Synthesis of Magnetic-Nanoparticle/Ansamitocin Conjugates-Inductive Heating Leads to Decreased Cell Proliferation In Vitro and Attenuation Of Tumour Growth In Vivo.

Conjugates based on nanostructured, superparamagnetic particles, a thermolabile linker and a cytotoxic maytansinoid were developed to serve as a model for tumour-selective drug delivery and release. It combines chemo- with thermal therapy. The linker-modified toxin was prepared by a combination of biotechnology and semisynthesis. Drug release was achieved by hyperthermia through an external oscillating electromagnetic field that induces heat inside the particles. Efficacy of this release concept was demonstrated both for cancer cell proliferation in vitro, and for tumour growth in vivo, in a xenograft mouse model. Biocompatibility studies for these magnetic-nanoparticle/ansamitocin conjugates complement this work.

Validation of an immunoassay to selectively quantify the naked antibody of a new Antibody Drug Conjugate--SAR566658--for pharmacokinetic interpretation improvement.

Given the nature of the ADCs (Antibody Drug Conjugates) as antibodies carrying cytotoxic drugs, two types of immunoassays are usually implemented to perform the analysis of preclinical and clinical study samples during the development phase. The first assay measures the conjugated antibody defined as the ADC carrying at least 1 drug molecule (i.e. drug/antibody ratio greater than or equal to 1). The other measures the total antibody, defined as the ADC irrespective of the drug load (i.e., drug/antibody ratio greater than or equal to 0). One analytical limitation of the total antibody assay is the difficulty to adequately calibrate the assay due to the lack of a representative standard reference for the different circulating entities which change in proportion with time following ADC administration. A new analytical approach that gets round the above highlighted limitation is presented with the development and the validation of a method to quantify selectively naked antibody to support the development of SAR566658 (huDS6-SPDB-DM4). Assessed on 6 separate occasions, the accuracy ranged from -4.3% to 8.9% of nominal values and the precision is 13% at most. The current assay was successfully validated for the quantitation of huDS6 in human LiHe plasma even in the presence of SAR566658 up to 2.00 µg/mL as demonstrated using in vitro spike in quality controls and in actual clinical samples. This innovative assay provides a new tool to document in vivo plasma stability of ADCs and potentially to optimize dose and regimen selection for ADC development.