480 Study: Phase 2b Open-label, Randomized Study in Treatment Naïve Subjects with HCV Genotype 1 to Compare the Efficacy, Safety, and Tolerability of the 480 µg Dose of Locteron™ Plus Ribavirin Given Bi-Weekly to 1.5 µg /kg PEG-Intron™ Plus Ribavirin Given Weekly

Start Date24 Jul 2009

Sponsor / Collaborator

Biolex Therapeutics, Inc.

NCT00953589 / CompletedPhase 2

480 STUDY: Phase 2b Open-label, Randomized Study in Treatment Naïve Subjects With HCV G1 to Compare the Efficacy, Safety, and Tolerability of the 480 µg Dose of Locteron™ Plus Ribavirin Given Bi-Weekly to PEG-Intron™ Plus Ribavirin Given Weekly

The purpose of this 12-week study was to assess in subjects with chronic hepatitis C (treatment-naïve, genotype 1) receiving weight-based doses of ribavirin the early virologic response to the 480 ug dose level of Locteron™, dosed every 2 weeks, in comparison with 1.5 ug/kg PEG-Intron™ dosed weekly.

Start Date01 Jul 2009

Sponsor / Collaborator

Biolex Therapeutics, Inc.

EUCTR2008-007649-30-BG / Not yet recruitingNot Applicable

SELECT-2: Phase 2B, Partially Blinded, Randomized Study In Treatment Naïve Subjects With HCV Genotype 1 To Compare The Efficacy, Safety, And Tolerability Of Three Doses of Locteron™ Plus Ribavirin Given Bi-weekly In Comparison With PEG-Intron™ Plus Ribavirin Given Weekly - SELECT-2

Start Date20 May 2009

Sponsor / Collaborator

Biolex Therapeutics, Inc.

100 Clinical Results associated with Biolex Therapeutics, Inc.

0 Patents (Medical) associated with Biolex Therapeutics, Inc.

Literatures (Medical) associated with Biolex Therapeutics, Inc.

16 Nov 2008·Blood

A Glyco-Optimized Anti-CD20 Antibody from the Aquatic Plant Lemna: Comparison of Pharmacokinetics, B-Cell Depletion and Complement Activation with Rituxan® in Cynomolgus Monkeys

Author: Regan, Jeff ; Gasdaska, John R ; Radtke, Klaus-Peter ; Sherwood, Steve ; Humphries, John E. ; Dalmia, Bipin ; Dickey, Lynn F

AbstractMonoclonal antibodies represent one of the largest classes of drugs in preclinical and clinical development. For many antibodies, the structure and extent of the N-glycans on the Fc region of the heavy chain plays a significant role in their therapeutic function. A glyco-optimized version of the anti-CD20 antibody (rituximab) was expressed in the clonal aquatic plant Lemna. The optimized glycosylation was accomplished by co-expressing an interfering RNA (RNAi) construct targeting the endogenous alpha-1,3-fucosyltransferase and beta-1,2-xylosyltransferase genes (Cox et al., 2006). The resulting glyco-optimized rituximab contained a single major G0 N-glycan (lacking terminal galactose) without any detectable xylose or fucose. Previous in vitro cell-based studies have shown that the glyco-optimized rituximab had similar CD20 binding affinity and apoptotic effects as Rituxan® produced in mammalian cells but with significantly enhanced (up to 100- fold) antibody-dependent cellular cytotoxicity (ADCC). Enhanced ADCC activity was found for all FcgRIIIa-158 genotypes. Reported here are the results of expanded studies comparing Rituxan® with the Lemna–derived glyco-optimized rituximab. B-cell depletion was measured in genotyped human whole blood after ex vivo treatment with both anti-CD20 antibodies. Consistent with prior in vitro ADCC studies, glyco-optimized rituximab showed a significant increase in B-cell depletion for all FcgRIIIa-158 genotypes when compared to Rituxan®. To extend these findings to an in vivo setting, a comparative monkey study was conducted to evaluate:pharmacokinetic impact of the optimized glycans, B-cell depletion, and complement activation.The study design included two male Cynomologus monkeys per group in a dose-escalation scheme where each group received a single administration of two dose levels of either Rituxan® or glycooptimized rituximab. Results showed no difference between the two antibodies in clinical observations and pharmacokinetic profile. Overall the rate of depletion and recovery of the monkey B-cells between Rituxan® and glyco-optimized rituximab was similar with evidence of an increase in the initial rate of depletion with the glyco-optimized rituximab. The latter finding is not unexpected due to sequence differences between FcgRIIIa in humans and monkeys. Interestingly, 50% higher complement activation (as measured by serum levels of C3a,) was observed with Rituxan®. This is consistent with our previous observation that glyco-optimized rituximab had up to a ten-fold decrease in complement dependent cytotoxicity (CDC) in Raji cells compared to Rituxan®. These studies suggest that an optimized anti-CD20 antibody therapeutic can have a similar pharmacokinetic profile with enhanced ADCC activity and decreased CDC activity compared to Rituxan®. Confirmation that these differences will translate into improved efficacy with decreased side effects associated with CDC activity (Clark and Ledbetter, 2005) will require clinical research. Cox et al (2006). Nat. Biotech. 24: 1591–15197. Clark et al (2005). Ann. Rheum Dis. 64: 77–80.

16 Nov 2006·Blood

Recombinant Plasmin from Lemna: Purification, Characterization and In Vitro Comparison with Human Plasma-Derived Plasmin.

Author: Radtke, Klaus-Peter ; Meijer, Piet ; Lounes, Karim C. ; Brookhart, Gary L. ; Tomalski, Michael D. ; Kluft, Cornelis

AbstractBackground: The fibrinolytic enzyme plasmin has gained renewed interest as a direct thrombolytic agent. Local delivery of plasmin via catheter into thrombi, combined with the efficient neutralization of plasmin that may escape from the clot by its inhibitors α2-antiplasmin (α2-AP) and α2-macroglobulin may provide safe and effective removal of pathologic blood clots.Objective: To overcome the potential for pathogen contamination associated with plasmin prepared from pooled human plasma, we have generated recombinant plasmin (r-PLM) from transgenic Lemna plants and compared its biological properties with those of plasma-derived plasmin (pd-PLM).Results: Lemna minor, an aquatic plant, was transfected with the c-DNA encoding human plasminogen, and grown in media under controlled conditions. Lemna-derived plasminogen (r-PLG) was extracted from plant-tissue, separated on lysine-Sepharose and subsequently converted into plasmin (r-PLM), using urokinase-type plasminogen activator (u-PA). r-PLM was further purified to homogeneity using affinity chromatography on benzamidine-Sepharose. r-PLG and r-PLM co-migrate with pd-PLG and pd-PLM on non-reducing SDS-PAGE with the respective molecular weights of about 90,000 kDa and 82,000 kDa. When analyzed on reducing SDS-PAGE, r-PLM, just like pd-PLM, separates into a 56,000 kDa heavy chain and a 26,000 light chain. On Western blots r-PLG and r-PLM cross-react with polyclonal antibodies that were raised against pd-PLG, indicating immunologic identity of r-PLG/PLM and pd-PLG/PLM. All three plasminogen activators (PA), tissue-type PA, u-PA and streptokinase, activate r-PLG. Activity assays using the PLM-specific chromogenic substrate S-2403 show that catalytic rates of r-PLM are indistinguishable from pd-PLM, indicating that in this assay r-PLM and pd-PLM have comparable activity. Purified r-PLM and pd-PLM have similar specific activities. Like pd-PLM, r-PLM activity is inhibited by its physiological inhibitor α2-AP and Kunitz-type inhibitors SBTI and aprotinin. Inhibition of r-PLM by α2-AP results in the formation of a high-molecular weight SDS-stable complex, which migrates on SDS-PAGE with a molecular weight of 150,000 kDa, the cumulative molecular weight of r-PLM (82,000 kDa) and α2-AP (65,000 kDa). In microtiter-based fibrinolysis assays, both pd- and r-plasmin dissolve fibrin clots at the same rate and in a concentration-dependent manner.Conclusion: This work demonstrates that proteins of the fibrinolytic system can be expressed in Lemna. Lemna-derived r-PLM and pd-PLM have comparable biochemical properties, activity, and are equally sensitive to known plasmin inhibitors. Plant-derived r-PLM may be a valuable alternative to PLM preparations from pooled human plasma.

01 Oct 2006·Journal of Thrombosis and HaemostasisQ2 · MEDICINE

Plasma contains protein S monomers and multimers with similar direct anticoagulant activity

Q2 · MEDICINE

Article

Author: L. Tonnu ; J. A. Fernández ; K.-P. Radtke ; M. J. Heeb

BACKGROUNDProtein S (PS) has activated protein C-independent, direct anticoagulant activity (PS-direct). We reported that both multimers and monomers of affinity-purified PS have PS-direct similar to that in plasma, in contrast to another report.OBJECTIVEWe extended our studies to establish the molecular forms and activity of plasma PS.METHODSNovel ELISAs were developed that could detect only multimeric, not monomeric, PS because they employed the same monoclonal antibody for capture and detection. PS forms were also examined on native PAGE immunoblots. A new activity assay for PS-direct was applied to plasma and gel-filtered plasma fractions.RESULTSPlasma PS multimers were clearly demonstrated using the ELISAs; 30-60% of free plasma PS appeared to be multimeric, a proportion similar to that of affinity-purified PS. On immunoblots, plasma PS multimers were more easily detected after gel filtration; plasma PS monomers and several apparent multimers comigrated with respective forms of affinity-purified PS. Antigen elution profiles after gel filtration of plasma revealed at least one major peak of apparent PS multimers (40-55% of free PS appeared multimeric). Biotin-factor Xa could bind to both plasma PS monomers and multimers. Strong plasma PS-direct was demonstrated, and plasma PS monomers, multimers, and PS-C4b-binding protein complexes each reconstituted PS-depleted plasma to similar levels of PS-direct.CONCLUSIONOur data are in disagreement with a report that monomeric purified PS has little PS-direct and that only monomeric PS exists in plasma. We find that both affinity-purified and plasma PS exist as monomers and multimers with similar PS-direct.

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Drug(Targets)	Indications	Global Highest Phase

Interferon alpha-2b(Biolex Therapeutics, Inc.) ( IFNAR )	Hepatitis C More	Discontinued
BLX-155 ( PLG )	Venous Thrombosis More	Discontinued
HX-8 ( HSV antigen )	Herpes Simplex More	Pending
Interferon alpha-2b controlled release(Biolex Therapeutics, Inc.) ( IFNAR )	Hepatitis C, Chronic More	Pending
NK4 (Kringle Pharma) ( HGF x c-Met )	Neoplasms More	Pending

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