Graffinity Pharmaceuticals GmbH

Heidelberg, Germany

Graffinity Pharmaceuticals GmbH

Heidelberg, Germany
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Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.3.4-2 | Award Amount: 7.92M | Year: 2013

The trypanosomatid diseases, leishmaniasis, Human African trypanosomiasis (HAT) and Chagas disease (CD), continue to impart a heavy toll on human health. The treatments available are limited and threatened by drug resistance with few newdrugs in the pipeline. The KINDReD consortium integrates five leading academic laboratories in Europe (Portugal, United Kingdom, and Switzerland), the USA (California) and South America (Brazil) with high throughput screening (HTS) facilities equally distributed between all three major kinetoplastid parasites. Intracellular amastigote screening will be employed as the most relevant for Leishmania spp and T cruzi. Compound libraries (focused, diversity oriented or natural) will be screened in these systems, as well as compound series devised through target screening and in silico approaches. For carefully chosen protein targets, all three kinetoplastid parasite homologs will be screened against the closest human homolog to establish selectivity. Promising lead compounds will be optimised for efficacy and tolerability in cell-based and animal disease models. Toxicological markers will be evaluated in human cell lines prior to toxicity (acute,subacute,chronic) testing in lower then higher mammals. In parallel, and in line with the FDAs Critical Path Initiative, several check point controls will be built into the pipeline to flag, identify and allow early correction of potential toxicity/efficacy issues. These will include (i) a systems biology approach to identify drug target and off-target interactions via activity-based chemoproteomics (ii) uptake and metabolismas potential modulators of drug efficacy and/or resistance and (iii) the establishment of a firm set of rules for drug efficacy and safety in kinetoplastid chemotherapy. Our goal is to strengthen the drug development pipeline in order to achieve at least one new Phase I clinical candidate for each trypanosomatid disease at or shortly after the project completion date.


Arnold M.,Graffinity Pharmaceuticals GmbH | Bittermann H.,Graffinity Pharmaceuticals GmbH | Kalbfuss-Zimmermann B.,Graffinity Pharmaceuticals GmbH | Neumann T.,Graffinity Pharmaceuticals GmbH | And 5 more authors.
Journal of Chromatography A | Year: 2011

Libraries of small molecules were searched for Fc-fragment selective binders to a recombinant human antibody (" MDJ8″, IgG1-subtype, κ-light chain) via SPR-based screening of chemical microarrays. Identified hit structures were immobilised on NHS-activated Sepharose for the determination of MDJ8 binding and selectivity versus typical proteineous impurities represented by the spend cell culture supernatant. Columns were packed and the most promising ligands further characterized in terms of binding constants, binding kinetics, as well as dynamic and equilibrium binding capacities. The performance of the best ligand, 2A10, was compared to standard Protein A chromatography. Using ligand 2A10 antibody capture from unprocessed cell culture supernatants was possible at similar recovery yield (>90%), purity (>80%), and eluting concentration (approximately 1g/L) as with Protein A. Affinity constants (Kd) of 2A10 were an order of magnitude higher than for the Protein A material, but still in the nM-range, while maximum binding capacities and binding kinetics were in the same order of magnitude. Ligand 2A10 was also able to capture a murine monoclonal antibody, again with similar efficiency as Protein A, as well as a number of humanised therapeutic antibodies. Antibody elution from the 2A10 column was possible using the Protein A standard protocol, i.e. 100mM glycine HCl pH 3.0, but also at near physiological pH, when some organic solvent or modifiers were present. Ligand 2A10 thus constitutes a cheaper, more robust alternative to Protein A as possible generic antibody binder. Moreover, the outlined approach to ligand selection could in principle by used to create suitable affinity ligands for other high value biotech products. © 2011 Elsevier B.V.


Patent
Graffinity Pharmaceuticals Gmbh | Date: 2011-08-03

The present invention relates to the use for affinity purification of an antibody or an fragment of an antibody, of a ligand-substituted matrix comprising a support material and at least one ligand covalently bonded to the support material, the ligand being represented by formula (I) wherein Sp is a spacer group;v is 0 or 1;Am is an amide group NR^(1)C(O), and wherein either NR^(1 )is attached to Ar^(1 )and C(O) is attached to Ar^(2), or C(O) is attached to Ar^(1 )and NR^(1 )is attached to Ar^(2); andR^(1 )is hydrogen or C_(1 )to C_(4 )alkyl, preferably hydrogen or methyl; and more preferably hydrogen;Ar^(1 )is a divalent 5- or 6-membered substituted or unsubstituted aromatic ring;Ar^(2 )is 5- or 6-membered heterocyclic aromatic ring which is(a) attached to a further 5- or 6-membered aromatic ring via a single bond; or(b) fused to a further 5- or 6-membered aromatic ring as part of a multicyclic ring system; or(c) attached to at least one substituent selected from C_(1 )to C_(4 )alkyl; C_(2 )to C_(4 )alkenyl; C_(2 )to C_(4 )alkynyl; a halogen; C_(1 )to C_(4 )haloalkyl; hydroxyl-substituted C_(1 )to C_(4 )alkyl; C_(1 )to C_(4 )alkoxy; hydroxyl-substituted C_(1 )to C_(4 )alkoxy; C_(1 )to C_(4 )alkylamino; C_(1 )to C_(4 )alkylthio; and combinations thereof.


PubMed | Graffinity Pharmaceuticals GmbH
Type: Comparative Study | Journal: Journal of chromatography. A | Year: 2011

Libraries of small molecules were searched for Fc-fragment selective binders to a recombinant human antibody (MDJ8, IgG(1)-subtype, -light chain) via SPR-based screening of chemical microarrays. Identified hit structures were immobilised on NHS-activated Sepharose for the determination of MDJ8 binding and selectivity versus typical proteineous impurities represented by the spend cell culture supernatant. Columns were packed and the most promising ligands further characterized in terms of binding constants, binding kinetics, as well as dynamic and equilibrium binding capacities. The performance of the best ligand, 2A10, was compared to standard Protein A chromatography. Using ligand 2A10 antibody capture from unprocessed cell culture supernatants was possible at similar recovery yield (>90%), purity (>80%), and eluting concentration (approximately 1 g/L) as with Protein A. Affinity constants (K(d)) of 2A10 were an order of magnitude higher than for the Protein A material, but still in the nM-range, while maximum binding capacities and binding kinetics were in the same order of magnitude. Ligand 2A10 was also able to capture a murine monoclonal antibody, again with similar efficiency as Protein A, as well as a number of humanised therapeutic antibodies. Antibody elution from the 2A10 column was possible using the Protein A standard protocol, i.e. 100mM glycine HCl pH 3.0, but also at near physiological pH, when some organic solvent or modifiers were present. Ligand 2A10 thus constitutes a cheaper, more robust alternative to Protein A as possible generic antibody binder. Moreover, the outlined approach to ligand selection could in principle by used to create suitable affinity ligands for other high value biotech products.


Patent
Graffinity Pharmaceuticals Gmbh | Date: 2013-02-08

The present invention relates to the use, for affinity purification of an antibody or an fragment of an antibody, of a ligand-substituted matrix comprising a support material and at least one ligand covalently bonded to the support material, the ligand being represented by formula (I) L-(Sp)_(v)-Ar^(1)AmAr^(2)(I) wherein L, SP, Ar^(1), AM, Ar^(2 )and v are defined herein.

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