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    CytomX - ein bahnbrechender Ansatz in der Tumortherapie (Seite 96)

    eröffnet am 01.07.16 16:03:16 von
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      schrieb am 16.10.17 19:49:11
      Beitrag Nr. 509 ()
      Antwort auf Beitrag Nr.: 55.961.227 von Joschka Schröder am 16.10.17 19:40:37Den letzten (LB-B33) abstract habe ich kaum gefunden. BMS stellt präklinische Daten von seinen zwei ipilimumab Varianten vor, darunter auch den Probody von CTMX. Wenn Abstracts "embargoed" sind, dann ist das besonders spannend.
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      schrieb am 16.10.17 19:44:25
      Beitrag Nr. 508 ()
      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

      October 29, 2017, 12:30 - 4:00 PM

      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
      Abstract embargoed at this time.
      1 Antwort
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      schrieb am 16.10.17 19:40:37
      Beitrag Nr. 507 ()
      Antwort auf Beitrag Nr.: 55.961.192 von Ville7 am 16.10.17 19:28:30Da warst Du schneller als ich. Das Abstract zu CX-2029 bietet einen schönen Einblick in die alltägliche Moleküloptimierung.
      1 Antwort
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      schrieb am 16.10.17 19:28:30
      Beitrag Nr. 506 ()
      Session PO.B19 - Therapeutic Agents: Biological
      B103 / 103 - A multi-analyte HPLC-MS/MS approach to assessing exposure of a Probody drug conjugate in preclinical studies

      October 29, 2017, 12:30 - 4:00 PM

      Presenter/Authors
      Laura Serwer1, Shweta Singh1, Claus Krebber1, Shouchun Liu1, Niharika Chauhan2, Robert Leanna2, Hong Lu1, Ilaria Badagnani2, Tracy Henriques2, Susan Morgan-Lappe2, William Mylott, Jr.3, Sridhar Viswanathan1, Jennifer Richardson1, Michael Kavanaugh1. 1CytomX Therapeutics, South San Francisco, CA; 2AbbVie, North Chicago, IL; 3PPD Laboratories, Richmond, VA
      Disclosures
      L. Serwer: ; CytomX Therapeutics. S. Singh: ; CytomX Therapeutics. C. Krebber: ; CytomX Therapeutics. S. Liu: ; CytomX Therapeutics. N. Chauhan: ; AbbVie. R. Leanna: ; AbbVie. H. Lu: ; CytomX Therapeutics. I. Badagnani: ; AbbVie. T. Henriques: ; AbbVie. S. Morgan-Lappe: ; AbbVie. W. Mylott: ; PPD Laboratories. S. Viswanathan: ; CytomX Therapeutics. J. Richardson: ; CytomX Therapeutics. M. Kavanaugh: ; CytomX Therapeutics.
      Abstract
      CX-2029 is a protease-activatable antibody prodrug (ProbodyTM Therapeutic) targeted against CD71 (transferrin receptor) and conjugated to a vcMMAE cytotoxic payload with a purified Drug to Probody Ratio (DPR) of 2. In the intact, prodrug form, each light chain of CX-2029 contains an N-terminal prodomain that masks the target-binding region of the parental antibody and decreases antigen binding. In vivo proteolytic cleavage of the prodomain in the tumor microenvironment exposes the target-binding region, yielding the active antibody. In this way, Probody therapeutics are designed to avoid on-target toxicity in normal tissues while preserving antitumor activity. In vivo, CX-2029 may be present in several forms as a result of activation of the antibody prodrug, as well as deconjugation of the cytotoxic payload. We have developed a multi-analyte HPLC-MS/MS approach to monitor levels of four analytes (Intact Probody Therapeutic, Total Probody Therapeutic, Probody-Conjugated MMAE, and Unconjugated MMAE) in cynomolgus monkey plasma to evaluate the exposure of both the intact CX-2029 and activated antibody prodrug, as well as to monitor changes in the DPR over time. To understand the impact of antidrug antibodies (ADA) on exposure, a bridging assay was developed to monitor the formation of ADA. These assays were used to assess exposure of CX-2029 in an ascending dose toxicity study (6, 12, and 18 mg/kg/dose) in cynomolgus monkeys, in support of dose selection for an IND-enabling study. CX-2029 was administered as an intravenous bolus dose to groups of 3 monkeys (2 males, 1 female) once every three weeks for a total of two doses. Samples were collected for pharmacokinetic analysis at time points spanning 21 days after the first dose and 7 days after the second dose. Samples were collected for ADA analysis prestudy and 7 days after the second dose. Dose-dependent increases in Cmax were observed between 6 and 18 mg/kg for the analytes measured. Half-life estimates were similar for Intact Probody Therapeutic, Total Probody Therapeutic, and Probody-Conjugated MMAE and ranged from 2.5 to 6.3 days. The ratio of Intact Probody Therapeutic to Total Probody Therapeutic was used to assess stability of the cleavable prodomain in the cynomolgus monkey over time. By 7 days post-dose, approximately 80% of CX-2029 in plasma was in the intact, prodrug form. The average DPR was evaluated over three weeks in vivo. Average DPR decreased from 2 shortly after dosing to approximately 0.5 by 21 days post-dose. ADA were detected in 3 of 9 animals dosed with CX-2029. In cynomolgus monkeys, CX-2029 exposure is maintained throughout the 21-day dosing interval, and the majority of CX-2029 in circulation is intact. CX-2029 is currently under development, with an IND filing expected in 2018. PROBODY is a trademark of CytomX Therapeutics, Inc.
      2 Antworten
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      schrieb am 16.10.17 19:25:31
      Beitrag Nr. 505 ()
      Session PO.B19 - Therapeutic Agents: Biological
      B116 / 116 - Optimizing a CD71-targeting Probody drug conjugate (PDC) for activity in multiple solid tumor and lymphoma models and for tolerability in nonhuman primates

      October 29, 2017, 12:30 - 4:00 PM

      Presenter/Authors

      Shweta Singh1, Laura Serwer1, Niharika Chauhan2, Amy DuPage1, Michael Krimm1, Ken Wong1, Yuanhui Huang1, Andrew Jang1, Eric Ureno1, Adam Miller1, Sarah Patrick1, Shanti Duvur1, Fritz Buchanan2, Matthew M. Ravn2, Rob Leanna2, Ilaria Badagnani2, Tracy Henriques2, Shouchun Liu1, Claus Krebber1, Sridhar Viswanathan1, Jennifer Richardson1, Susan Morgan-Lappe2, Michael Kavanaugh1. 1CytomX Therapeutics, South San Francisco, CA; 2Abbvie, North Chicago, IL
      Disclosures
      S. Singh: ; CytomX. L. Serwer: ; CytomX. N. Chauhan: ; Abbvie. A. DuPage: ; CytomX. M. Krimm: ; CytomX. K. Wong: ; CytomX. Y. Huang: ; CytomX. A. Jang: ; CytomX. E. Ureno: ; CytomX. A. Miller: ; CytomX. S. Patrick: ; CytomX. S. Duvur: ; CytomX. F. Buchanan: ; Abbvie. M.M. Ravn: ; Abbvie. R. Leanna: ; Abbvie. I. Badagnani: ; Abbvie. T. Henriques: ; Abbvie. S. Liu: ; CytomX. C. Krebber: ; CytomX. S. Viswanathan: ; CytomX. J. Richardson: ; CytomX. S. Morgan-Lappe: ; Abbvie. M. Kavanaugh: ; CytomX.
      Abstract
      ProbodyTM therapeutics are antibody prodrugs designed to remain largely inactive until proteolytically activated in the tumor microenvironment (TME), potentially enabling the safer targeting of antigens that are highly expressed in both tumor and normal tissue. CD71 (transferrin receptor) is an example of an ideal Probody Drug Conjugate (PDC) target, not only because it efficiently internalizes and can deliver a cytotoxic payload intracellularly, but also because it is expressed at high levels both in many different tumor types as well as in dividing normal cells. We have previously demonstrated that while an anti-CD71 antibody drug conjugate (ADC) is highly toxic, a CD71-targeting PDC is both efficacious in mouse tumor models and well tolerated in nonhuman primates. Two key components of a Probody therapeutic prodomain that reduce its binding to normal tissue and allow for its tumor-specific activation are 1) a mask that reduces the ability of the antibody binding site to interact with target antigen and 2) a protease-activatable substrate that is cleaved in the TME, resulting in removal of the mask. Here, we demonstrate how modulating mask strength and substrate cleavability can optimize efficacy and safety of a CD71-targeting PDC in preclinical models. Through this process, we have selected a lead molecule, CX-2029, for further development. CX-2029 is a CD71-targeting PDC conjugated to vcMMAE with a Drug to Probody Ratio (DPR) of 2, achieved by purification. At dose levels consistent with those expected in humans, a more strongly masked PDC, CX-2018, was less efficacious in a mouse xenograft tumor model compared to PDC CX-2016, which has a weaker mask, demonstrating that mask strength affects antitumor activity. Further, PDC CX-2019, which has the same mask but a less cleavable substrate than CX-2016, was similarly efficacious in a mouse xenograft tumor model, demonstrating that both substrates are sufficiently cleaved in the TME to activate the PDCs. However, CX-2019 was better tolerated in NHP at 6 mg/kg than CX-2016, suggesting that the less cleavable substrate in CX-2019 leads to a better therapeutic index. Using a LC/MS/MS method, we showed lower levels of circulating activated CX-2019 compared with circulating activated CX-2016, which is consistent with CX-2019’s improved tolerability. Lead CX-2029 contains the same mask and substrate as CX-2019 but differs in having a DPR of 2 versus ~3 for CX-2019. Up to 6 mg/kg of CX-2029 as a single dose produced complete regressions and durable responses in mouse xenograft tumor models encompassing multiple indications, and was tolerated in monkeys at doses of up to 12 mg/kg. These data demonstrate that, in preclinical models, tuning of mask strength and substrate cleavability can optimize the efficacy and tolerability of Probody Therapeutics and have the potential to enable the safe and effective targeting of highly expressed tumor antigens like CD-71. CX-2029 is currently under development, with an IND filing expected in 2018. PROBODY is a trademark of CytomX Therapeutics, Inc.

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      schrieb am 16.10.17 19:22:38
      Beitrag Nr. 504 ()
      Session SPR01 - Spotlight on Proffered Papers Session 1
      A164 - EGFR-CD3 bispecific Probody™ therapeutic induces tumor regressions and increases maximum tolerated dose >60-fold in preclinical studies

      October 27, 2017, 11:00 - 11:10 AM

      Presenter/Authors
      Leila M. Boustany, Laurie Wong, Clayton W. White, Linnea Diep, Yuanhui Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, Bryan A. Irving. CytomX Therapeutics, South San Francisco, CA
      Disclosures
      L.M. Boustany: ; CytomX Therapeutics. L. Wong: ; CytomX Therapeutics. C.W. White: ; CytomX Therapeutics. L. Diep: ; CytomX Therapeutics. Y. Huang: ; CytomX Therapeutics. S. Liu: ; CytomX Therapeutics. J.H. Richardson: ; CytomX Therapeutics. W.M. Kavanaugh: ; CytomX Therapeutics. B.A. Irving: ; CytomX Therapeutics.
      Abstract
      T cell-engaging bispecific antibodies (TCBs) are highly potent therapeutics that direct the activity of cytotoxic T cells to tumors. TCBs have shown clinical activity in hematologic malignancies, but development of TCBs for solid tumor indications is proving more challenging. Due to their high potency, TCBs can target normal tissues with low antigen expression, resulting in significant on-target, off-tumor toxicity that can limit dosing to low levels. As a result, it has been difficult to reach the level of drug exposure required for efficacy without excessive toxicity. Therefore, novel methods are needed to enable the potent antitumor activity of TCBs while minimizing toxicity due to cytokine release and damage to healthy tissues. CytomX has developed a new class of recombinant, proteolytically activated antibody prodrugs (ProbodyTM therapeutics) that are “masked” to prevent binding to antigen in healthy tissue, but can become “unmasked” by proteases that are preferentially activated in the tumor microenvironment. In this way, Probody therapeutics are designed to increase therapeutic index by maximizing efficacy and minimizing on-target toxicity in normal tissues. Here we describe a T cell-engaging Bispecific Probody therapeutic (Pb-TCB) targeting Epidermal Growth Factor Receptor (EGFR) and CD3 that has been optimized for affinity, effector function, masking, and cleavability. In vitro, under protease-deficient conditions, we demonstrate that the unmasked EGFR-CD3 TCB has potent, EGFR-dependent tumor cell killing, while the doubly-masked EGFR-CD3 Pb-TCB reduces target-dependent cytotoxicity by more than 100,000-fold. However, in established tumor models where tumor-resident proteases are expected to be active, we demonstrate that Pb-TCBs potently induce tumor regressions. In nonhuman primates, the maximum tolerated dose (MTD) of the EGFR-CD3 Pb-TCB is more than 60-fold higher than the MTD of the unmasked TCB, and the tolerated exposure (AUC) is more than 10,000-fold higher. Finally, despite the 60-fold dose differential at the MTDs, transient serum cytokine and AST/ALT increases observed in nonhuman primates treated with the Pb-TCB are still lower than those induced by the TCB. By localizing activity to the tumor microenvironment, Pb-TCBs have the potential to expand clinical opportunities for T cell-engaging bispecific therapies that are limited by on-target toxicities, especially in solid tumors. Moreover, an EGFR-CD3 Pb-TCB has the potential to address EGFR-expressing tumors that are poorly responsive to existing EGFR-directed therapies. PROBODY is a trademark of CytomX Therapeutics, Inc.
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      schrieb am 16.10.17 17:40:50
      Beitrag Nr. 503 ()
      Antwort auf Beitrag Nr.: 55.951.382 von Joschka Schröder am 13.10.17 22:43:05teilweise off topic:

      Mittlerweile habe ich meine Recherchen zu Mersana weitgehend abgeschlossen. Auf eine für mich wichtige Antwort des Unternehmens warte ich noch. Schon jetzt läßt sich aber sagen, dass Mersana mit CytomX nicht vergleichbar ist, CytomX´s Probody-Technik ist viel interessanter. Wer MRSN am Freitag oder heute zu unter 16 USD gekauft hat, könnte nach dem aktuellen, 5 %igen Kursanstieg daran denken, seinen Trading-Gewinn zu realisieren. CytomX bleibt nach wie vor mein persönlicher Favorit im Biotech-Sektor, gefolgt von Ablynx, dessen Kurs heute Kapriolen schlägt (Kursschwankungen zwischen 16,73 EUR und 18,28 EUR, was für eine gewisse Desorientiertheit der Anleger spricht).
      5 Antworten
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      schrieb am 14.10.17 09:59:57
      Beitrag Nr. 502 ()
      Antwort auf Beitrag Nr.: 55.952.222 von Ville7 am 14.10.17 09:15:43Das kann ich nicht beurteilen. Ich schaue mir nur den NBI und ca. 10 Biotech-Werte an, die für mich interessant sind. Unter diesen Werten ist sonst nur IMGN eingebrochen, dort war die große KP-Erhöhung der Grund. Aber klar, es kann viele Ursachen für den Kursrückgang bei Mersana geben, Unternehmensneuigkeiten waren es jedenfalls nicht.
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      schrieb am 14.10.17 09:15:43
      Beitrag Nr. 501 ()
      Antwort auf Beitrag Nr.: 55.951.382 von Joschka Schröder am 13.10.17 22:43:05Der Abverkauf bei Mersana folgt dem Muster, den ich in den letzten 2-3 Tagen bei anderen Biotechs auch beobachtet habe. Kursgewinne von Biotechs, die in letzter Zeit hoch geflogen sind, werden einfach wieder weitgehend kassiert. Das muss gar nichts mit irgendwelchen kommenden Daten-Veröffentlichungen zu tun haben.
      1 Antwort
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      schrieb am 13.10.17 22:43:05
      Beitrag Nr. 500 ()
      Off topic:

      Wilde Kursbewegungen bei Mersana ohne greifbaren Grund. Nachdem die Aktie ohne News bis 20 USD durchgestartet war (was mir übertrieben schien), ist die Aktie während der vergangenen Tage nunmehr wieder auf 16,1 USD zurückgekommen und notiert nicht mehr weit über dem Emissionskurs (15 USD). Ein Grund für den aktuellen Kurseinbruch könnte sein, dass am Montag die Abstracts der EEORTC-NCI-AACR-Conference freigeschaltet werden, bei der Mersana über XMT-1522 berichten wird. Einige Anleger haben deshalb wohl heiße Füsse bekommen. Ich rechne nicht damit, dass sich im Abstract nennenswerte Neuigkeiten finden, sondernerwarte eher ältere Verträglichkeitsdaten (Abstract wurde schon vor Monaten eingereicht). Insoweit könnte der gegenwärtige Kurseinbruch für Trader evt. eine interessante Kaufgelegenheit darstellen. Meinen eigenen Meinungsbildungsprozess habe ich noch immer nicht abgeschlossen, die ADC-Technik ist zweifellos interessant, ob das ganze tatsächlich wie gewünscht funktionieren wird, ist nach aktuellem Kenntnisstand aber schwer abschätzbar.
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      CytomX - ein bahnbrechender Ansatz in der Tumortherapie