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 | Hebel | Details |
|---|---|---|
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ISIN: DE0006632003
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ISIN: DE0006632003
Symbol: MOR
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Saaletaler
schrieb am 23.01.12 18:38:03
Beitrag Nr.251
(42.634.650)
Antwort
Zitat
Zitat von eck64Was aber sicher nicht ausgewertet sein kann:
http://clinicaltrials.gov/ct2/show/NCT00786201?term=NCT00786…
A Study to Evaluate the Safety and Effectiveness of CNTO 888 Administered Intravenously (IV) in Subjects With Idiopathic Pulmonary Fibrosis (IPF)
Die Studie läuft noch, ist doopel-blind und placebo-kontrolliert. Da weiß man eigentlich nichts vor Abschluss.
Die IPF-Studie dosiert sogar nur alle 4 Wochen. Damit dürfte dort das gleiche passieren wie bei den 3 Tumor-Studien: Der CCL2-Pegel sinkt für einen Tag ab, um sich dann rasch sogar auf ein höheres Niveau zu erholen. Es wäre also m.E. sehr verwunderlich, wenn die CNTO888-Therapie in der IPF-Studie Wirksamkeit nachweisen könnte.
Zumal die IPF-P2-Studie bereits Ende 2008 gestartet wurde und man offenbar erst in 2011 bemerkt hat, dass die CCL2-Blockierung nur etwa einen Tag lang funktioniert.
Ein wirklich fundiertes Urteil maße ich mir nicht an. Trotzdem klingt das Vorgehen für mich etwas dilettantisch. Zumal Noxxon, die ebenfalls anti-CCL2-Studien laufen haben, schon seit der Präklinik alle 2 Tage (!) dosiert und das Problem der Hochregulierung damit (laut Präsentationen) gelöst haben.
Zitat von eck64Vielleicht machen die bei Janssen noch eine subkutan-Studie mit täglich einer kleinen Dosis? Um nicht ganz ohne dazustehen?
Die Frage ist, ob man dann wieder mit einer P1 anfangen muss, da in allen 4 bekannten Studien nur mit 14-täglicher Dosierung (oder länger) getestet wurde. Zumindest wäre es einen Versuch wert, denn bislang ist man an der (dauerhaften) CCL2-Blockierung gescheitert. Das Target kann ja trotzdem sehr attraktiv bleiben, wie verschiedenste Präklinik-Ergebnisse gezeigt haben.
Grüße
evotecci
schrieb am 23.01.12 20:13:37
Beitrag Nr.252
(42.635.266)
Antwort
Zitat
Antwort auf Beitrag Nr.:
42.634.650 von Saaletaler am 23.01.12
18:38:03Die Frage ist, ob man dann wieder mit einer
P1 anfangen muss, da in allen 4 bekannten Studien nur mit
14-täglicher Dosierung (oder länger) getestet wurde.
Das ist sicherlich der Fall, weil es sich um ein völlig neues Dosierungsschema handeln würde.
Bei täglicher/2täglicher Dosierung müsste man wieder verschiedene Dosen studieren, um zu erkennen, bei welcher Dosis die beste Balance zwischen Sicherheit/Verträglichkeit u. voraussichtlicher Wirksamkeit (in dem Fall CCL2 Blockade) besteht.
Deine Argumentation bezügl. der IPF Studie kann ich gut nachvollziehen!
Das ist sicherlich der Fall, weil es sich um ein völlig neues Dosierungsschema handeln würde.
Bei täglicher/2täglicher Dosierung müsste man wieder verschiedene Dosen studieren, um zu erkennen, bei welcher Dosis die beste Balance zwischen Sicherheit/Verträglichkeit u. voraussichtlicher Wirksamkeit (in dem Fall CCL2 Blockade) besteht.
Deine Argumentation bezügl. der IPF Studie kann ich gut nachvollziehen!
eck64
schrieb am 08.02.12 14:22:11
Beitrag Nr.253
(42.719.323)
Bewertung: 2 x
Antwort
Zitat
BPS804 läuft mittlerweile in mindestens 3 P2-Studien.
Für BPS804 als Morphosys-AK spricht sehr vieles, auch wenn es keine offizielle Bestätigung gibt.
Hier jedenfalls ein link zur zunehmenden Bedeutung von BPS804 für Novartis:
Published on 16 November 2011
http://www.datamonitor.com/store/News/tarsa_novartiss_fractu…
Tarsa: Novartis's fracture data do not bode well for Ostora
Novartis's SMC021 has failed to meet its main fracture reduction endpoint in a Phase III trial for osteoporosis. This is a setback for other firms aiming to stimulate the class's growth, such as Tarsa, which may now struggle to bring its pipeline drug Ostora to the market. Novartis is expected to discontinue the development of SMC021 and focus on more attractive targets for osteoporosis treatment.
....
The failure of SMC021 to meet its endpoints is a major setback for the companies aiming to stimulate the growth of the calcitonin class. Datamonitor believes that it is unlikely that Novartis will continue the development of SMC021, and that it will instead focus its resources on developing more attractive targets for osteoporosis, such as its Phase II antisclerostin candidate BPS-804.
xxxxxxxxxxxxxxxxx
http://www.medpagetoday.com/MeetingCoverage/ASHHematology/30…
ASH: Sclerostin Levels Elevated in Multiple Myeloma
This report is part of a 12-month Clinical Context series.
By Ed Susman, Contributing Writer, MedPage Today
Published: December 14, 2011
.... One of the characteristic findings in multiple myeloma is osteolytic bone disease.
Eda noted that sclerostin strongly inhibits osteoblasts -- key ingredients in building bones -- and also stimulates osteoclastogenesis, which tends to lead to bone destruction.
"We see that sclerostin is a really good target for multiple myeloma," Eda said.
.... They also studied the effect of sclerostin on growth and survival of multiple myeloma cells in vitro. "Exogenous recombinant sclerostin did not affect multiple myeloma cell viability, survival, or proliferation," Eda reported.
The researchers noted that sclerostin concentrations similar to those detected in multiple myeloma patients' plasma inhibited osteoblasts and increased osteoclasts and bone pit formation. Eda said that anti-sclerostin antibodies appeared to reverse the bone damage.
"These data demonstrate that increased sclerostin levels in multiple myeloma patients inhibit osteoblastogenesis and stimulate osteoclastogenesis," he suggested. "Taken together, sclerostin may be a good target to inhibit myeloma bone disease and help restore normal bone homeostasis."
xxxxxxxxxxxxxxxxxx
The Journal of Clinical Endocrinology & Metabolism January 11, 2012 jc.2011-2332
Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives
.... Whereas recombinant human PTH treatment is being revisited with different formulations and attempts to regulate endogenous PTH secretion via the calcium-sensing receptor, antibodies to sclerostin and dickkopf1 are currently in clinical trials and may prove to be even more efficient at increasing bone mass, possibly independent of bone turnover. Each of these anabolic approaches has its own limitations and safety issues, but the prospects of effective anabolic therapy for osteoporosis are indeed bright.
DKK1 ist BHQ880 von Novartis, ein HuCAL-AK, Antisclerostin ist BPS80e von Novartis, wahrscheinlich ebenfalls HuCAL-AK.
xxxxxxxxxxxxxxxxxxxxxx
Auf gehts Novartis, raus mit den ersten Ergebnissen des Proof of concept und Bekenntnis zum Programm.
Für BPS804 als Morphosys-AK spricht sehr vieles, auch wenn es keine offizielle Bestätigung gibt.
Hier jedenfalls ein link zur zunehmenden Bedeutung von BPS804 für Novartis:
Published on 16 November 2011
http://www.datamonitor.com/store/News/tarsa_novartiss_fractu…
Tarsa: Novartis's fracture data do not bode well for Ostora
Novartis's SMC021 has failed to meet its main fracture reduction endpoint in a Phase III trial for osteoporosis. This is a setback for other firms aiming to stimulate the class's growth, such as Tarsa, which may now struggle to bring its pipeline drug Ostora to the market. Novartis is expected to discontinue the development of SMC021 and focus on more attractive targets for osteoporosis treatment.
....
The failure of SMC021 to meet its endpoints is a major setback for the companies aiming to stimulate the growth of the calcitonin class. Datamonitor believes that it is unlikely that Novartis will continue the development of SMC021, and that it will instead focus its resources on developing more attractive targets for osteoporosis, such as its Phase II antisclerostin candidate BPS-804.
xxxxxxxxxxxxxxxxx
http://www.medpagetoday.com/MeetingCoverage/ASHHematology/30…
ASH: Sclerostin Levels Elevated in Multiple Myeloma
This report is part of a 12-month Clinical Context series.
By Ed Susman, Contributing Writer, MedPage Today
Published: December 14, 2011
.... One of the characteristic findings in multiple myeloma is osteolytic bone disease.
Eda noted that sclerostin strongly inhibits osteoblasts -- key ingredients in building bones -- and also stimulates osteoclastogenesis, which tends to lead to bone destruction.
"We see that sclerostin is a really good target for multiple myeloma," Eda said.
.... They also studied the effect of sclerostin on growth and survival of multiple myeloma cells in vitro. "Exogenous recombinant sclerostin did not affect multiple myeloma cell viability, survival, or proliferation," Eda reported.
The researchers noted that sclerostin concentrations similar to those detected in multiple myeloma patients' plasma inhibited osteoblasts and increased osteoclasts and bone pit formation. Eda said that anti-sclerostin antibodies appeared to reverse the bone damage.
"These data demonstrate that increased sclerostin levels in multiple myeloma patients inhibit osteoblastogenesis and stimulate osteoclastogenesis," he suggested. "Taken together, sclerostin may be a good target to inhibit myeloma bone disease and help restore normal bone homeostasis."
xxxxxxxxxxxxxxxxxx
The Journal of Clinical Endocrinology & Metabolism January 11, 2012 jc.2011-2332
Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives
.... Whereas recombinant human PTH treatment is being revisited with different formulations and attempts to regulate endogenous PTH secretion via the calcium-sensing receptor, antibodies to sclerostin and dickkopf1 are currently in clinical trials and may prove to be even more efficient at increasing bone mass, possibly independent of bone turnover. Each of these anabolic approaches has its own limitations and safety issues, but the prospects of effective anabolic therapy for osteoporosis are indeed bright.
DKK1 ist BHQ880 von Novartis, ein HuCAL-AK, Antisclerostin ist BPS80e von Novartis, wahrscheinlich ebenfalls HuCAL-AK.
xxxxxxxxxxxxxxxxxxxxxx
Auf gehts Novartis, raus mit den ersten Ergebnissen des Proof of concept und Bekenntnis zum Programm.
eck64
schrieb am 15.02.12 22:07:48
Beitrag Nr.254
(42.757.506)
Bewertung: 3 x
Antwort
Zitat
Antwort auf Beitrag Nr.:
42.463.361 von eck64 am 10.12.11
09:34:05Ich habe ein Präklinik-Programm von Merck jetzt
sicher als Morphosys-Antikörper identifiziert:
Ein 18-seitiges PDF von Merck über den Anti-PCSK9 Antikörper 1B20 von Merck:
2012; 8(3):310-327. doi: 10.7150/ijbs.3524
Research Paper
An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising therapeutic target for treating coronary heart disease. We report a novel antibody 1B20 that binds to PCSK9 with sub-nanomolar affinity and antagonizes PCSK9 function in-vitro. In CETP/LDLR-hemi mice two successive doses of 1B20, administered 14 days apart at 3 or 10 mpk, induced dose dependent reductions in LDL-cholesterol (≥ 25% for 7-14 days) that correlated well with the extent of PCSK9 occupancy by the antibody. In addition, 1B20 induces increases in total plasma antibody-bound PCSK9 levels and decreases in liver mRNA levels of SREBP-regulated genes PCSK9 and LDLR, with a time course that parallels decreases in plasma LDL-cholesterol (LDL-C). Consistent with this observation in mice, in statin-responsive human primary hepatocytes, 1B20 lowers PCSK9 and LDLR mRNA levels and raises serum steady-state levels of antibody-bound PCSK9. In addition, mRNA levels of several SREBP regulated genes involved in cholesterol and fatty-acid synthesis including ACSS2, FDPS, IDI1, MVD, HMGCR, and CYP51A1 were decreased significantly with antibody treatment of primary human hepatocytes. In rhesus monkeys, subcutaneous (SC) dosing of 1B20 dose-dependently induces robust LDL-C lowering (maximal ~70%), which is correlated with increases in target engagement and total antibody-bound PCSK9 levels. Importantly, a combination of 1B20 and Simvastatin in dyslipidemic rhesus monkeys reduced LDL-C more than either agent alone, consistent with a mechanism of action that predicts additive effects of an-ti-PCSK9 agents with statins. Our results suggest that antibodies targeting PCSK9 could provide patients powerful LDL lowering efficacy on top of statins, and lower cardiovascular risk.
.....
In summary, the data presented here suggest that antibodies targeting PCSK9 could provide pa-tients powerful LDL lowering efficacy on top of statins and would be expected to lower cardiovascu-lar risk. Our findings in human primary hepatocytes demonstrate the critical role of liver cells and provide new insight in PCSK9 biology. The anti-PCSK9 anti-body 1B20 can serve as a valuable tool in further elu-cidating the mechanism of action of PCSK9. Finally, the results from this study will help in the design of next generation PCSK9 inhibitors and clinical trials.
.....
Materials and Methods
Isolation of anti-PCSK9 antibody 1B20
The human combinatorial antibody HuCAL GOLD phage display libraries were panned against recombinant human PCSK9-V5-His protein immobi-lized on Nunc Maxisorp plates. Initial expression and purification of 1B20 Fab was performed as previously described(28). Full 1B20 IgG2m4 was expressed and purified from CHO cells.
.....
Und wann geht es ab in die Klinik mit 1B20?
Ein 18-seitiges PDF von Merck über den Anti-PCSK9 Antikörper 1B20 von Merck:
2012; 8(3):310-327. doi: 10.7150/ijbs.3524
Research Paper
An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising therapeutic target for treating coronary heart disease. We report a novel antibody 1B20 that binds to PCSK9 with sub-nanomolar affinity and antagonizes PCSK9 function in-vitro. In CETP/LDLR-hemi mice two successive doses of 1B20, administered 14 days apart at 3 or 10 mpk, induced dose dependent reductions in LDL-cholesterol (≥ 25% for 7-14 days) that correlated well with the extent of PCSK9 occupancy by the antibody. In addition, 1B20 induces increases in total plasma antibody-bound PCSK9 levels and decreases in liver mRNA levels of SREBP-regulated genes PCSK9 and LDLR, with a time course that parallels decreases in plasma LDL-cholesterol (LDL-C). Consistent with this observation in mice, in statin-responsive human primary hepatocytes, 1B20 lowers PCSK9 and LDLR mRNA levels and raises serum steady-state levels of antibody-bound PCSK9. In addition, mRNA levels of several SREBP regulated genes involved in cholesterol and fatty-acid synthesis including ACSS2, FDPS, IDI1, MVD, HMGCR, and CYP51A1 were decreased significantly with antibody treatment of primary human hepatocytes. In rhesus monkeys, subcutaneous (SC) dosing of 1B20 dose-dependently induces robust LDL-C lowering (maximal ~70%), which is correlated with increases in target engagement and total antibody-bound PCSK9 levels. Importantly, a combination of 1B20 and Simvastatin in dyslipidemic rhesus monkeys reduced LDL-C more than either agent alone, consistent with a mechanism of action that predicts additive effects of an-ti-PCSK9 agents with statins. Our results suggest that antibodies targeting PCSK9 could provide patients powerful LDL lowering efficacy on top of statins, and lower cardiovascular risk.
.....
In summary, the data presented here suggest that antibodies targeting PCSK9 could provide pa-tients powerful LDL lowering efficacy on top of statins and would be expected to lower cardiovascu-lar risk. Our findings in human primary hepatocytes demonstrate the critical role of liver cells and provide new insight in PCSK9 biology. The anti-PCSK9 anti-body 1B20 can serve as a valuable tool in further elu-cidating the mechanism of action of PCSK9. Finally, the results from this study will help in the design of next generation PCSK9 inhibitors and clinical trials.
.....
Materials and Methods
Isolation of anti-PCSK9 antibody 1B20
The human combinatorial antibody HuCAL GOLD phage display libraries were panned against recombinant human PCSK9-V5-His protein immobi-lized on Nunc Maxisorp plates. Initial expression and purification of 1B20 Fab was performed as previously described(28). Full 1B20 IgG2m4 was expressed and purified from CHO cells.
.....
Und wann geht es ab in die Klinik mit 1B20?
eck64
schrieb am 15.02.12 22:09:36
Beitrag Nr.255
(42.757.519)
Antwort
Zitat
Antwort auf Beitrag Nr.:
42.757.506 von eck64 am 15.02.12
22:07:48Den link vergessen:
Ein 18-seitiges PDF von Merck über den Anti-PCSK9 Antikörper 1B20 von Merck:
http://biolsci.org/v08p0310.pdf
An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes
Ein 18-seitiges PDF von Merck über den Anti-PCSK9 Antikörper 1B20 von Merck:
http://biolsci.org/v08p0310.pdf
An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes
SLGramann
schrieb am 16.02.12 09:03:08
Beitrag Nr.256
(42.758.668)
Antwort
Zitat
Antwort auf Beitrag Nr.:
42.757.506 von eck64 am 15.02.12
22:07:48Eck, danke, schöner Fund.
Vermutet wurde das ja schon eine Weile. Ich glaube Pathfinder hatte die erste Verbindung zu Merck ausgegraben.
Eigentlich ein sehr spannender Kandidat.
Sehr schade, dass Regeneron und Sanofi zeitlich so weit voraus sind:
REGN727, an antibody to Proprotein Convertase Substilisin/Kexin type 9 (PCSK9), a novel target for LDL cholesterol ("bad cholesterol") reduction, is in Phase 2 studies. During 2011, three Phase 2 studies with subcutaneous regimens of REGN727 were initiated: (1) a randomized, double-blind, multi-dose, placebo controlled, 75-patient trial in patients with heterozygous familial hypercholesterolemia (heFH), (2) a randomized, double-blind, multi-dose, placebo controlled, 90-patient trial in combination with atorvastatin in patients with primary hypercholesterolemia, and (3) a randomized, double-blind, multi-dose, placebo controlled, 180-patient trial in combination with atorvastatin in patients with primary hypercholesterolemia and on stable doses of atorvastatin. The primary endpoint of each Phase 2 study is the change in LDL cholesterol from baseline compared to placebo over the study period.
Vermutet wurde das ja schon eine Weile. Ich glaube Pathfinder hatte die erste Verbindung zu Merck ausgegraben.
Eigentlich ein sehr spannender Kandidat.
Sehr schade, dass Regeneron und Sanofi zeitlich so weit voraus sind:
REGN727, an antibody to Proprotein Convertase Substilisin/Kexin type 9 (PCSK9), a novel target for LDL cholesterol ("bad cholesterol") reduction, is in Phase 2 studies. During 2011, three Phase 2 studies with subcutaneous regimens of REGN727 were initiated: (1) a randomized, double-blind, multi-dose, placebo controlled, 75-patient trial in patients with heterozygous familial hypercholesterolemia (heFH), (2) a randomized, double-blind, multi-dose, placebo controlled, 90-patient trial in combination with atorvastatin in patients with primary hypercholesterolemia, and (3) a randomized, double-blind, multi-dose, placebo controlled, 180-patient trial in combination with atorvastatin in patients with primary hypercholesterolemia and on stable doses of atorvastatin. The primary endpoint of each Phase 2 study is the change in LDL cholesterol from baseline compared to placebo over the study period.
eck64
schrieb am 16.02.12 09:25:27
Beitrag Nr.257
(42.758.761)
Antwort
Zitat
Antwort auf Beitrag Nr.:
42.758.668 von SLGramann am 16.02.12
09:03:08Genau,
es war klar, das Merck ein Patent zu PCSK9 und Therapieoptionen mit Antikörpern besitzt, aber Patente hängen schon mal luftleer im Raum. Pathfinder hatte früher das target ins Spiel gebracht, deshalb habe ich auch ab und an nach PCSK9 und Merck gescreent.
Das pdf zeigt nun: Es gibt einen HuCAL mAB namen 1B20 mit dem sehr intensiv in präklinischen Versuchen gearbeitet wurde und der dargestellten Studienergebnissen entnehme ich einen gewissen Optimismus dem Programm gegenüber.
Was sicher stimmt: Auch hier gibts Wettbewerber mit zeitlichem Vorsprung. Wenn Merck seine Präklinik nicht herschenken will, dann müssen sie schleunigst in die Klinik gehen.
Wenn sie beschliessen gegen REGN727 nicht anstinken zu können, dann wird 1B20 in der Schublade verschwinden.
es war klar, das Merck ein Patent zu PCSK9 und Therapieoptionen mit Antikörpern besitzt, aber Patente hängen schon mal luftleer im Raum. Pathfinder hatte früher das target ins Spiel gebracht, deshalb habe ich auch ab und an nach PCSK9 und Merck gescreent.
Das pdf zeigt nun: Es gibt einen HuCAL mAB namen 1B20 mit dem sehr intensiv in präklinischen Versuchen gearbeitet wurde und der dargestellten Studienergebnissen entnehme ich einen gewissen Optimismus dem Programm gegenüber.
Was sicher stimmt: Auch hier gibts Wettbewerber mit zeitlichem Vorsprung. Wenn Merck seine Präklinik nicht herschenken will, dann müssen sie schleunigst in die Klinik gehen.
Wenn sie beschliessen gegen REGN727 nicht anstinken zu können, dann wird 1B20 in der Schublade verschwinden.
yok
schrieb am 16.02.12 18:58:03
Beitrag Nr.258
(42.762.664)
Bewertung: 1 x
Antwort
Zitat
Antwort auf Beitrag Nr.:
42.758.761 von eck64 am 16.02.12
09:25:27Der Kandidat ist bereits in der Schublade
verschwunden, du hast es ja schon zitiert und hervorgehoben:
The anti-PCSK9 anti-body 1B20 can serve as a valuable tool in further elu-cidating the mechanism of action of PCSK9. Finally, the results from this study will help in the design of next generation PCSK9 inhibitors and clinical trials.
Übersetzt: der Kandidat ist tot, aber wir publizieren unsere Arbeit wenigstens noch.
Ich glaube, dass jeder namhafte Pharma einen anti-PCSK9 laufen hat.
The anti-PCSK9 anti-body 1B20 can serve as a valuable tool in further elu-cidating the mechanism of action of PCSK9. Finally, the results from this study will help in the design of next generation PCSK9 inhibitors and clinical trials.
Übersetzt: der Kandidat ist tot, aber wir publizieren unsere Arbeit wenigstens noch.
Ich glaube, dass jeder namhafte Pharma einen anti-PCSK9 laufen hat.
eck64
schrieb am 23.02.12 09:14:13
Beitrag Nr.259
(42.793.669)
Antwort
Zitat
Es fehlt noch:
LFG316 mit 3. P2-Studie.
CNTO3157 ist abgeschlossen
(Gantenerumab und MOR103-MS-Studie mit immer mehr beteiligten Kliniken)
Gutes gelingen bicypapa beim restaurieren.
Saaletaler
schrieb am 19.03.12 16:58:23
Beitrag Nr.260
(42.924.198)
Antwort
Zitat
Neuigkeiten von Carlumab (= CNTO 888)
----------------------------------------------------------
Puchalski et al. (2012): A novel preclinical study in cynomolgus monkeys examining CCL2 production rate and kinetic profile after escalating dose administration of anti-CCL2 human monoclonal antibody carlumab (CNTO 888)
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=28…
Purpose: Carlumab (CNTO 888) is a human IgG1κ monoclonal antibody that binds CCL2 with high affinity in vitro. The objective of this study was to estimate the production rate and kinetic profile of CCL2 following escalating doses of carlumab with the goal of predicting the dose that would maintain suppression of free CCL2 throughout the dosing interval.
Patients and methods: Eighteen male cynomolgus (cyno) monkeys were allocated to 3 treatment groups: low dose [LD], fixed dose [FD] or high dose [HD], (6 per group) and received various doses of carlumab weekly (qw) or every other week (q2w) over a 6-week study period. LD received a starting dose of 1 mg/kg qw for 3 weeks, followed by an increase to 5 mg/kg qw for 3 more weeks. FD received 15 mg/kg q2w. HD received a starting dose of 12.5 mg/kg qw for 2 weeks, increased to 25 mg/kg qw for 2 weeks and then increased to 50 mg/kg qw for the final 2 weeks. Serial serum samples were collected and analyzed using immunoassay methods to determine the concentrations of free CCL2, carlumab-CCL2 complex and carlumab.
Results: Based on the slope of the carlumab-CCL2 complex concentration-time profile immediately after dosing, the production rate of CCL2 did not appear to significantly change as the dose of carlumab was increased from 1 to 50 mg/kg. Increasing the dose from 1 to 25 mg/kg resulted in a dose-proportional increase in the carlumab-CCL2 complex; however, increasing the dose from 25 to 50 mg/kg did not result in further increase of the carlumab-CCL2 complex, suggesting that a very high proportion of the CCL2 in the serum was bound by carlumab at a dose of 25 mg/kg. In LD, the concentration of free CCL2 was lower compared with the higher dose regimens. Free CCL2 increased after the carlumab dose increased from 12.5 to 25 mg/kg but decreased after a dose increase from 25 to 50 mg/kg. This finding suggested that a dose >50 mg/kg would be required to maintain suppression of free CCL2 throughout the dosing interval due to the large amount of free CCL2 that continuously disassociates from the complex. After a dose of 15 mg/kg every 2 weeks, carlumab, free CCL2 and carlumab-CCL2 complex concentration-time profiles demonstrated similar results to those observed in cancer patients.
Conclusions: In this novel comprehensive PK/PD study in cyno monkeys, the production rates of CCL2 did not appear to correlate with increasing doses of carlumab and suggested that a dose of >50 mg/kg every week would be needed to continuously maintain suppression of free CCL2 below baseline levels. This study design demonstrated that the cyno monkey is a relevant species in which to examine the binding of carlumab on CCL2. This study methodology could be applied to test other therapeutic monoclonal antibodies targeting soluble ligands in cyno monkeys for which the cyno homolog demonstrates cross reactivity.
----------------------------------------------------------
J&J testet also weiterhin präklinisch mit CNTO-888. Nicht klar ist mir, ob die Dosierungen bei den Affen 1:1 auf den Menschen zu übertragen sind. In den P2-Studien hat J&J bislang maximal 15 mg/kg alle 2 bis 4 Wochen dosiert. Nun steht eine Dosierung von >50 mg/kg jede Woche als Empfehlung im Raum (sofern die Daten 1:1 gelten).
Sind das noch realistische Größenordnungen für mAb-Behandlungen an Menschen? Scheint mir ziemlich heftig. Wie auch immer, falls CNTO 888 weiter leben soll, dürften neue P1-Studien mit deutlich erhöhten Dosen anstehen.
----------------------------------------------------------
Puchalski et al. (2012): A novel preclinical study in cynomolgus monkeys examining CCL2 production rate and kinetic profile after escalating dose administration of anti-CCL2 human monoclonal antibody carlumab (CNTO 888)
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=28…
Purpose: Carlumab (CNTO 888) is a human IgG1κ monoclonal antibody that binds CCL2 with high affinity in vitro. The objective of this study was to estimate the production rate and kinetic profile of CCL2 following escalating doses of carlumab with the goal of predicting the dose that would maintain suppression of free CCL2 throughout the dosing interval.
Patients and methods: Eighteen male cynomolgus (cyno) monkeys were allocated to 3 treatment groups: low dose [LD], fixed dose [FD] or high dose [HD], (6 per group) and received various doses of carlumab weekly (qw) or every other week (q2w) over a 6-week study period. LD received a starting dose of 1 mg/kg qw for 3 weeks, followed by an increase to 5 mg/kg qw for 3 more weeks. FD received 15 mg/kg q2w. HD received a starting dose of 12.5 mg/kg qw for 2 weeks, increased to 25 mg/kg qw for 2 weeks and then increased to 50 mg/kg qw for the final 2 weeks. Serial serum samples were collected and analyzed using immunoassay methods to determine the concentrations of free CCL2, carlumab-CCL2 complex and carlumab.
Results: Based on the slope of the carlumab-CCL2 complex concentration-time profile immediately after dosing, the production rate of CCL2 did not appear to significantly change as the dose of carlumab was increased from 1 to 50 mg/kg. Increasing the dose from 1 to 25 mg/kg resulted in a dose-proportional increase in the carlumab-CCL2 complex; however, increasing the dose from 25 to 50 mg/kg did not result in further increase of the carlumab-CCL2 complex, suggesting that a very high proportion of the CCL2 in the serum was bound by carlumab at a dose of 25 mg/kg. In LD, the concentration of free CCL2 was lower compared with the higher dose regimens. Free CCL2 increased after the carlumab dose increased from 12.5 to 25 mg/kg but decreased after a dose increase from 25 to 50 mg/kg. This finding suggested that a dose >50 mg/kg would be required to maintain suppression of free CCL2 throughout the dosing interval due to the large amount of free CCL2 that continuously disassociates from the complex. After a dose of 15 mg/kg every 2 weeks, carlumab, free CCL2 and carlumab-CCL2 complex concentration-time profiles demonstrated similar results to those observed in cancer patients.
Conclusions: In this novel comprehensive PK/PD study in cyno monkeys, the production rates of CCL2 did not appear to correlate with increasing doses of carlumab and suggested that a dose of >50 mg/kg every week would be needed to continuously maintain suppression of free CCL2 below baseline levels. This study design demonstrated that the cyno monkey is a relevant species in which to examine the binding of carlumab on CCL2. This study methodology could be applied to test other therapeutic monoclonal antibodies targeting soluble ligands in cyno monkeys for which the cyno homolog demonstrates cross reactivity.
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J&J testet also weiterhin präklinisch mit CNTO-888. Nicht klar ist mir, ob die Dosierungen bei den Affen 1:1 auf den Menschen zu übertragen sind. In den P2-Studien hat J&J bislang maximal 15 mg/kg alle 2 bis 4 Wochen dosiert. Nun steht eine Dosierung von >50 mg/kg jede Woche als Empfehlung im Raum (sofern die Daten 1:1 gelten).
Sind das noch realistische Größenordnungen für mAb-Behandlungen an Menschen? Scheint mir ziemlich heftig. Wie auch immer, falls CNTO 888 weiter leben soll, dürften neue P1-Studien mit deutlich erhöhten Dosen anstehen.
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