CytomX - ein bahnbrechender Ansatz in der Tumortherapie (Seite 69)

[Merger-one]

Wenn C. Gerichte bemühen muss, um Anteile möglicher Umsätze anderer zu erhalten, verschlechtert sich das Chance-Risiko Profil der Aktie. Die Risiken steigen nochmals, die Chancen scheinen mir ebenfalls geringer zu sein, wenn auch immer noch extrem groß im Erfolgsfall. Auch könnten die Preise für die Therapien bei mehreren Anbietern generell niedriger gewählt werden, so dass Umsatzbeteiligungen weniger Ergebnis für C. bedeuteten.

[Joschka Schröder]

Antwort auf Beitrag Nr.: 57.529.568 von Ville7 am 12.04.18 18:43:39

Auch wenn sich die Maskierungen voneinander unterscheiden, scheint es sich hier um klare Verstöße gegen bestehende CytomX-Patente zu handeln. Bis zu einer etwaigen Zulassung ist dies irrelevant und nicht sanktionierbar (Forschungsfreiheit), mit Beginn der Vermarktung wird sich dies aber ändern.

Gelegentlich sollte man mal nachfragen, welche Abwehrstrategien CytomX verfolgt, zumal es Patentanmeldungen anderer Unternehmen gibt, die ebenfalls mit existierenden CytomX-Patenten kollidieren.

[Ville7]

Antwort auf Beitrag Nr.: 57.529.568 von Ville7 am 12.04.18 18:43:39

Das Prinzip ist das gleiche wie bei CTMX. Das zeigt schon mal, dass SGEN den Ansatz prinzipiell für potentiell erfolgreich hält, trotz CTMX Patenten. Wie gut sind die Patente von CTMX?

"Protease-cleavable linkers were introduced between the coiled-coil peptides and antibody termini, and protease-catalyzed removal of the coiled-coil domains restored antibody binding affinity to that of the unmasked parent antibody."

[Ville7]

Antwort auf Beitrag Nr.: 57.529.364 von Ville7 am 12.04.18 18:19:02

abstract #750, nicht #250

http://www.abstractsonline.com/pp8/#!/4562/presentation/3012

Session PO.ET01.01 - Antibody-Drug Conjugates: Agents and Technology
750 / 17 - Modular coiled-coil masking domains for tumor-specific antibody activation

Presenter/Authors
V. H. Trang, X. Zhang, M. M. Dominguez, W. Zeng, J. H. Cochran, I. J. Stone, P. D. Senter, M. R. Levengood; Seattle Genetics, Bothell, WA
Disclosures
V.H. Trang: ; Seattle Genetics. X. Zhang: ; Seattle Genetics. M.M. Dominguez: ; Seattle Genetics. W. Zeng: ; Seattle Genetics. J.H. Cochran: ; Seattle Genetics. I.J. Stone: ; Seattle Genetics. P.D. Senter: ; Seattle Genetics. M.R. Levengood: ; Seattle Genetics.
Abstract
The power of monoclonal antibody therapeutics arises from their remarkable selectivity for a particular antigen. However, antibody therapies can still be limited by serious side effects that result from target-mediated toxicity when the antigen is also expressed on non-diseased tissue. An emerging concept in the field of therapeutic antibodies is to restrict antibody binding in healthy tissues while empowering the antibody at sites of disease. This has previously been accomplished by fusing masking groups to the antibody through cleavable sequences that can be activated upon hydrolysis by disease-associated proteases. Here, we present a novel approach to mask antibodies utilizing a variety of leucine zipper coiled-coil peptides fused to the N-termini of antibody heavy and light chains. An optimized heterodimeric coiled-coil masking domain was identified that significantly impaired the binding of multiple antibodies to their cognate receptors with no antibody-specific optimization required. Protease-cleavable linkers were introduced between the coiled-coil peptides and antibody termini, and protease-catalyzed removal of the coiled-coil domains restored antibody binding affinity to that of the unmasked parent antibody. The coiled-coil mask did not impair production of antibody-drug conjugates (ADCs) of varying drug-to-antibody ratios, and masked antibodies and ADCs had similar stability and pharmacokinetic profiles to unmasked counterparts. However, coiled-coil masked ADCs and antibodies displayed decreased functional activity in biological assays, commensurate with the decrease in affinity afforded by masking, and this activity could be restored upon cleavage of the mask. Lastly, coiled-coil masked antibodies and ADCs had been tested in vivo and had demonstrated improved safety benefits as well as equivalent antitumor activity compared to the unmasked counterparts. Coiled-coil masked antibodies represent an advance in the field of antibody pro-drugging, as this modular domain can be rapidly applied to an array of therapeutic antibodies and ADCs.

[Ville7]

Antwort auf Beitrag Nr.: 57.529.064 von infomi am 12.04.18 17:48:37

Das sind präklinische Ergebnisse: "in mice bearing human xenograft or murine syngeneic tumors"

Die Konzentration des radiolabeled Probody im Tumor scheint etwas höher zu sein als der radiolabeled Control-mab.
8,7% vs. 3,8% im einen Modell (mice bearing human xenograft MDA-MB-231)
6.5% vs 5.5% im anderen Modell (murine syngeneic MC38)

Wie aussagekräftig diese Werte sind und was das dann im Menschen bedeutet und wie es sich dort verhält ist weiter unklar. POC im Menschen steht noch aus...

[Ville7]

Seattle Genetics stellt eigene Maskierungstechnologie auf AACR 2018 vor:

https://www.businesswire.com/news/home/20180412005347/en/Sea…

"An innovative approach to masking antibodies for tumor specific activation will be featured in a poster presentation on Sunday, April 15, 2018 (Abstract #250). Preclinical data demonstrate that coiled-coil masked antibodies and ADCs show improved tolerability and equivalent antitumor activity compared to unmasked counterparts. The data suggest this technology may be applied to a range of antibodies or ADCs and could enable their development against previously inaccessible cancer targets."

[infomi]

Antwort auf Beitrag Nr.: 57.528.905 von Ville7 am 12.04.18 17:35:07

CONCLUSION 89Zr-CX-072 accumulates more in PD-L1-expressing tumor tissues than in lymphoid tissues.

sorry, wie ist das zu verstehen; ist das schon der POC oder nur, was in Mäusen schon mehr oder weniger bekannt war?

Auch wenn die Substanz akkumuliert - geschieht das in einem Ausmaß, die therapeutisch genutzt werden könnte ?

anyone

[Ville7]

AACR 2018 - abstract

Session PO.TB07.01 - Cancer Imaging: Immunology and Systems Analysis in Vivo
3035 / 8 - 89Zr-labeled anti-PD-L1 Probody therapeutic CX-072 biodistribution in mice bearing human xenograft or murine syngeneic tumors

April 17, 2018, 8:00 AM - 12:00 PM

Presenter/Authors
D. Giesen1, L. N. Broer1, M. N. Lub-de Hooge1, I. Popova2, B. Howng2, O. Vasiljeva2, E. G. E. de Vries1, M. Pool1; 1Univ. Med. Ctr. Groningen, Groningen, Netherlands, 2CytomX Therapeutics Inc., San Francisco, CA
Disclosures
D. Giesen: None. L.N. Broer: None. M.N. Lub-de Hooge: None. I. Popova: ; CytomX Therapeutics Inc. B. Howng: ; CytomX Therapeutics Inc. O. Vasiljeva: ; CytomX Therapeutics Inc. E.G.E. de Vries: ; CytomX Therapeutics Inc.. M. Pool: None.

Abstract
BACKGROUND Immune checkpoint inhibiting antibodies have antitumor activity across several tumor types, but are not effective in all patients and can elicit side effects. CX-072, a fully human Probody™ therapeutic currently in a phase 1/2 clinical trial, is reactive to the murine and human programmed cell death-ligand 1 (PD-L1) immune checkpoint. Probody therapeutics are engineered antibodies with target-binding region blocking masking peptides, which can be preferentially cleaved by tumor-associated proteases, yielding fully active antibodies. CX-072 may thus preserve anti-tumor efficacy, while limiting side effects. We radiolabeled CX-072 with the positron emission tomography (PET) isotope zirconium-89 (89Zr) to reveal its tumor targeting properties and whole body distribution using non-invasive PET imaging.

METHODS CX-072 and a non-specific Probody therapeutic control (PbCtrl) were radiolabeled with 89Zr. For in vivo studies, PD-L1 expressing MDA-MB-231 human breast cancer cells were subcutaneously (sc) engrafted in Balb/c nude mice. To assess tracer protein dose dependency of the tumor uptake, mice received 10 μg 89Zr-CX-072 or 89Zr-PbCtrl (~5 MBq) supplemented with 0, 40 or 240 µg of unlabeled CX-072 or PbCtrl. To evaluate 89Zr-CX-072 biodistribution in an immune-competent setting, C57BL6 mice were implanted sc with low PD-L1 expressing MC38 syngeneic murine colon adenocarcinoma cells. All mice underwent serial in vivo PET imaging 1, 3 and 6 days post injection (pi), quantified by mean standardized uptake value (SUVmean) and followed by ex vivo biodistribution. Activated Probody species in tissues were detected by Western capillary electrophoresis.
RESULTS PET imaging revealed increasing 89Zr-CX-072 tumor accumulation between 1-6 days pi, with the highest SUVmean of 1.5 (± 0.2) observed for 10 µg at 6 days pi. Ex vivo biodistribution analysis showed 8.7 % injected dose per gram (%ID/g) tumor uptake for 10 µg 89Zr-CX-072 versus 3.8 %ID/g for 10 µg 89Zr-PbCtrl (P<0.01) in MDA-MB-231 xenografted mice. In the syngeneic MC38 model biodistribution analysis showed modest tumor uptake for 10 μg 89Zr-CX-072 and 89Zr-PbCtrl (6.5 vs 5.5 %ID/g, P=0.24; tumor-to-blood ratio of 0.61 vs 0.45, P<0.05). 89Zr-CX-072 uptake in lymphoid tissues (spleen, lymph nodes) was similar to 89Zr-PbCtrl. Activated Probody species were predominantly detected in tumor with lesser amounts present in lymphoid tissues.

CONCLUSION 89Zr-CX-072 accumulates more in PD-L1-expressing tumor tissues than in lymphoid tissues. A sub-study of an ongoing clinical study (PROCLAIM-CX-072) is designed to validate study drug distribution in patients using a good manufacturing practice (GMP) quality 89Zr-CX-072 tracer.

[Joschka Schröder]

Antwort auf Beitrag Nr.: 57.480.827 von Gustl24 am 06.04.18 14:17:37

Meinen Aufzeichnungen zufolge hat die CMO am 2.3. einige Aktien (aus ihrem Optionsprogramm) verkauft, danach nichts mehr. Für mich ist das irrelevant.
Was die klinischen Studienergebnisse betrifft, so müssen wir abwarten. Ob die Maskierung klinisch funktioniert oder nicht, konnte die CMO am 2.3. jedenfalls genauso wenig wissen wie wir.

[Gustl24]

Antwort auf Beitrag Nr.: 57.468.323 von Joschka Schröder am 05.04.18 11:14:03

40T Aktien wurden in den letzten 6 Wochen von der CMO verkauft...das ist nicht unerheblich.
Ein bisschen ins Grübeln bringen mich die Insider Transaktionen (auch wenns überwiegend Optionsprogramme sind bis auf den Director Gluck) schon auch, ein bisschen