for their effect to inhibit the Con-A induced stimulation of the chemiluminescence-activity. All three hormones inhibited significantly the stimulation: prednisone up to 52.5% (concentration = 150 micrograms/ml, p = 0.000005), 16-methylen-prednisolone up to 22.5% (concentration = 2.5 micrograms/ml, p = 0.006) and ACTH up to 33% (concentration = 10 micrograms/ml, p = 0.0036).