A quantitative evaluation of the molecular binding affinity between a monoclonal antibody conjugated to a nanoparticle and an antigen by surface plasmon resonance

Q2 · MEDICINE

Article

Author: Nir Debotton ; Hagit Zer ; Simon Benita ; Jean Kadouche ; Oshrat Harush-Frenkel ; Marcela Parnes

We have designed a site-specific drug colloidal carrier ultimately for improving pancreatic and lung cancer treatment. It is based on a nanoparticulate drug delivery system that targets tumors overexpressing H-ferritin. A monoclonal antibody, AMB8LK, specifically recognizing H-ferritin was thiolated and conjugated to maleimide-activated polylactide nanoparticles (NPs) resulting in the formation of immunonanoparticles (immunoNPs). The AMB8LK immunoNPs exhibited a mean diameter size of 112+/-20nm and a density of 76 antibody molecules per NP. AMB8LK immunoNPs were evaluated for uptake and binding properties on CAPAN-1 and A-549 cell lines, using confocal microscopy. ImmunoNPs demonstrated specific binding and increased uptake of the desired cells by means of monoclonal antibodies (MAbs), compared to nonconjugated NPs. A lipophilic paclitaxel derivative, paclitaxel palmitate (pcpl), was encapsulated within the various NP formulations, and their cytotoxic effect was evaluated on A-549 cells using MTT assay. Pcpl-loaded AMB8LK immunoNPs showed a significantly increased cytotoxic effect when compared to pcpl solution and pcpl NPs. Surface plasmon resonance (SPR) was used to determine quantitatively the affinity constants of native AMB8LK and AMB8LK immunoNPs to gain insight on the affinity of the MAbs following the conjugation process onto NPs. The results of the association/dissociation and affinity kinetics of the interaction between H-ferritin and native AMB8LK or AMB8LK immunoNPs revealed similar constant values, showing that the conjugation process of the MAb to the NPs did not alter the intrinsic specificity and affinity of the MAb to the antigen. In conclusion, at the cellular level, AMB8LK immunoNPs may carry drugs to desired overexpressing antigen cells with adequate affinity properties, potentially leading to improved drug therapy and reduced systemic adverse effects.

01 Apr 2007·Nuclear Medicine and BiologyQ4 · MEDICINE

In vitro and in vivo comparison of DTPA- and DOTA-conjugated antiferritin monoclonal antibody for imaging and therapy of pancreatic cancer

Q4 · MEDICINE

Article

Author: Stephen J. Mather ; Didier Decaudin ; Ciara Finucane ; Jean Kadouche ; Emmanuelle N. Sabbah ; David Ellison

Pancreatic cancer has a very poor prognosis with a less than 5% survival rate at 5 years. Neither external beam radiation nor chemotherapy, alone or in combination, have given encouraging results so far. A possible solution might come from the use of targeted therapy such as radioimmunotherapy. We present here the results obtained from the preclinical development of a new monoclonal antiferritin antibody (Ab), AMB8LK. Ferritin is overexpressed in pancreatic cancer and could thus be used as a target for the delivery of radioactivity at the tumour sites. The AMB8LK Ab was conjugated to three chelating agents: the 2-(4-isothiocyanatobenzyl)-diethylenetriamine pentaacetic acid (PSCN-Bz-DTPA), the (R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (p5CN-Bz-CHX-A"-DTPA) and the 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (pSCN-Bz-DOTA). Radiolabelling of the three immunoconjugates with indium 111 and yttrium 90 as well as in vitro stability and immunoreactivity against pure ferritin and cells expressing ferritin were analysed. In vivo biodistribution studies were conducted on normal and on human pancreatic adenocarcinoma CAPAN-1 tumour bearing mice. These experiments demonstrated good radiolabelling (>95%), stability and immunoreactivity of the three compounds. In the biodistribution studies, differences between the three immunoconjugates were apparent in the rate of blood clearance and in tumour, liver and bone uptake. A very good pancreatic adenocarcinoma tumour targeting was observed especially with the Bz-DTPA-AMB8LK: 20% of the injected dose of the indium-labelled compound 3 days after injection; 15% of the injected dose 5 days after that of the yttrium-labelled Ab. Altogether, these results in animal models suggest that (90)Y-Bz-DTPA-AMB8LK is a good candidate for further therapeutic efficacy studies.

01 Nov 2005·Journal of Controlled ReleaseQ1 · MEDICINE

The design and evaluation of a novel targeted drug delivery system using cationic emulsion–antibody conjugates

Q1 · MEDICINE

Article

Author: Simon Benita ; Danny Goldstein ; Taher Nassar ; Gregory Lambert ; Jean Kadouche

In an attempt to design a targeted drug delivery system to tumors' over-expressing H-ferritin specifically recognized by a monoclonal antibody, AMB8LK, a cationic emulsion - AMB8LK conjugate was prepared. A novel cross-linker molecule bearing maleimide group was synthesized and added to cationic emulsion formulation for AMB8LK Fab' fragment covalent coupling. NMR spectroscopy confirmed the cross-linker synthesis and the preservation of the active maleimide function. SDS gel-electrophoresis results corroborated the formation of the Fab' fragment. Different densities of Fab' fragments (10-200 Fab'/oil droplet) were conjugated to emulsion droplet interface and no changes in the physico-chemical properties were observed ( approximately 120 nm size and zeta potential of approximately +30 mV). The coupling efficiency ranged from 55% to 70% and was visualized by TEM showing gold particles attached to the droplet interface. Cell culture studies demonstrated specific binding to cells as confirmed by the occurrence of the marked reduction in binding when free AMB8LK Mab was incubated before adding the AMB8LK-emulsion conjugate to the cells. The coupling of AMB8LK Fab' fragment to the cationic emulsion increased the cells uptake by 50% as compared to non-conjugated respective cationic emulsion. Appropriate conditions were, thus, identified for coupling AMB8LK Fab' fragment to cationic emulsion without altering the specificity and affinity of the Mab fragment to the tumor antigen.

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Indication	Highest Phase	Country/Location	Organization	Date
Hodgkin's Lymphoma	Discovery	FR	MABLife SAS	-
Liver Cancer	Discovery	FR	MABLife SAS	-
Pancreatic Cancer	Discovery	FR	MABLife SAS	-

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