Monoclonal anti-EGFreceptor antibody (ior-R3) pharmacokinetic study in tumor bearing nude mice: role of the receptor-mediated endocytosis on drug clearance.

With the purpose of describing the MAb ior-R3's kinetic behavior in disease state, this paper is focused on the study of this response using a human cancer (lung carcinoma cell line, H125) bearing nude mice animal model. This MAb was administered by a single 16 mg/Kg intravenous bolus dose and the blood samples were collected at several times ranging from 0 to 72 hours for serum drug quantification. The experimental data set was best fitted using a classical two-compartment mammilary pharmacokinetic (PK) model and the corresponding PK parameters were determined. Comparatively, the analysis of the more relevant physiologically-based PK parameters showed a significant enhancing of clearance as compound with the earlier reported study on healthy mice, increasing from 0.09 to 0.19 mL/h (p<0.01). However, the corresponding distribution volumes don't seem to be altered by the tumor xenograft. We conclude that all of these evidences suggest a possible mechanism of receptor-mediated endocytosis (RME) as a major cause of this increased drug clearance which also contributed to the faster decrease of the drug disposition.

Tumor-specific immunotherapy based on dominant models of natural tolerance.

The assumption that cancer immunotherapy may be based on the existence of autoreactive lymphocytes recognizing self-antigens on cancer cells, obviously opens a new opportunity. Nevertheless this analysis, relying on a recessive model of natural tolerance, limits the approach to try to activate peripheral lymphocytes, by increasing co-stimulatory signals or using modified self-antigens for immunization. Here we hypothesize that, based on emerging dominant tolerance notions in autoimmunity, it would be possible to induce a specific autoimmunity against tumor cells and arrest their growth following the removal of regulatory T cells. These immunoregulatory cells suppress available immunocompetent autoreactive cells capable of destroying tumor cells. Therefore, in order to reach a complete tumor-specific autoimmunity it is necessary to combine the T cell immunosuppression which abrogates the regulatory cells, with the cancer vaccines, which induces extensive proliferation of lymphoid cells directed towards specificities on tumor cells.

Toxic effects of interleukin-2-activated lymphocytes on vascular endothelial cells.

IL-2-activated lymphocytes (LAK cells) show increased adherence to, and killing of, human vascular endothelial cells compared to resting lymphocytes. In the present work, we have found that supernatants from LAK cell cultures also are toxic to human umbilical vein endothelial cells (HUVEC) when tested for 48 h in a neutral red uptake assay. Recombinant TNF-alpha and IFN-gamma at high concentrations are also toxic under the same test conditions, and TNF-alpha was directly detected in LAK cell supernatants. An inconsistent inhibition of toxicity was found with anti-TNF-alpha whereas anti IFN-gamma antibodies had a partial inhibitory effect. The susceptibility of HUVEC to cellular killing by LAK cells could be up- and down-regulated with insulin-like growth factor I and IFN-gamma, respectively. It is concluded that damage to vascular endothelium during high dose IL-2 treatments may be partially related to an excessive production of lymphokines such as IFN-gamma and TNF-alpha. IFN-gamma may, in addition, be protective for HUVEC during cellular interactions with LAK cells.

Tropical treatment of cutaneous T-cell lymphoma skin lesions with the mouse anti-CD6 monoclonal antibody IOR-T1 / Tratamiento tópico de lesiones de piel en linfomas cutáneos de células T con el anticuerpo monoclonal murino anti-Cd6 IOR-T1

Los linfomas cutáneos a células T (CTCL) constituyen un grupo de enfermedades neoplásicas caracterizadas por infiltrados de células T malignas en piel, con una pobre respuesta a la terapia convencional. La aplicación intravenosa de anticuerpos monoclonales (AcM) contra antígenos de diferenciación de células T ha sido experimentalmente evaluada como modalidad terapéutica en estas enfermedades, con respuestas antitumorales limitadas. El IOR-T1 es un Acm de ratón del isotipo IgG2a dirigido contra el antígeno CD6. Este anticuerpo monoclonal identifica una alta proporción de células T malignas en pacientes con CTCL y no induce la modulación edel antígeno. En el presente artículo reportamos la regresión de placas cutáneas limitadas en ytraes pacientes de CTCL que fueron tratados con una crema neutra hidrofilica que contenía 3 mg/g de IOR-T1. La crema fue aplicada tres veces al día durante un mes. En lesiones similares de estos pacientes, tratadas con un AcM anti antigeno carcinoembrionario, o placebo (solo crema), no se observó efecto alguno sobre las características de las lesiones. El diseño de este estudio y sus resultados indican que el IOR-T1 es absorbido a través de la piel y produce importantes cambios en las lesiones, compatibles con una respuesta antitumoral objetiva. Nuestros resultados sugieren la posibilidad de que la aplicación tópica de AcM pueda convertirse en una nueva modalidad terapéutica adyuvante en CTCL

Low IL-1 beta production in leukemic cells from progressive B cell chronic leukemia (B-CLL).

In vitro production of IL-1 beta by cells from 32 patients with benign monoclonal lymphocytosis of undetermined significance (MLUS) and B cell chronic lymphocytic leukemia (B-CLL) was investigated. Normal B lymphocytes (2 x 10(6)) secreted approximately 5 ng/ml of IL-1 beta during 24 h and approximately ten times more after stimulation with Staphylococcus aureus, strain Cowan 1 (SAC). When patients were studied, a loss of IL-1 beta production was found in leukemic cells from progressive disease. Cells from MLUS patients secreted near normal levels of IL-1 beta and responded to SAC stimulation, whereas cells from patients with progressive B-CLL produced no, or little IL-1 beta, and did not respond to SAC. Loss of IL-1 beta production in progressively growing B-CLL may be related to an increased malignant character of these cells. This is discussed in relation to the immunogenicity of the leukemic cells and their capacity to differentiate.

Obtención de un anticuerpo monoclonal que identifica timocitos humanos / Obtention of a monoclonal antibody that identifies human thymocytes

El anticuerpo monoclonal (AcM) IOR-T7, del tipo IgM, es secretado por un hibridoma generado por la inmunización de ratones BALB/c con células de la línea de cultivo CEM y la fusión de los linfocitos esplénicos con el mieloma P3/x63.Ag8.6.5.3. Este AcM no reconoce, o lo hace en muy bajo porcentaje, las poblaciones celulares de la sangre periférica, mientras que identifica el 76 y el 79% de timocitos fetales y pediátricos, respectivamente, y las líneas celulares CEM y Molt-4, de origen T. El antígeno reconocido por este AcM parece estar relacionado con estadios tempranos de la ontogenia de los linfocitos humanos

Obtención de hibridomas de ratón productores de anticuerpos monoclonales que reconocen células humanas de origen T: II. Caracterización de los anticuerpos monoclonales IOR-T1 e IOR-T2 / Obtention of mice hybridomas producing monoclonal antibodies which recognize human T cells: II. Characterization of IOR-T1 and IOR-T2 monoclonal antibodies

Los anticuerpos monoclonales han contribuído de manera particular a la caracterización de las diferentes subpoblaciones celulares del sistema linfoide y han demostrado su utilidad para el diagnóstico, pronóstico y tratamiento de diferentes enfermedades. En el presente trabajo se estudian dos anticuerpos monoclonales: IOR-T1 e IOR-T2, secretados por hibridomas estables obtenidos por la fusión de la línea de mieloma murino P3/x63-Ag8-6.5.3 y células esplénicas de ratones Balb/cHab, inmunizados con células mononucleares periféricas de un paciente con síndrome de Sézary. Las especificidades fueron probadas sobre células mononucleares periféricas de individuos sanos, pacientes con linfomas T cutáneos y pacientes con leucemias, y sobre diferentes líneas celulares de cultivo. Por otra parte se realizaron comparaciones con el anticuerpo monoclonal OKT 3 y con el método de Rosetas-E. Se demostró que el IOR-T1 reconoce específicamente el marcador de las células T humanas y que puede ser utilizado confiablemente para el diagnóstico inmunológico de las leucemias y linfomas. El IOR-T2 parece identificar un antígeno tumor asociado relacionado con alguna de las etapas de la progresión y/o proliferación neoplásica de los linfomas T cutáneos