CytomX - ein bahnbrechender Ansatz in der Tumortherapie (Seite 94)
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Für die Präklinik gibt es nun genug "Beweise". Ob es im Menschen dann wirklich funktioniert und wie gut muss sich noch zeigen...
Noch 197 Tage bis zum Release der ASCO abstracts 2018. Noch 213 Tage bis zum Meeting. Da sollten wir dann schlauer sein, zumindest bezüglich CX-072...
Für die Präklinik gibt es nun genug "Beweise". Ob es im Menschen dann wirklich funktioniert und wie gut muss sich noch zeigen...
Noch 197 Tage bis zum Release der ASCO abstracts 2018. Noch 213 Tage bis zum Meeting. Da sollten wir dann schlauer sein, zumindest bezüglich CX-072...
Der Vollständigkeit halber noch das Poster zur Pharmakokinetik des CX-2029 -> http://cytomx.com/wp-content/uploads/2017/10/CX-2029_PK_AACR…
Zur Optimierung des anti-CD71-PDC aus der Kooperation mit AbbVie -> http://cytomx.com/wp-content/uploads/2017/10/CX-2029_Lead-Se…
Das zu lesen macht Spaß -> http://cytomx.com/wp-content/uploads/2017/10/CytomX-PbTCB_AA…
Antwort auf Beitrag Nr.: 56.051.112 von StefanR am 29.10.17 08:16:22Wenn das so kommt würde ich das ala einen eher schlechten Ausgang bezeichnen, denn dann hätte die Probody Technologie nicht wirklich gegriffen. Ich persönlich erhoffe mir klare Vorteile sowohl in Kombi als auch Mono.
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Antwort auf Beitrag Nr.: 56.050.494 von Joschka Schröder am 28.10.17 21:43:19@joschka, es stimmt daß bms (zeitverzögert) die Kooperation erwähnt, direkt nach dem Mega-Abschluß (zumindest für cytomx vom upfront volumen her) wurde in Quartalsberichten von bms nichts berichtet, deswegen meine Vermutung der Diskretion.
Ganz allgemein bin ich gespannt, wie sich die beiden ctla-4 AB von bms im gegenseitigen Wettbewerb entwickeln.
Im günstigen Fall für bms kommt Monotherapie non- fucosylated, und Kombi für den ctla-4Probody raus.
Ganz allgemein bin ich gespannt, wie sich die beiden ctla-4 AB von bms im gegenseitigen Wettbewerb entwickeln.
Im günstigen Fall für bms kommt Monotherapie non- fucosylated, und Kombi für den ctla-4Probody raus.
Antwort auf Beitrag Nr.: 56.049.834 von StefanR am 28.10.17 18:59:35
In der Q3-Konferenz von Bristol Myers hieß es "And the second is the Probody technology that we're looking at with our partner, CytomX, again, that looks very exciting and we hope to begin clinical trials in that very soon. ... I do believe that they have the potential – just like CTLA-4 is foundational to us now, they have the potential to offer that kind of benefit to patients down the road."
Ich halte das für ausreichend. Zum jetzigen Zeitpunkt gibt es da eigentlich nicht mehr zu kommunizieren. Mit dem Eintritt in die klinische Testung ist wohl zu Jahresbeginn zu rechnen.
Zitat von StefanR: Die Kooperation von amgen mit cytomx ist für amgen so bedeutend, daß sie die Vereinbarung im CC erwähnen, im Gegensatz zu Bristol myers, die die cytomx Kooperation eher wenig kommentiert hatten (Diskretionsgründe?).
In der Q3-Konferenz von Bristol Myers hieß es "And the second is the Probody technology that we're looking at with our partner, CytomX, again, that looks very exciting and we hope to begin clinical trials in that very soon. ... I do believe that they have the potential – just like CTLA-4 is foundational to us now, they have the potential to offer that kind of benefit to patients down the road."
Ich halte das für ausreichend. Zum jetzigen Zeitpunkt gibt es da eigentlich nicht mehr zu kommunizieren. Mit dem Eintritt in die klinische Testung ist wohl zu Jahresbeginn zu rechnen.
Aus dem conference call von amgen third quarter 2017
„Turning to our bispecific T cell engager programs, we recently announced the collaboration with CytomX to expand our immuno-oncology capabilities with an additional and complementary bispecific technology. As part of the agreement, we will co-develop a T cell engaging bispecific antibody against epithelial growth factor receptor, or EGFR, employing their Probody technology. And we've also have exclusive rights to develop up to three additional undisclosed targets.
In our BiTE platform, we have several extended half-life BiTEs moving into Phase 1: AMG 673, directed against CD33 for AML, AMG 596 against EGFR Variant III for glioblastoma and AMG 701 against BCMA for multiple myeloma. Importantly, we have also seen data recently that markedly increased our confidence that BiTEs can have impressive activity in solid tumors.“
Die Kooperation von amgen mit cytomx ist für amgen so bedeutend, daß sie die Vereinbarung im CC erwähnen, im Gegensatz zu Bristol myers, die die cytomx Kooperation eher wenig kommentiert hatten (Diskretionsgründe?).
Weiterhin ist das Interesse von amgen in der Entwicklung von bispecific antibodies mit längerer HWZ interessant und zielführend, da hierdurch zum einen die compliance erhöht werden kann ( vgl blincyto 4 Wochen Infusion).
Weiterhin ist eine verlängerte HWZ speziell für probodies interessant, die zur Demaskierung im Tumorgewebe und damit Scharfschaltung eine ausreichend lange systemische HWZ benötigen.
LG
StefanR
„Turning to our bispecific T cell engager programs, we recently announced the collaboration with CytomX to expand our immuno-oncology capabilities with an additional and complementary bispecific technology. As part of the agreement, we will co-develop a T cell engaging bispecific antibody against epithelial growth factor receptor, or EGFR, employing their Probody technology. And we've also have exclusive rights to develop up to three additional undisclosed targets.
In our BiTE platform, we have several extended half-life BiTEs moving into Phase 1: AMG 673, directed against CD33 for AML, AMG 596 against EGFR Variant III for glioblastoma and AMG 701 against BCMA for multiple myeloma. Importantly, we have also seen data recently that markedly increased our confidence that BiTEs can have impressive activity in solid tumors.“
Die Kooperation von amgen mit cytomx ist für amgen so bedeutend, daß sie die Vereinbarung im CC erwähnen, im Gegensatz zu Bristol myers, die die cytomx Kooperation eher wenig kommentiert hatten (Diskretionsgründe?).
Weiterhin ist das Interesse von amgen in der Entwicklung von bispecific antibodies mit längerer HWZ interessant und zielführend, da hierdurch zum einen die compliance erhöht werden kann ( vgl blincyto 4 Wochen Infusion).
Weiterhin ist eine verlängerte HWZ speziell für probodies interessant, die zur Demaskierung im Tumorgewebe und damit Scharfschaltung eine ausreichend lange systemische HWZ benötigen.
LG
StefanR
Der initiale Kursrückgang in NY ist mir ein Rätsel, da muss jemand etwas mißverstanden haben. Wenn es heißt "BMS-986249 having the least effects", so bezieht sich das ausschließlich auf die systemischen Nebenwirkungen!
Antwort auf Beitrag Nr.: 55.961.235 von Ville7 am 16.10.17 19:44:25
Mittlerweile ist das Abstract online, der Probody hat wie erwartet und erhofft das mit Abstand beste Sicherheitsprofil:
Presenter/Authors
Karen D. Price, Frank Simutis, Anthony Fletcher, Lila Ramaiah, Rima Srour, John Kozlosky, Jean Sathish, John Engelhardt, Annette Capozzi, James Crona, Courtni Newsome, Jennifer Wheeler, Daniel Szatkowski, Austin Thekkumthala, Bojing Wang, Wendy Freebern, Helen Haggerty, Todd Bunch, Michael Graziano. Bristol-Myers Squibb Co., New Brunswick, NJ
Disclosures
K.D. Price: ; BRISTOL-MYERS SQUIBB CO. F. Simutis: ; Bristol-Myers Squibb Co. A. Fletcher: ; Bristol-Myers Squibb Co. L. Ramaiah: ; Bristol-Myers Squibb Co. R. Srour: ; Bristol-Myers Squibb Co. J. Kozlosky: ; Bristol-Myers Squibb Co. J. Sathish: ; Bristol-Myers Squibb Co. A. Capozzi: ; Bristol-Myers Squibb Co. J. Crona: ; Bristol-Myers Squibb Co. C. Newsome: ; Bristol-Myers Squibb Co. J. Wheeler: ; Bristol-Myers Squibb Co. D. Szatkowski: ; Bristol-Myers Squibb Co. A. Thekkumthala: ; Bristol-Myers Squibb Co. B. Wang: ; Bristol-Myers Squibb Co. W. Freebern: ; Bristol-Myers Squibb Co. H. Haggerty: ; Bristol-Myers Squibb Co. T. Bunch: ; Bristol-Myers Squibb Co. M. Graziano: ; Bristol-Myers Squibb Co.
Abstract
Ipilimumab is a fully human immunoglobulin G1 (IgG1) monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA‑4), an inhibitory receptor expressed on activated effector T cells and regulatory T cells (Treg), that inhibits the binding of CTLA4 to B7 ligands. BMS‑986218 and BMS-986249 are second generation molecules that share the same amino acid sequence and ligand blocking properties as ipilimumab, but are mechanistically distinct. BMS-986218 is non-fucosylated (NF) and has an increased affinity for the activating Fcγ receptor (FcγR, CD16) affording the possibility of increased anti-tumor activity via depletion of Treg in the tumor. In contrast, BMS-986249 is a Probody™ of ipilimumab that has a masking peptide covering the active antigen-binding site of the antibody which is clipped by specific proteases within tumors, exposing the fully active antibody, and potentially offering reduced systemic toxicity liabilities with comparable efficacy to ipilimumab. In 1-month toxicity studies in monkeys (n = 5/sex/group) at weekly doses of 3, 15, or 75 mg/kg IV of BMS-986218 or 10 or 50 mg/kg IV of BMS-986249 or ipilimumab, profound enhancement of peripheral T-cell activation occurred in a dose-dependent manner for all 3 compounds following neoantigen immunization (keyhole limpet hemocyanin [KLH], HIV necessary and enforcing factor [Nef], and HIV group specific antigen [Gag] peptides), consistent with target pharmacology. Consistent with the intended mechanistic differences, peripheral T cell activation was generally increased at corresponding doses of BMS-986218 compared to ipilimumab, and was delayed and reduced in monkeys given BMS-986249. BMS‑986218, ipilimumab, and BMS-986249 were clinically tolerated by monkeys at doses up to 3, 10, and 50 mg/kg, respectively, with generally mild, loose feces in some monkeys and/or minimal body weight decrease. At higher doses, early euthanasia occurred for 1 and 6 monkeys at 15 and 75 mg/kg BMS-986218, respectively, from Days 22-53 and 1 monkey at 50 mg/kg ipilimumab on Day 55 due to profound clinical toxicity. The predominant microscopic finding was generally dose-related lymphohistiocytic inflammation within a variety of tissues at all doses for all compounds, with BMS-986218 resulting in the greatest incidence, severity, and distribution of tissues and BMS-986249 having the least effects. The GI tract (stomach, cecum, and colon) and the kidney were the most severely and consistently affected, whereas additional organs were affected at higher doses. Most changes were partially or fully reversible during an 8-week recovery period with the exceptions of one monkey at 75 mg/kg BMS-986218 and one monkey at 50 mg/kg ipilimumab that were euthanatized on Days 53 or 55 due to unresolved GI toxicity, persistent lymphohistocytic inflammation, and/or unchanged or progressive increases in AST and ALT. Based on the tolerability and generally mild severity of lymphohistiocytic tissue inflammation, the highest non-severely toxic doses (HNSTD) for BMS-986218, ipilimumab, and BMS-986249 in monkeys following 1 month of dosing were 3 mg/kg (mean AUC 0-168h = 11,300 μg•h/mL), 10 mg/kg (AUC[0‑168h] =44,600 µg·h/mL), and 50 mg/kg (AUC[0-168h] =205,000 µg·h/mL), respectively. Overall, these results support the potential of these 2nd generation anti-CTLA4 antibodies to offer an improved risk /benefit profile with increased activity of the NF variant and improved safety of the Probody™ relative to ipilimumab.
Zitat von Ville7: Session LBPO.B14 - Toxicology
LB-B33 / LB-33 - Nonclinical safety evaluation of two distinct second generation variants of anti-CTLA4 monoclonal antibody, ipilimumab, in monkeys
Abstract embargoed at this time.
Mittlerweile ist das Abstract online, der Probody hat wie erwartet und erhofft das mit Abstand beste Sicherheitsprofil:
Presenter/Authors
Karen D. Price, Frank Simutis, Anthony Fletcher, Lila Ramaiah, Rima Srour, John Kozlosky, Jean Sathish, John Engelhardt, Annette Capozzi, James Crona, Courtni Newsome, Jennifer Wheeler, Daniel Szatkowski, Austin Thekkumthala, Bojing Wang, Wendy Freebern, Helen Haggerty, Todd Bunch, Michael Graziano. Bristol-Myers Squibb Co., New Brunswick, NJ
Disclosures
K.D. Price: ; BRISTOL-MYERS SQUIBB CO. F. Simutis: ; Bristol-Myers Squibb Co. A. Fletcher: ; Bristol-Myers Squibb Co. L. Ramaiah: ; Bristol-Myers Squibb Co. R. Srour: ; Bristol-Myers Squibb Co. J. Kozlosky: ; Bristol-Myers Squibb Co. J. Sathish: ; Bristol-Myers Squibb Co. A. Capozzi: ; Bristol-Myers Squibb Co. J. Crona: ; Bristol-Myers Squibb Co. C. Newsome: ; Bristol-Myers Squibb Co. J. Wheeler: ; Bristol-Myers Squibb Co. D. Szatkowski: ; Bristol-Myers Squibb Co. A. Thekkumthala: ; Bristol-Myers Squibb Co. B. Wang: ; Bristol-Myers Squibb Co. W. Freebern: ; Bristol-Myers Squibb Co. H. Haggerty: ; Bristol-Myers Squibb Co. T. Bunch: ; Bristol-Myers Squibb Co. M. Graziano: ; Bristol-Myers Squibb Co.
Abstract
Ipilimumab is a fully human immunoglobulin G1 (IgG1) monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA‑4), an inhibitory receptor expressed on activated effector T cells and regulatory T cells (Treg), that inhibits the binding of CTLA4 to B7 ligands. BMS‑986218 and BMS-986249 are second generation molecules that share the same amino acid sequence and ligand blocking properties as ipilimumab, but are mechanistically distinct. BMS-986218 is non-fucosylated (NF) and has an increased affinity for the activating Fcγ receptor (FcγR, CD16) affording the possibility of increased anti-tumor activity via depletion of Treg in the tumor. In contrast, BMS-986249 is a Probody™ of ipilimumab that has a masking peptide covering the active antigen-binding site of the antibody which is clipped by specific proteases within tumors, exposing the fully active antibody, and potentially offering reduced systemic toxicity liabilities with comparable efficacy to ipilimumab. In 1-month toxicity studies in monkeys (n = 5/sex/group) at weekly doses of 3, 15, or 75 mg/kg IV of BMS-986218 or 10 or 50 mg/kg IV of BMS-986249 or ipilimumab, profound enhancement of peripheral T-cell activation occurred in a dose-dependent manner for all 3 compounds following neoantigen immunization (keyhole limpet hemocyanin [KLH], HIV necessary and enforcing factor [Nef], and HIV group specific antigen [Gag] peptides), consistent with target pharmacology. Consistent with the intended mechanistic differences, peripheral T cell activation was generally increased at corresponding doses of BMS-986218 compared to ipilimumab, and was delayed and reduced in monkeys given BMS-986249. BMS‑986218, ipilimumab, and BMS-986249 were clinically tolerated by monkeys at doses up to 3, 10, and 50 mg/kg, respectively, with generally mild, loose feces in some monkeys and/or minimal body weight decrease. At higher doses, early euthanasia occurred for 1 and 6 monkeys at 15 and 75 mg/kg BMS-986218, respectively, from Days 22-53 and 1 monkey at 50 mg/kg ipilimumab on Day 55 due to profound clinical toxicity. The predominant microscopic finding was generally dose-related lymphohistiocytic inflammation within a variety of tissues at all doses for all compounds, with BMS-986218 resulting in the greatest incidence, severity, and distribution of tissues and BMS-986249 having the least effects. The GI tract (stomach, cecum, and colon) and the kidney were the most severely and consistently affected, whereas additional organs were affected at higher doses. Most changes were partially or fully reversible during an 8-week recovery period with the exceptions of one monkey at 75 mg/kg BMS-986218 and one monkey at 50 mg/kg ipilimumab that were euthanatized on Days 53 or 55 due to unresolved GI toxicity, persistent lymphohistocytic inflammation, and/or unchanged or progressive increases in AST and ALT. Based on the tolerability and generally mild severity of lymphohistiocytic tissue inflammation, the highest non-severely toxic doses (HNSTD) for BMS-986218, ipilimumab, and BMS-986249 in monkeys following 1 month of dosing were 3 mg/kg (mean AUC 0-168h = 11,300 μg•h/mL), 10 mg/kg (AUC[0‑168h] =44,600 µg·h/mL), and 50 mg/kg (AUC[0-168h] =205,000 µg·h/mL), respectively. Overall, these results support the potential of these 2nd generation anti-CTLA4 antibodies to offer an improved risk /benefit profile with increased activity of the NF variant and improved safety of the Probody™ relative to ipilimumab.
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CytomX - ein bahnbrechender Ansatz in der Tumortherapie
