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  • 1
    In: ADC Review / Journal of Antibody-drug Conjugates, Sunvalley Communication, ( 2019-11-12)
    Abstract: With the approval of meanwhile five ADCs and more than 80 ADCs in clinical trials, the ADC landscape has developed rapidly during the last decade. However, as indicated also by the large number of ADCs which failed in the clinic, it remains challenging to achieve a sufficiently large therapeutic window in cancer patients. Furthermore, the identification of ADC payload classes with a novel mode of action would increase therapeutic options and potentially help to overcome resistance. Inhibitors of kinesin spindle protein (KSP/Eg5) have raised great interest because of their high antitumor potency which, however, could not be transferred into highly efficient clinical regimens due to dose limiting side effects such as neutropenia and mucositis.
    Type of Medium: Online Resource
    ISSN: 2327-0152
    Language: Unknown
    Publisher: Sunvalley Communication
    Publication Date: 2019
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  • 2
    Online Resource
    Online Resource
    Wiley ; 2000
    In:  Pharmacology and Toxicology Vol. 87, No. 2 ( 2000-08), p. 89-95
    In: Pharmacology and Toxicology, Wiley, Vol. 87, No. 2 ( 2000-08), p. 89-95
    Type of Medium: Online Resource
    ISSN: 0901-9928 , 1600-0773
    Language: English
    Publisher: Wiley
    Publication Date: 2000
    detail.hit.zdb_id: 2151592-X
    detail.hit.zdb_id: 2027010-0
    SSG: 15,3
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 287-287
    Abstract: The spindle assembly checkpoint represents a highly conserved surveillance mechanism which safeguards correct chromosome segregation by delaying anaphase onset until all chromosomes are properly bi-oriented on the spindle apparatus. Non-catalytic functions of the mitotic kinase BUB1 (budding uninhibited by benzimidazoles 1) were reported to be essential for spindle assembly checkpoint activation. In contrast, the catalytic function of BUB1 plays a minor role in spindle assembly checkpoint activation but is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors. Here, we disclose for the first time the structure and functional characterization of a novel, first-in-class Bub1 kinase inhibitor. Medicinal chemistry efforts resulted in BAY 1816032 featuring high potency, long target residence time and good oral bioavailablity. It inhibits BUB1 enzymatic activity with an IC50 of 7 nanomol/L, shows slow dissociation kinetics resulting in a long target residence time of 87 min, and an excellent selectivity on a panel of 395 kinases. Mechanistically BAY 1816032 abrogated nocodazole-induced Thr-120 phosphorylation of the major BUB1 target protein histone H2A in HeLa cells with an IC50 of 29 nanomol/L, induced lagging chromosomes and mitotic delay. Persistent lagging chromosomes and missegregation were observed upon combination with low concentrations of paclitaxel. Single agent BAY 1816032 inhibited proliferation of various tumor cell lines with a median IC50 of 1.4 micromol/L and demonstrated synergy or additivity with paclitaxel or docetaxel in almost all cell lines evaluated (minimal combination index 0.3). In tumor xenograft studies BAY 1816032 only marginally inhibited tumor growth as single agent upon oral administration, however, upon combination with paclitaxel or docetaxel a strong and statistically significant reduction of tumor size as compared to the respective monotherapy was observed. Intratumoral levels of phospho-Thr120 H2A were found to be strongly reduced, and no hints on drug-drug interactions were found. In line with the good tolerability in xenograft studies, no relevant findings from non-GLP 2 weeks toxicological studies in rat and dog were reported. Our findings validate the innovative concept of interference with mitotic checkpoints and justify clinical proof of concept studies evaluating BUB1 inhibitor BAY 1816032 in combination with taxanes in order to enhance their efficacy and potentially overcome resistance. Citation Format: Gerhard Siemeister, Anne Mengel, Wilhelm Bone, Jens Schröder, Sabine Zitzmann-Kolbe, Hans Briem, Amaury E. Fernández-Montalván, Simon Holton, Ursula Mönning, Oliver von Ahsen, Sandra Johanssen, Arwed Cleve, Marion Hitchcock, Kirstin Meyer, Franz von Nussbaum, Michael Brands, Dominik Mumberg, Karl Ziegelbauer. BAY 1816032, a novel BUB1 kinase inhibitor with potent antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 287. doi:10.1158/1538-7445.AM2017-287
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 410466-3
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4828-4828
    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.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Frontiers Media SA ; 2024
    In:  Frontiers in Pharmacology Vol. 15 ( 2024-7-17)
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 15 ( 2024-7-17)
    Abstract: N-nitrosamines and nitrosamine drug substance related impurities (NDSRIs) became a critical topic for the development and safety of small molecule medicines following the withdrawal of various pharmaceutical products from the market. To assess the mutagenic and carcinogenic potential of different N-nitrosamines lacking robust carcinogenicity data, several approaches are in use including the published carcinogenic potency categorization approach (CPCA), the Enhanced Ames Test (EAT), in vivo mutagenicity studies as well as read-across to analogue molecules with robust carcinogenicity data. We employ quantum chemical calculations as a pivotal tool providing insights into the likelihood of reactive ion formation and subsequent DNA alkylation for a selection of molecules including e.g., carcinogenic N-nitrosopiperazine ( NPZ ), N-nitrosopiperidine ( NPIP ), together with N-nitrosodimethylamine ( NDMA ) as well as non-carcinogenic N-nitrosomethyl-tert-butylamine ( NTBA ) and bis (butan-2-yl) (nitros)amine ( BBNA ). In addition, a series of nitroso-methylaminopyridines is compared side-by-side. We draw comparisons between calculated reaction profiles for structures representing motifs common to NDSRIs and those of confirmed carcinogenic and non-carcinogenic molecules with in vivo data from cancer bioassays. Furthermore, our approach enables insights into reactivity and relative stability of intermediate species that can be formed upon activation of several nitrosamines. Most notably, we reveal consistent differences between the free energy profiles of carcinogenic and non-carcinogenic molecules. For the former, the intermediate diazonium ions mostly react, kinetically controlled, to the more stable DNA adducts and less to the water adducts via transition-states of similar heights. Non-carcinogenic molecules yield stable carbocations as intermediates that, thermodynamically controlled, more likely form the statistically preferred water adducts. In conclusion, our data confirm that quantum chemical calculations can contribute to a weight of evidence approach for the risk assessment of nitrosamines.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2024
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
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  • 6
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 4 ( 2019-02-15), p. 1404-1414
    Abstract: The catalytic function of BUB1 is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors and plays only a minor role in spindle assembly checkpoint activation. Here, we present the identification and preclinical pharmacologic profile of the first BUB1 kinase inhibitor with good bioavailability. Experimental Design: The Bayer compound library was screened for BUB1 kinase inhibitors and medicinal chemistry efforts to improve target affinity and physicochemical and pharmacokinetic parameters resulting in the identification of BAY 1816032 were performed. BAY 1816032 was characterized for kinase selectivity, inhibition of BUB1 signaling, and inhibition of tumor cell proliferation alone and in combination with taxanes, ATR, and PARP inhibitors. Effects on tumor growth in vivo were evaluated using human triple-negative breast xenograft models. Results: The highly selective compound BAY 1816032 showed long target residence time and induced chromosome mis-segregation upon combination with low concentrations of paclitaxel. It was synergistic or additive in combination with paclitaxel or docetaxel, as well as with ATR or PARP inhibitors in cellular assays. Tumor xenograft studies demonstrated a strong and statistically significant reduction of tumor size and excellent tolerability upon combination of BAY 1816032 with paclitaxel or olaparib as compared with the respective monotherapies. Conclusions: Our findings suggest clinical proof-of-concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors to enhance their efficacy and potentially overcome resistance.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 7
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. 1 ( 2022-01-05), p. 52-63
    Abstract: Metastasis to the brain is a major challenge with poor prognosis. The blood-brain barrier (BBB) is a significant impediment to effective treatment, being intact during the early stages of tumor development and heterogeneously permeable at later stages. Intravenous injection of tumor necrosis factor (TNF) selectively induces BBB permeabilization at sites of brain micrometastasis, in a TNF type 1 receptor (TNFR1)-dependent manner. Here, to enable clinical translation, we have developed a TNFR1-selective agonist variant of human TNF that induces BBB permeabilization, while minimizing potential toxicity. Methods A library of human TNF muteins (mutTNF) was generated and assessed for binding specificity to mouse and human TNFR1/2, endothelial permeabilizing activity in vitro, potential immunogenicity, and circulatory half-life. The permeabilizing ability of the most promising variant was assessed in vivo in a model of brain metastasis. Results The primary mutTNF variant showed similar affinity for human TNFR1 than wild-type human TNF, similar affinity for mouse TNFR1 as wild-type mouse TNF, undetectable binding to human/mouse TNFR2, low potential immunogenicity, and permeabilization of an endothelial monolayer. Circulatory half-life was similar to mouse/human TNF and BBB permeabilization was induced selectively at sites of micrometastases in vivo, with a time window of ≥24 hours and enabling delivery of agents within a therapeutically relevant range (0.5-150 kDa), including the clinically approved therapy, trastuzumab. Conclusions We have developed a clinically translatable mutTNF that selectively opens the BBB at micrometastatic sites, while leaving the rest of the cerebrovasculature intact. This approach will open a window for brain metastasis treatment that currently does not exist.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 8
    In: Cancers, MDPI AG, Vol. 12, No. 11 ( 2020-11-20), p. 3464-
    Abstract: IL3RA (CD123) is the alpha subunit of the interleukin 3 (IL-3) receptor, which regulates the proliferation, survival, and differentiation of hematopoietic cells. IL3RA is frequently expressed in acute myeloid leukemia (AML) and classical Hodgkin lymphoma (HL), presenting an opportunity to treat AML and HL with an IL3RA-directed antibody–drug conjugate (ADC). Here, we describe BAY-943 (IL3RA-ADC), a novel IL3RA-targeting ADC consisting of a humanized anti-IL3RA antibody conjugated to a potent proprietary kinesin spindle protein inhibitor (KSPi). In vitro, IL3RA-ADC showed potent and selective antiproliferative efficacy in a panel of IL3RA-expressing AML and HL cell lines. In vivo, IL3RA-ADC improved survival and reduced tumor burden in IL3RA-positive human AML cell line-derived (MOLM-13 and MV-4-11) as well as in patient-derived xenograft (PDX) models (AM7577 and AML11655) in mice. Furthermore, IL3RA-ADC induced complete tumor remission in 12 out of 13 mice in an IL3RA-positive HL cell line-derived xenograft model (HDLM-2). IL3RA-ADC was well-tolerated and showed no signs of thrombocytopenia, neutropenia, or liver toxicity in rats, or in cynomolgus monkeys when dosed up to 20 mg/kg. Overall, the preclinical results support the further development of BAY-943 as an innovative approach for the treatment of IL3RA-positive hematologic malignancies.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 9
    Online Resource
    Online Resource
    Wiley ; 2008
    In:  Pharmacology & Toxicology Vol. 87, No. 2 ( 2008-06-28), p. 89-95
    In: Pharmacology & Toxicology, Wiley, Vol. 87, No. 2 ( 2008-06-28), p. 89-95
    Type of Medium: Online Resource
    ISSN: 0901-9928
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 2151592-X
    SSG: 15,3
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4829-4829
    Abstract: KSP inhibitors (KSPis) are a versatile new payload class for the generation of highly potent and selective antibody-drug conjugates (ADCs) against different targets. For HER2 (c-ERBB2)- and TWEAKR (Fn14/ TNFRSF12A)-KSPi-ADCs, we have previously shown that they have potent and selective anti-proliferative activity and induce apoptosis in HER2- or TWEAKR-positive cancer cell lines in vitro. Moreover, TWEAKR-KSPi-ADCs induced strong and long-lasting anti-tumor efficacy and complete tumor regression in cell line- and patient-derived xenograft models. Shortcomings of clinically tested and marketed ADC payload classes are the off-target / on-toxophore dose-limiting toxicities observed in the clinic, in particular neutropenia and thrombocytopenia. Thrombocytopenia is a common side effect of 3 of 4 approved ADCs (including T-DM1, Kadcyla). Thrombocytes are generated by proliferation, differentiation and fragmentation of specific megakaryocyte (MK) progenitors. As ADCs can be taken up by differentiating hematopoietic stem cells the released toxic payload can inhibit MK proliferation/differentiation and prevent generation of platelets resulting in thrombocytopenia. The potential to induce thrombocytopenia of KSPi-based ADCs with different effector chemistries (ECs) was compared with the clinically approved ADC T-DM1 (with a non-cleavable SMCC linker) by evaluating their impact on in vitro megakaryocyte differentiation. To this end, the HemaToxTM MK assay (Stemcell, Cologne, Germany) was used which allows to assess the impact of compounds on proliferation/differentiation of CD34+ stem cells into GPIIb/IIIa (CD41) and CD45 double positive megakaryocytes by flow cytometry. Whereas the anti-HER2 Ab trastuzumab had no impact on MK differentiation, T-DM1 elicited MK toxicity in vitro. HER2-targeted or isotype control KSPi-ADCs with a legumain (LGMN) cleavable EC showed a comparably benign profile in the MK assay as trastuzumab, and a further improved profile versus KSPi-ADCs with a non-cleavable EC. Both features, the LGMN specific cleavage of KSPi-ADCs after internalization and cellular trafficking to the lysosome, and the released, non-cell-permeable KSPi payload, may contribute to an improved safety profile compared to T-DM1. This is further supported by the safety profile of a KSPi-ADC with a LGMN cleavable EC was also studied in vivo: In a repeat dose Cynomolgus study with the IL3RA-KSPi-ADC (BAY-943) dosed up to 10 mg/kg (QWx3), thrombocytopenia was not observed. These results indicate that KSPi-ADCs with specifically designed effector chemistries containing LGMN cleavable linkers have an improved safety profile in the MK assay with first evidence that this may translate also in a better safety profile with regard to lack of induction of thrombocytopenia in vivo. Citation Format: Anette Sommer, Pascale Buchmann, Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Christian Bertling, Jenny Thoennes, Sandra Johanssen, Christoph Schatz, Dominik Mumberg. Improved safety profile of HER2-KSPi-ADCs compared to T-DM1 in in vitro megakaryocyte assay predictive of thrombocytopenia [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 4829.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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