“APG101”的意思、由来-开放百科全书

APG101 blocks the CD95–ligand (CD95L) from binding to the CD95-receptor (CD95), which induces apoptosis. In oncology, this blockade is intended to prevent the killing of activated T cells^[6] that can be induced by tumor-associated macrophages (TAMs)^[7], endothelial cells^[8] or fibroblasts^[9].

In MDS, CD95L-signaling is a negative regulator of erythrocyte production in the bone marrow and its blockade has been shown to rescue erythroid progenitors^[10].

Clinical development

A randomized, double-blind, placebo-controlled phase I study to examine the safety and tolerability of APG101 has shown that it is well tolerated.^[11] The efficacy of APG101 was tested in a phase II randomized controlled trial with patients suffering from GBM. A total of 83 patients with first or second relapse of GBM were enrolled in the successful proof-of-concept trial. The primary goal of doubling the number of patients reaching progression-free survival at six months (PFS6) was substantially exceeded.^[12]

APG101 has also been successfully tested in a phase I trial to treat patients with MDS.^[13] MDS is a disease in which the bone marrow does not make enough healthy blood cells, which leads to blood cytopenias, especially anemia.^[14]

References

1. ^{{cite web|url=http://apogenix.com/en/ |title=Protein therapeutics for cancer & inflammatory diseases |publisher=Apogenix}}
2. ^{{cite web|url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=82093|title=Orphan designation, Europe |publisher= Orphanet, the portal for rare diseases and orphan drugs |date=2017-10-05}}
3. ^{{cite web|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=293009|title= Treatment of glioblastoma multiforme |publisher= U.S. Food and Drug Administration (FDA)|date=2012-07-24}}
4. ^{{cite web|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=371612 |title=Treatment of Myelodysplastic Syndrome |publisher=U.S. Food and Drug Administration (FDA)|date=2009-10-13}}
5. ^{{cite web|url=https://www.ema.europa.eu/documents/chmp-annex/recommendations-eligibility-prime-scheme-adopted-chmp-meeting-15-18-may-2017_en.pdf |title=Asunercep, PRIME Designation |publisher=European Medicines Agency (EMA)|date=2017-05-27}}
6. ^{{cite journal | vauthors = Zhu J, Petit PF, Van den Eynde BJ | title= Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism | journal = Cancer Immunol Immunother| year = 2018| pmid = 30406374 | doi = 10.1038/s41467-017-00784-1}}
7. ^{{cite journal | vauthors = Zhu J, Powis de Tenbossche CG, Cané S, Colau D, van Baren N, Lurquin C, Schmitt-Verhulst AM, Liljeström P, Uyttenhove C, Van den Eynde BJ | title= Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes | journal = Nat Commun | volume = 8| issue = 1| pages = 1404 | year = 2017 | pmid = 29123081 | doi = 10.1038/s41467-017-00784-1}}
8. ^{{cite journal | vauthors = Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G | title= Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors | journal= Nat Med| volume=20| issue=6| pages=607-15 | year=2014 | pmid=24793239 | doi=10.1038/nm.3541}}
9. ^{{cite journal | vauthors = Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD | title= Cancer-associated fibroblasts induce antigen-specific deletion of CD8+ T Cells to protect tumour cells | journal=Nat Commun | volume=9| issue=1| pages =948 | year=2018 | pmid=29507342 | doi=10.1038/s41467-018-03347-0 }}
10. ^{{cite journal | vauthors = Raimbault A, Pierre-Eugene C, Rouquette A, Deudon C, Willems L, Chapuis N, Mathis S, Kunz C, Fricke H, Kosmider O, Bardet V, Fontenay M, ((Groupe Francophone des Myélodysplasies)) | title= APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis| journal=Oncotarget| volume=22| issue=12| pages=14898-911 | year=2016 | pmid=26910909 | doi=10.18632/oncotarget.7469}}
11. ^{{cite journal| vauthors = Tuettenberg J, Seiz M, Debatin KM, Hollburg W, von Staden M, Thiemann M, Hareng B, Fricke H, Kunz C | title=Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients | volume=13 | issue=1 | date=2012 | pages=93–100| pmid=22446296 | doi=10.1016/j.intimp.2012.03.004}}
12. ^{{cite journal| vauthors = Wick W, Fricke H, Junge K, Kobyakov G, Martens T, Heese O, Wiestler B, Schliesser MG, von Deimling A, Pichler J, Vetlova E, Harting I, Debus J, Hartmann C, Kunz C, Platten M, Bendszus M, Combs SE | title=A phase II, randomized, study of weekly APG101+reirradiation versus reirradiation in progressive glioblastoma | volume= 15 | issue =24 | date= 2014 | pages=6304-13| pmid = 25338498 | doi=10.1158/1078-0432.CCR-14-0951-T}}
13. ^{{cite journal| vauthors = Boch T, Luft T, Metzgeroth G, Mossner M, Jann JC, Nowak D, Meir F, Schumann C, Klemmer J, Brendel S, Fricke H, Kunz C, Weiß C, Hofmann WK, Nolte F | title=Safety and efficacy of the CD95-ligand inhibitor asunercept in transfusion-dependent patients with low and intermediate risk MDS | volume= 68 | date= 2018 | pages=62-69| pmid = 29549809 | doi=10.1016/j.leukres.2018.03.007}}
14. ^National Cancer Institute: http://www.cancer.gov/cancertopics/pdq/treatment/myelodysplastic/Patient/page1

Mechanism of action

Clinical development

References