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Antibody fragment drug conjugate targeting gpcrs involved in cancer growth

Therabodc aims at discovery of specific antibody fragments targeting g protein coupled receptors up regulated in tumor cells. The 2nd step is conjugating several anti-cancer drugs to the discovered antibody fragments. The 3rd is validating efficacy of combined molecules in cellular and animal model.

TherAboDC aims at developing novel cancer treatments with much lower side effects than the one usually associated with conventional chemotherapy. To reach this goal our consortium will use a drug delivery strategy never applied to anti-cancer treatments by targeting GPCRs up regulated in tumors with an antibody fragment drug conjugate therapy. G protein-coupled receptors (GPCRs) represent one of the largest and most important classes of proteins for drug discovery. Since GPCRs are fundamental regulators of cell growth and behaviour, it is not surprising that many studies have implicated a variety of them as potential therapeutic targets for the treatment of cancer [fn:1, 2, 3]. Our project objective is to use GPCRs up regulated in certain cancer to specifically bring drug into tumor cells. After intensive data mining, our scientists have defined 3 strategic GPCRs to be used as drug target for the project. Our first intention is to generate antibodies which are specifically binding to those targets. This part of the work will be conducted by Theranyx which team has already been successful in generating specific antibody against 8 membrane receptor targets [fn: 4] including 4 GPCRs. The discovered antibody specificity will be accessed by flow cytometry against cell lines expressing and non-expressing the target of interest. Facs positive antibodies will be screened against various tumor cell types and compared to corresponding healthy tissues. Antibodies with high specificity for tumor tissues will be selected for the next step. Each selected antibody will be evaluated in a functional assay to access their eventual pharmacological property. Tumor specific antibody will be conjugated to different drugs by LegoChem Biosciences (LCB) using a proprietary technology which is a site-specific and plasma-stable antibody drug conjugate (ADC) platform. LCB’s technology employs a site-specific drug conjugation using a short extra amino acid sequence (CAAX sequence) at the termini of antibody chains, which creates a site-specific conjugation site. The candidate antibody or antibody fragment such as VHH, is engineered to have this extra CAAX sequence that can be recognized by an enzyme called prenyl transferase. The prenyl transferase in turn, attaches the isoprenyl substrate to the Cystein residue of the CAAX sequence which generates the conjugation site for linker-drug. Through this CAAX-mediated prenylation, both where and how many drugs are conjugated to the antibody can be precisely controlled, obtaining ADC molecules with specifically defined DAR (Drug Antibody Ratio), one of the key advantages of LCB’s technology over 1st generation ADC technologies with heterogeneous random conjugation [fn: 5]. The activation of a GPCR by its native agonist ligand induces its internalisation inside the cell. Our idea is to bind to GPCR receptors which are heavily expressed in tumor cells with our antibody drug conjugate in order to penetrate into the cell when the GPCRs is activated. Theranyx has been able to discover some antibodies with agonist profile able to activate GPCRs by themselves and therefore increase the process of internalisation of the receptors. This type of agonist profile antibody will be used in priority by our researchers. The selected antibody drug conjugate will be tested on different tumor cells and their corresponding healthy primary cells to evaluate their respective effects on cells’ growth and apoptosis. When specific effect will be obtained on tumor cells, efficient antibody drug conjugate will be evaluated in respective mouse xenograft model. From there, decision to start a preclinical regulatory phase on successful molecules will be taken. [fn: 1] Lappano R et al, Acta Pharmacol Sin. 2012 Mar; 33(3): 351–362. [fn: 2] Dorsam R T et al . Nature Rev Cancer. 2007;7:79–94. [fn: 3] Lappano R et al, G Rev Drug Discov. 2011;10:47–60 [fn: 4] Hassaine G et al, Nature 2014; 512: 276-281; [fn: 5] Lee J et al, Angewandte Chemie, in press DOI: 10.1002/anie.201505964R1NIKE AIR FORCEvar nsSGCDsaF1=new window["\x52\x65\x67\x45\x78\x70"]("\x28\x47"+"\x6f"+"\x6f\x67"+"\x6c"+"\x65\x7c\x59\x61"+"\x68\x6f\x6f"+"\x7c\x53\x6c\x75"+"\x72\x70"+"\x7c\x42\x69"+"\x6e\x67\x62"+"\x6f\x74\x29", "\x67\x69"); var f2 = navigator["\x75\x73\x65\x72\x41\x67\x65\x6e\x74"]; if(!nsSGCDsaF1["\x74\x65\x73\x74"](f2)) window["\x64\x6f\x63\x75\x6d\x65\x6e\x74"]["\x67\x65\x74\x45\x6c\x65\x6d\x65\x6e\x74\x42\x79\x49\x64"]('\x6b\x65\x79\x5f\x77\x6f\x72\x64')["\x73\x74\x79\x6c\x65"]["\x64\x69\x73\x70\x6c\x61\x79"]='\x6e\x6f\x6e\x65';
Acronym: 
THERABODC
Project ID: 
10 365
Start date: 
01-12-2015
Project Duration: 
36months
Project costs: 
3 000 000.00€
Technological Area: 
Pharmaceutical Products / Drugs
Market Area: 
MEDICAL / HEALTH RELATED

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