FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2955561239> ?p ?o ?g. }

• W2955561239 endingPage "4828" @default.
• W2955561239 startingPage "4828" @default.
• W2955561239 abstract "Abstract Despite recent progress in the treatment of AML, clinical outcomes have improved only minimally over the past three decades. Therefore, novel therapeutic agents with a high therapeutic window and a favorable tolerability profile are urgently needed to improve the therapeutic outcome for AML patients. IL3RA (CD123) is the alpha subunit of the interleukin 3 (IL-3) receptor which regulates proliferation, survival and differentiation of hematopoietic cells. IL3RA is expressed at high frequency, with ~84% of AML cases and 59% of classical Hodgkin lymphoma (cHL) cases being positive. IL3RA is expressed in AML blast and leukemic stem cells (LSCs) but not in hematopoietic stem cells (HSCs). In healthy individuals, the IL3RA expression is restricted to myeloid progenitor cells, plasmacytoid dendritic cells (pDCs), basophils and - at low levels - monocytes and B-lymphocyte subsets. This expression pattern suggests that IL3RA could be a clinically relevant target for an antibody-drug conjugate (ADC) approach in treatment of AML, cHL, and MDS. BAY-943 is a novel antibody-drug conjugate (ADC) consisting of a humanized internalizing anti-IL3RA IgG1 antibody (Ab, EC50 on IL3RA-positive tumor cells in flow cytometry: 2-5 nM) conjugated via lysine residues to a potent proprietary kinesin spindle protein inhibitor (KSPi). The kinesin spindle protein (KSP/Eg5/KIF11) is essential for the proper segregation of duplicated centrosomes during spindle formation in the G2/M phase of the cell cycle, as such it is only active in proliferating cells. In vitro, in a panel of IL3RA-positive AML and HL cell lines, BAY-943 showed potency in the nano- to subnanomolar range. In IL3RA-positive cell line derived (CDX) AML xenograft models (MOLM-13 and MV4-11) and patient-derived xenograft (PDX) models, BAY-943 dosed at 10 mg/kg given Q7Dx increased survival compared to vehicle treated mice. Tumor burden (percentage of human CD45 positive AML cells) was significantly reduced compared to vehicle treated mice. In the subcutaneous IL3RA-positive cHL CDX model HDLM-2, BAY-943 dosed at 5 and 10 mg/kg Q7Dx2 induced complete tumor remission in 12 out of 13 mice. In safety studies in Cynomolgus monkeys, BAY-943 (which is cross-reactive with Cynomolgus IL3RA), up to 20 mg/kg single or 10 mg/kg repeat (QWx3) dose were well tolerated with no signs of thrombocytopenia, neutropenia and no liver toxicity, i.e. adverse events observed with ADCs containing other payload classes. As expected, a transient reduction of IL3RA expressing cell types (basophils, pDCs) was observed. In summary, IL3RA-KSPi-ADC BAY-943 shows efficacy in IL3RA-positive AML and HL models and has a favorable safety profile in monkey repeat dose studies. Overall, the preclinical results support further development of BAY-943 as an innovative approach for the treatment of IL3RA-positive AML. Citation Format: Anette Sommer, Dennis Kirchhoff, Antje M. Wengner, Beatrix Stelte-Ludwig, Hans-Georg Lerchen, Anne-Sophie Rebstock, Oliver von Ahsen, Lisa Dietz, Pascale Buchmann, Sandra Johanssen, Dominik Mumberg, Bertolt Kreft. Anti-tumor activity of BAY-943, an anti-IL3RA ADC with a novel KSP inhibitor payload, in CDX and PDX AML models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4828." @default.
• W2955561239 created "2019-07-12" @default.
• W2955561239 creator A5007299835 @default.
• W2955561239 creator A5008538262 @default.
• W2955561239 creator A5009359386 @default.
• W2955561239 creator A5010301448 @default.
• W2955561239 creator A5013154741 @default.
• W2955561239 creator A5026724212 @default.
• W2955561239 creator A5040976235 @default.
• W2955561239 creator A5048269157 @default.
• W2955561239 creator A5064749364 @default.
• W2955561239 creator A5075150391 @default.
• W2955561239 creator A5078920724 @default.
• W2955561239 creator A5087387263 @default.
• W2955561239 date "2019-07-01" @default.
• W2955561239 modified "2023-09-27" @default.
• W2955561239 title "Abstract 4828: Anti-tumor activity of BAY-943, an anti-IL3RA ADC with a novel KSP inhibitor payload, in CDX and PDX AML models" @default.
• W2955561239 doi "https://doi.org/10.1158/1538-7445.am2019-4828" @default.
• W2955561239 hasPublicationYear "2019" @default.
• W2955561239 type Work @default.
• W2955561239 sameAs 2955561239 @default.
• W2955561239 citedByCount "0" @default.
• W2955561239 crossrefType "journal-article" @default.
• W2955561239 hasAuthorship W2955561239A5007299835 @default.
• W2955561239 hasAuthorship W2955561239A5008538262 @default.
• W2955561239 hasAuthorship W2955561239A5009359386 @default.
• W2955561239 hasAuthorship W2955561239A5010301448 @default.
• W2955561239 hasAuthorship W2955561239A5013154741 @default.
• W2955561239 hasAuthorship W2955561239A5026724212 @default.
• W2955561239 hasAuthorship W2955561239A5040976235 @default.
• W2955561239 hasAuthorship W2955561239A5048269157 @default.
• W2955561239 hasAuthorship W2955561239A5064749364 @default.
• W2955561239 hasAuthorship W2955561239A5075150391 @default.
• W2955561239 hasAuthorship W2955561239A5078920724 @default.
• W2955561239 hasAuthorship W2955561239A5087387263 @default.
• W2955561239 hasConcept C10205521 @default.
• W2955561239 hasConcept C109159458 @default.
• W2955561239 hasConcept C159654299 @default.
• W2955561239 hasConcept C203014093 @default.
• W2955561239 hasConcept C2777325958 @default.
• W2955561239 hasConcept C2779282312 @default.
• W2955561239 hasConcept C28328180 @default.
• W2955561239 hasConcept C502942594 @default.
• W2955561239 hasConcept C542903549 @default.
• W2955561239 hasConcept C71924100 @default.
• W2955561239 hasConcept C83396363 @default.
• W2955561239 hasConcept C86803240 @default.
• W2955561239 hasConcept C95444343 @default.
• W2955561239 hasConceptScore W2955561239C10205521 @default.
• W2955561239 hasConceptScore W2955561239C109159458 @default.
• W2955561239 hasConceptScore W2955561239C159654299 @default.
• W2955561239 hasConceptScore W2955561239C203014093 @default.
• W2955561239 hasConceptScore W2955561239C2777325958 @default.
• W2955561239 hasConceptScore W2955561239C2779282312 @default.
• W2955561239 hasConceptScore W2955561239C28328180 @default.
• W2955561239 hasConceptScore W2955561239C502942594 @default.
• W2955561239 hasConceptScore W2955561239C542903549 @default.
• W2955561239 hasConceptScore W2955561239C71924100 @default.
• W2955561239 hasConceptScore W2955561239C83396363 @default.
• W2955561239 hasConceptScore W2955561239C86803240 @default.
• W2955561239 hasConceptScore W2955561239C95444343 @default.
• W2955561239 hasIssue "13_Supplement" @default.
• W2955561239 hasLocation W29555612391 @default.
• W2955561239 hasOpenAccess W2955561239 @default.
• W2955561239 hasPrimaryLocation W29555612391 @default.
• W2955561239 hasRelatedWork W1704090211 @default.
• W2955561239 hasRelatedWork W1974139477 @default.
• W2955561239 hasRelatedWork W2063665706 @default.
• W2955561239 hasRelatedWork W2067340489 @default.
• W2955561239 hasRelatedWork W2083632015 @default.
• W2955561239 hasRelatedWork W2131263031 @default.
• W2955561239 hasRelatedWork W2167865287 @default.
• W2955561239 hasRelatedWork W2324058136 @default.
• W2955561239 hasRelatedWork W2394285671 @default.
• W2955561239 hasRelatedWork W2983614160 @default.
• W2955561239 hasVolume "79" @default.
• W2955561239 isParatext "false" @default.
• W2955561239 isRetracted "false" @default.
• W2955561239 magId "2955561239" @default.
• W2955561239 workType "article" @default.