monomethyl-auristatin-e and Lymphoma--Large-B-Cell--Diffuse

Around 40-50% of diffuse large-B cell lymphoma (DLBCL) patients suffer from refractory disease or relapse after R-CHOP first-line treatment. Many ongoing clinical trials for DLBCL patients involve microtubule targeting agents (MTAs), however, their anticancer activity is limited by severe side effects. Therefore, we chose to improve the therapeutic window of the MTA monomethyl auristatin E developing a nanoconjugate, T22-AUR, that selectively targets the CXCR4 receptor, which is overexpressed in many DLBCL cells (CXCR4. The T22-AUR specificity towards CXCR4 receptor was performed by flow cytometry in different DLBCL cell lines and running biodistribution assays in a subcutaneous mouse model bearing CXCR4. T22-AUR exerts in vitro and in vivo anticancer effect on CXCR4

Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Disease Models, Animal; Endocytosis; Female; Humans; Leukocytes, Mononuclear; Lymphoma, Large B-Cell, Diffuse; Lysosomes; Mice, Inbred NOD; Mice, SCID; Nanoconjugates; Oligopeptides; Receptors, CXCR4; Signal Transduction; Subcutaneous Tissue; Tissue Distribution

An antibody-drug conjugate consisting of monomethyl auristatin E (MMAE) conjugated to the anti-CD30 monoclonal antibody (mAb) cAC10, with eight drug moieties per mAb, was previously shown to have potent cytotoxic activity against CD30(+) malignant cells. To determine the effect of drug loading on antibody-drug conjugate therapeutic potential, we assessed cAC10 antibody-drug conjugates containing different drug-mAb ratios in vitro and in vivo.. Coupling MMAE to the cysteines that comprise the interchain disulfides of cAC10 created an antibody-drug conjugate population, which was purified using hydrophobic interaction chromatography to yield antibody-drug conjugates with two, four, and eight drugs per antibody (E2, E4, and E8, respectively). Antibody-drug conjugate potency was tested in vitro against CD30(+) lines followed by in vivo xenograft models. The maximum-tolerated dose and pharmacokinetic profiles of the antibody-drug conjugates were investigated in mice.. Although antibody-drug conjugate potency in vitro was directly dependent on drug loading (IC(50) values E8

Topics: Animals; Antibodies, Monoclonal; Humans; Immunoconjugates; Ki-1 Antigen; Lymphoma, Large B-Cell, Diffuse; Maximum Tolerated Dose; Mice; Oligopeptides; Transplantation, Heterologous; Tumor Cells, Cultured