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  • 1
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    Abstract 1993: Biomarker analyses from the Phase I clinical trial of the first-in-class SIRPa immune checkpoint inhibitor BI765063 in patients with advanced solid tumors
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1993-1993
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1993-1993
    Abstract: Background: BI 765063 (OSE-172) is a humanised IgG4 monoclonal antibody which binds selectively to the V1 allele of Signal Regulatory Protein α [SIRPα] blocking the SIRPα/CD47 “don't eat me” pathway. Preclinical studies showed that SIRPα blockage led to macrophage and T-cell recruitment into tumor xenografts, and induced upregulation of chemokines, cytokines and adaptive immune function genes in human tumor explants (Gauttier et al., 2020). The goal of the biomarker analyses was to characterize the BI 765063 impact on peripheral blood immune cells (PBMCs) and the tumor microenvironment (TME). Methods: Fifty patients (26 V1/V1, 24 V1/V2) received BI 765063 IV from 0.02 mg/kg to 36 mg/kg every 3 weeks. Paired tumor biopsies were collected before and 2 weeks after first BI 765063 infusion. PBMCs were collected before, then 4 h, 1, 14, and 21 days after first infusion. BI 765063 receptor occupancy (RO) was determined on peripheral CD14+ monocytes. Immunophenotyping of PBMCs was performed by flow-cytometry. TME was analysed with a Brightplex® IHC panel including CD8+ T-cells, CD68+ macrophages, SIRPα, CD47, and PD-L1. Tumor gene expression profiling was performed using the Pan Cancer Immune gene set. Results: BI 765063 full RO saturation was achieved at trough levels (C2D1, pre-dose) in V1/V1 patients treated with doses of 6 mg/kg and higher, while V1/V2 patients showed a more heterogeneous RO ranging from 40-80%, reaching an apparent saturation at ≥ 12 mg/kg. An increase of activated CD80+/CD14+ and CD40+/CD14+ monocytes in PBMCs was observed at 24 h post-treatment in both, V1/V1 and V1/V2 patients. In paired tumor biopsies, IFNγ, MHCII antigen presentation gene pathways, and CCL7 transcripts appeared to be upregulated at C1D15 in patients with a systemic exposure of ≥ 100 µg/ml. One patient with hepatocellular carcinoma (HCC) and liver and lung metastases treated with BI 765063 monotherapy at 24 mg/kg achieved partial response (Champiat et al., ASCO, 2021). Baseline tumor biopsy of that patient showed that 66% of HCC tumor cells were CD47+ and 87% of CD68+ macrophages were SIRPα+. Furthermore, high levels of CD8+ T-cells were observed at baseline. At C1D15 increased CD68+ macrophage infiltration, sustained CD8 T-cell tumor accumulation and higher PD-L1 CPS (48% at baseline vs 75% at C1D15) were observed. Analysis of paired tumor biopsies in other patients showed that often, increased levels of tumor CD68+ macrophages were accompanied by CD8+ T-cell infiltration. Conclusion: This early biomarker analysis in patients with a wide range of solid tumors and treated with the first-in-class SIRPa inhibitor BI 765063 show encouraging signs of potentially mode-of-action related changes, both in peripheral blood and the TME. These early signals will be further evaluated in similar samples from the ongoing expansion cohorts in more homogeneous patient populations. Citation Format: Stephane Champiat, Philippe A. Cassier, Nuria Kotecki, Carlos Gomez-Roca, Aurélien Marabelle, Armelle Vinceneux, Christiane Jungels, Mabrouk Elgadi, Ralph Graeser, Thomas Vandewalle, Isabelle Girault, Nina Salabert-Le Guen, Nicolas Poirier, Bérangère Vasseur, Dominique Costantini, Claudia Fromond, Jean-Pierre Delord. Biomarker analyses from the Phase I clinical trial of the first-in-class SIRPa immune checkpoint inhibitor BI765063 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1993.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1993
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    Abstract 105: A rational approach for the discovery of inhibitors of NSD2 for the treatment of cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 105-105
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 105-105
    Abstract: Multiple myeloma (MM) is a plasma cell malignancy which accounts for approximately 10% of hematologic malignancies. Despite the introduction of new therapeutic agents, MM remains incurable and nearly all patients ultimately relapse. About 20% of MM are due to a chromosomal translocation t(4;14) leading to overexpression of the NSD2 histone methyltransferase. NSD2 catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Several studies have shown that in MM harboring the translocation t(4;14), oncogenic programming is dependent on the methyltransferase activity of NSD2. In addition, the NSD2 overactivity is also observed in prostate and lung cancers. Thus, NSD2 is a potential target for cancers, for which no selective drug is available to date. Using the AlphaLisa™ technology, we screened 240,000 compounds coming from our proprietary library. The assay is based on the detection of H3K36me2 on nucleosome by a specific antibody. False positives hits were removed by a technological counterscreen, and compounds with redox activity were excluded. This strategy allowed us to identify about 200 compounds. To focus on the most interesting ones, an orthogonal counterscreen based on 3H SAM incorporation is being completed. In parallel to the biochemical screening, we are developing secondary cellular assays based on the H3K36me2 methylation and proliferation to further confirm hit activity. To our knowledge, no NSD2 inhibitor have been identified to date despite several screening effort performed by other groups. Our library has already produced new chemical starting points for other KMTs, and we believe that our hits could be promising starting points to generate potent and selective NSD2 inhibitors. Citation Format: Claudia Fromond, Xavier Espanel, Anne Soudé, Laurent Chene, Philippe Masson, Benaïssa Boubia, Christian Montalbetti, Pierre Broqua. A rational approach for the discovery of inhibitors of NSD2 for the treatment of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 105. doi:10.1158/1538-7445.AM2015-105
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-105
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    366 Combined exploratory immunophenotyping and transcriptomic tumor analysis in patients treated with OSE2101 vaccine in HLA-A2+ advanced non-small cell lung cancer (NSCLC) from the ATALANTE-1 trial
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. Suppl 2 ( 2021-11), p. A394-A394
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. Suppl 2 ( 2021-11), p. A394-A394
    Abstract: OSE2101 (Tedopi®) is an anticancer vaccine with HLA-A2+ restricted modified epitopes targeting five tumor-associated antigens (TAAs) frequently expressed in lung cancer (CEA, HER2, MAGE2, MAGE3, P53). Step-1 results of the phase III, randomized, open-label ATALANTE-1 study comparing Tedopi® vs standard treatment (SoC) showed a favorable benefit/risk of Tedopi® over SoC (HR 0.71 for overall survival OS) in HLA-A2+ NSCLC patients in 2nd or 3rd line treatment after progression on immune checkpoint blockers (ICB). 1 We analyze available tumor biopsies at initial diagnosis from some patients treated with Tedopi® to determine the expression of the 5 TAAs and to identify other tumor factors associated with long-term survival. Methods Tumor biopsies were available for 8 HLA-A2+ (blood test) stage IV NSCLC patients included in the trial. Primary ( 〈 12 weeks) and secondary (≥ 12 weeks) resistance to ICB were observed in 3 (38%) and 5 (62%) of patients. Best response to Tedopi® and OS were: 1 partial response (PR) (OS of 33 months), 3 stable disease (SD) (OS of 22, 26 and 41 mo.) and 4 disease progression (PD) (OS of 3, 4, 30 and 31 mo.). HLA-class I, PD-L1, CD8 T-cells, HER2, CEA and P53 tumor expression were evaluated by immunohistochemistry (IHC). NanoString gene expression profiling was performed using the Pan Cancer Immune gene set. Results HLA-class I was expressed in all tumor samples. IHC analysis revealed that P53, CEA and HER2 were expressed in 6/7, 5/7 and 0/7 patients, respectively. P53, CEA, HER2, MAGE2, and MAGE3 were detected at RNA level in 5/5 tested patients (table 1). IMMUNOSCORE® IC CD8/PDL1 analysis showed High/High, High/Low and Low/Low scores for 1/7, 1/7 and 5/7 patients, respectively. The High/High IMMUNOSCORE® with a pronounced CD8+ T-cell tumor infiltration was observed in the patient with PR. High percentage of tumor cells expressing P53 (69%–97%) and overexpression of genes associated with activated macrophages (TREM2, MARCO, SLC11A1, CHIT1, SERPINB2) were observed in the PR and SD patients. High IFN-gamma and Expanded Immune Gene Signature scores were observed in long-term survivor patients with secondary resistance to ICB, even after progressive disease. Abstract 366 Table 1 Summary of clinical and translational data CEA Carcinoembryonic antigen; HER2: Human Epidermal Growth Factor Receptor-2; ICB: Immune checkpoint blocker; IHC: Immunohistochemistry; ND: Not determined; OS: Overall Survival; Patient ID: Patient identification; PDL1: Programmed death-ligand 1; PFS: Progression-free survival; ssGSEA: Single-sample Gene Set Enrichment Analysis. Blue bars = Length of overall survival; Green bars = Gene Signature upregulation; Red bars = Gene Signature downregulation Conclusions This study shows that all HLA-A2+ patients (blood test), expressed HLA class I in the tumors at initial diagnosis. Transcriptomic data in the patients that benefited from Tedopi® showed activated macrophage pathway, high IFN-gamma and Expanded Immune Gene Signatures scores. These data will be validated on larger number of patients treated with Tedopi® after the step 2 analysis. Acknowledgements We thank Julie Le Boulicaut, François Montestruc and Constant Josse (eXYSTAT, Malakoff, France) for the statistical analysis, and HalioDx for the IHC and NanoString analysis. Trial Registration EudraCT number 2015-003183-36; NCT number: NCT02654587 Reference Giaccone, et al. Activity of OSE-2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (ICI): step 1 results of phase III ATALANTE-1 randomised trial. ESMO meeting 2020, abstract #1260MO. Ethics Approval The study protocol and its related documents (including the patient information and informed consent form) received approval from the Institutional Review Board (IRB), and the Competent Authority prior to study initiation. Consent Each patient gave his/her written informed consent prior to study enrolment.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-SITC2021.366
    Language: English
    Publisher: BMJ
    Publication Date: 2021
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    Abstract 894: Discovery of YAP-TEAD protein-protein interaction (PPI) inhibitors for cancer therapy
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 894-894
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 894-894
    Abstract: The Hippo pathway is emerging as a critical player in several processes involved in cancer progression, including cell proliferation and EMT. YAP mediates the downstream effects of Hippo signaling, and high nuclear expression of YAP has been documented in many tumors types. YAP translocates to the nucleus, binds to TEAD transcription factor and drives the expression of growth factors, including CTGF, Cyr61 and surviving, suggesting that therapies targeting YAP-TEAD interaction are likely to have clinical impact for the treatment of cancer patients. However, due to the challenging nature of protein-protein interactions, a potent inhibitor that surpasses the affinity of the YAP-TEAD interactions has not been developed. All the critical residues for the YAP-TEAD interaction belong to interface S3. In order to identify interface S3 binders able to disrupt the YAP-TEAD interaction, we started a drug discovery program based on combined FBS/HTS strategy. TEAD protein drugabbility was assessed by fragment screen using NMR and SPR technologies. This approach, supported by assigned HSQC protein NMR information, provided fragment hits which were used as starting points for the identification of more potent binders. We also designed an AlphaLisa assay to validate the ability of our compounds to disrupt the YAP-TEAD interaction. 240,000 compounds of our proprietary library were screened using AlphaLisa assay. Several hits in the μM range were identified and further confirmed using SPR. Successful chemistry optimization generated compounds showing inhibitory activity in the AlphaLisa assay at 50-100 nM for the best compounds. To confirm the validity of our inhibitors, we constructed plasmids encoding TEAD protein fused to Gal4 DNA-binding domain. We transfected HEK293 cells with these plasmids together with Gal4-driven luciferase reporter plasmid in the presence of YAP S127A/S397A. Our compounds showed marked inhibition of cell-based transactivation assay at 3-10 μM. In order to establish a panel of cancer cell lines whose proliferation and target gene expression were either dependent or independent of YAP/TEAD, we selected several cell lines based on their mutational status, YAP nuclear localization, and their proliferative response to a siRNA targeting either YAP or TEAD. Our data show that YAP-TEAD inhibitors block both cell proliferation and target gene expression only in YAP/TEAD-dependent cell lines. In conclusion, we have successfully demonstrated that YAP-TEAD PPI can be inhibited by small molecules, and our compounds show activity in cell-based assays. Medicinal chemistry optimization on various series is ongoing to improve potency and DMPK parameters for further in vivo evaluation in cancer xenograft models. Citation Format: Anne Soude, Martine Barth, Stephanie Bocart, Frederic Thoreau, Philippe Masson, Isabelle Braccini, Christian Montalbetti, Pierre Broqua, Claudia Fromond. Discovery of YAP-TEAD protein-protein interaction (PPI) inhibitors for cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 894.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-894
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    Abstract A129: Generation of YAP-TEAD Protein-Protein Interaction (PPI) inhibitors for the treatment of cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A129-A129
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A129-A129
    Abstract: In the last few years the Hippo pathway has been recognized as a critical player in several processes involved in cancer progression, including cell proliferation, apoptosis and EMT. YAP and TAZ mediate the downstream effects of Hippo signaling, and high nuclear expression of YAP has been documented in many tumors including lung, colorectal, ovarian and skin cancers. When YAP translocates to the nucleus it binds to TEAD transcription factor and drives the expression of several growth factors, including CTGF, Cyr61 and survivin. This suggests that therapies targeting YAP-TEAD interaction are likely to have clinical impact for the treatment of cancer patients. However, due to the challenging nature of protein-protein interactions (PPIs), a potent inhibitor that surpasses the affinity of the YAP-TEAD interactions has not been developed. The YAP-TEAD complex has 3 interfaces, and all the critical residues for YAP-TEAD interaction belong to interface S3. In order to identify interface S3-TEAD binders able to disrupt the YAP-TEAD interaction, we started a drug discovery program based on a combined FBLD/HTS strategy. Drugabbility of TEAD protein was assessed by a fragment screen using NMR and SPR technologies. This approach, supported by assigned HSQC protein NMR information, provided fragment hits which were used as starting points for the identification of more potent binders. We also designed a dedicated AlphaScreen assay to validate the ability of our compounds to disrupt the YAP-TEAD interaction. Fifty thousand compounds of Inventiva's proprietary library were screened using the AlphaScreen assay. Several hits in the μM range were identified and further confirmed using SPR. Successful chemistry optimization based on the critical choice of starting Hit series during the Hit-to-Lead phase led us to generate compounds showing inhibitory activity in the AlphaScreen assay in the range of 50-100 nM for the best compounds. To further confirm the validity of our YAP-TEAD inhibitors, we constructed plasmids encoding TEAD protein fused to the Gal4 DNA-binding domain and transfected HEK293 cells with these plasmids together with a Gal4-driven luciferase reporter plasmid in the presence of YAP S127A. Our compounds showed a marked inhibition in the YAP-TEAD cell-based transactivation assay at concentrations ranging from 3-10 μM. In conclusion, we have successfully demonstrated that YAP-TEAD protein-protein interaction can be inhibited by small molecules, and that our compounds show activity in a cell-based assay. They are currently being evaluated for their ability to block cancer cell proliferation, and SAR on the various series is currently ongoing to improve potency and DMPK parameters for further in vivo evaluation in appropriate cancer xenograft models. Citation Format: Anne Soude, Martine Barth, Stephanie Bocart, Frederic Thoreau, Elina Mandry, Sylvie Contal, Philippe Masson, Isabelle Braccini, Christian Montalbetti, Pierre Broqua, Claudia Z-A Fromond. Generation of YAP-TEAD Protein-Protein Interaction (PPI) inhibitors for the treatment of cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A129.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-A129
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    Abstract 2129: Predictive response biomarkers from Phase I clinical trial of a SIRPalpha inhibitor BI765063, stand-alone and in combination with ezabenlimab, a PD1 inhibitor, in patients with advanced solid tumors
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2129-2129
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2129-2129
    Abstract: Background: Signal Regulatory Protein α [SIRPα] is an inhibitory membrane receptor expressed by myeloid cells (macrophages and myeloid-derived suppressor cells, MDSCs) and specifically binds to CD47. BI765063 is a selective anti-SIRPα monoclonal antibody acting as a checkpoint inhibitor of SIRPα/CD47 axis, promoting anti-tumor immunity through increase of dendritic cells antigen presentation, enabling MDSC differentiation, potentiating macrophage phagocytic/inflammatory properties and reinstating myeloid cell chemokine secretion and human T cell migration1. The escalation phase I study in advanced solid tumor patients (pts) showed preliminary efficacy as monotherapy (MONO), and in combination with PD-1 inhibitor ezabenlimab (COMBO). Our goal was to investigate BI765063 predictive response markers. Methods: A total of 68 patients (50 in MONO arm, 18 in COMBO arm) have been enrolled. Receptor occupancy (RO) was determined on peripheral CD14+ monocytes. Tumor biopsies were collected before treatment from 44 pts (62%) representative of overall population. Tumor microenvironment (TME) was analysed using a Brightplex® IHC panel comprised of CD68+ macrophages, CD11b+myeloid cells, SIRPα, and CD47. NanoString tumor profiling used PanCancer IO360 panel. Results: One partial response (PR) in MONO (Hepatocellular carcinoma HCC), and 4 PRs in COMBO (2 endometrial cancer, 1 HCC, 1 iRecist PR in MSS CRC) were observed2. BI 765063 full RO saturation was achieved in V1/V1 pts treated with doses of 6 mg/kg and higher, while V1/V2 patients showed a more heterogeneous RO ranging between 40-80%, reaching an apparent saturation at doses of 12 mg/kg and higher. Comparison of pts by best response showed that baseline tumor SIRPα+ expression in CD68+ macrophages and in CD11b+ myeloid cells were higher in PR versus PD pts. High percentage of CD11b+SIRPα+ myeloid cells at baseline significantly correlated with better OS (p=0.023), while CD68+SIRPα+ macrophages high expression in TME showed a trend for a better OS but did not reach statistical significance. The CD47 tumor expression did not correlate with the OS. Responder signature based on the top deregulated genes in responders versus non-responders at baseline was devised to sort relevant TCGA cohorts and showed strong positive correlation with TME MDSC infiltration (p≤0.0001). Conclusions: High levels of CD11b+SIRPα+ myeloid cells in TME at baseline, but not CD47 tumor expression, correlates with longer survival while MDSC signature in TME at baseline correlates with clinical response. Thus, suggesting that MDSCs expressing SIRPα in TME could represent a predictive efficacy biomarker. References: 1. Gauttier V. et al., 2020. J. Clin. Invest. 130: 6109; 2. Kotecki N. et al., 2021. ESMO meeting, abstract #983P Citation Format: Stéphane Champiat, Philippe A. Cassier, Nuria Kotecki, Carlos Gomez-Roca, Iphigenie Korakis, Ouali Kaissa, Antoine Italiano, Mabrouk M. Elgadi, Thomas Vandewalle, Isabelle Girault, Nina Salabert-Le Guen, Donogh O’Brien, Nicolas Poirier, Bérangère Vasseur, Dominique Costantini, Claudia Fromond, Françoise Bono, Jean-Pierre Delord. Predictive response biomarkers from Phase I clinical trial of a SIRPalpha inhibitor BI765063, stand-alone and in combination with ezabenlimab, a PD1 inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2129.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2129
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract 4524: A rational approach for the discovery of inhibitors of NSD2 for the treatment of multiple myeloma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4524-4524
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4524-4524
    Abstract: Multiple myeloma (MM) is a plasma cell malignancy which accounts for approximately 10% of hematologic malignancies. Despite the introduction of new therapeutic agents, MM remains incurable and nearly all patients ultimately relapse. About 20% of MM are due to a chromosomal translocation t(4;14) leading to overexpression of the NSD2 histone methyltransferase. NSD2 catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Several studies have shown that in MM harboring the translocation t(4;14), oncogenic programming is dependent on the methyltransferase activity of NSD2. Thus, NSD2 inhibitors are potential therapeutics for this devastating cancer Using the AlphaLisa™ technology, we screened 240,000 compounds coming from our proprietary library. The assay was based on the detection of H3K36me2 on nucleosome by a specific antibody. False positives hits were removed by a technological counterscreen, and compounds with redox or metal contamination activity were excluded. For confirmation purposes, an orthogonal counter-screen based on 3H SAM incorporation was performed. The IC50 obtained for one of the best compounds across the AlphaLisa and 3H SAM incorporation are very similar, showing values of 0.15 μM and 0.29 μM respectively for compound 1. Binding affinities measured by MST and SPR for compound 1 were consistent with the IC50 observed in the biochemical assays KD = 0.19 μM for MST and 1.7 μM by SPR. This compound was also shown to be a good binder by NMR (STD), and further experiments are planned to elucidate the selectivity and MOA of this series. To our knowledge, no NSD2 inhibitor have been identified to date despite several screening efforts performed by other groups. We believe that our hits are promising starting points to generate potent and selective NSD2 inhibitors. Citation Format: Claudia Fromond, Xavier Espanel, Severine Estevez, Vanessa Adarbes, Stephanie Bocart, Bruno Loillier, Anne Soude, Nathalie Urban, Frederic Bell, Philippe Masson, Benaïssa Boubia, Pierre Broqua, Christian Montalbetti. A rational approach for the discovery of inhibitors of NSD2 for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4524.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-4524
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    Safety, pharmacokinetics, efficacy, and preliminary biomarker data of first-in-class BI 765063, a selective SIRPα inhibitor: Results of monotherapy dose escalation in phase 1 study in patients with advanced solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 2623-2623
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 2623-2623
    Abstract: 2623 Background: BI 765063 is a humanized IgG4 monoclonal antibody antagonist of SIRPα (Signal Regulatory Protein α), which blocks the “don't eat me” signal of the SIRPα/CD47 axis, a critical innate immune checkpoint. SIRPα is expressed on myeloid cells. BI 765063 binds to the V1 SIRPα allele with high affinity and to the V2 SIRPα allele with low affinity. BI 765063 lacks SIRPγ binding to preserve T-cell activation. We report results of the completed BI 765063 monotherapy dose escalation in patients with advanced solid tumors. Methods: This study involves a step 1 dose escalation to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD), then a step 2 dose-confirmation expansion at recommended phase 2 dose. In Step 1, BI 765063 ascending doses, given IV every 3 weeks, were tested using a Bayesian Logistic Regression Model (BLRM) approach with overdose control. The endpoints were safety, pharmacokinetics, receptor occupancy (RO) in peripheral CD14 + monocytes and efficacy (RECIST 1.1). Results: Fifty patients (26 V1/V1, 24 V1/V2) received at least one dose of BI 765063. The most frequent tumors were ovarian (9), colorectal (8), lung (5), breast (4), melanoma (3), and kidney (3). No DLTs were reported up to the highest dose tested. MTD was not reached. The most frequent related adverse events were infusion related reaction (IRR) (46%), fatigue (12%), headache (10%), arthralgia and diarrhea (8% each). All related adverse events were mild to moderate, except one case of IRR Grade 3. No related anemia nor thrombocytopenia were observed. BI 765063 showed dose proportional exposure and full RO saturation in Cycle 1 after the fourth dose level. Clinical benefit was observed in 21/47 (45%) patients evaluable per RECIST 1.1. One patient with hepatocellular carcinoma (HCC) with liver and lung metastases and 7 prior lines of therapy showed a durable partial response maintained for 27 weeks treatment (ongoing). The baseline tumor biopsy of this patient showed high CD8 T-cell and macrophage infiltration. There was an increase in CD8 T-cell infiltration and activation on treatment. An increase in PD-L1 expression on tumor cells 2 weeks after first dosing was also observed. Analysis of paired tumor biopsies in other patients is ongoing. Conclusions: The first-in-class SIRPα inhibitor BI 765063 was well-tolerated, showed monotherapy activity, and sustained RO saturation. A durable partial response was observed in an advanced HCC patient. The on-treatment biopsy of the responder showed an increase in CD8 T-cell infiltration and activation. PD-L1 expression on tumor cells also increased. BI 765063 dose escalation in combination with ezabenlimab (anti-PD1 antibody) is ongoing. Clinical trial information: NCT03990233.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.2623
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    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 9
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    First-in-Human Study in Healthy Subjects with the Noncytotoxic Monoclonal Antibody OSE-127, a Strict Antagonist of IL-7Rα
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 6 ( 2023-03-15), p. 753-763
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 6 ( 2023-03-15), p. 753-763
    Abstract: OSE-127 is a humanized mAb targeting the IL-7Rα-chain (CD127), under development for inflammatory and autoimmune disease treatment. It is a strict antagonist of the IL-7R pathway, is not internalized by target cells, and is noncytotoxic. In this work, a first-in-human, phase I, randomized, double-blind, placebo-controlled, single-center study was carried out to determine the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of OSE-127 administration. Sixty-three healthy subjects were randomly assigned to nine groups: six single ascending dose groups with i.v. administration (0.002–10 mg/kg), a single s.c. treatment group (1 mg/kg), and two double i.v. injection groups (6 or 10 mg/kg). Subjects were followed during & lt;146 d. OSE-127’s pharmacokinetic half-life after a single dose increased from 4.6 (1 mg/kg) to 11.7 d (10 mg/kg) and, after a second dose, from 12.5 (6 mg/kg) to 16.25 d (10 mg/kg). Receptor occupancy was ≥95% at doses ≥0.02 mg/kg, and this saturation level was maintained & gt;100 d after two i.v. infusions at 10 mg/kg. IL-7 consumption was inhibited by OSE-127 administration, as demonstrated by a decreased IL-7 pathway gene signature in peripheral blood cells and by ex vivo T lymphocyte restimulation experiments. OSE-127 was well tolerated, with no evidence of cytokine-release syndrome and no significant alteration of blood lymphocyte counts or subset populations. Altogether, the observed lack of significant lymphopenia or serious adverse events, concomitant with the dose-dependent inhibition of IL-7 consumption by target cells, highlights that OSE-127 may show clinical activity in IL-7R pathway–involved diseases.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2200635
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
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  • 10
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    Abstract 99: Identification of G9a inhibitors by AlphaLisa™ technology and hit confirmation using MT-Glo™
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 99-99
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 99-99
    Abstract: Epigenetic processes control gene expression and play a major role in cell proliferation, survival and differentiation. Dysregulation of epigenetic mechanisms may lead to alterations in gene expression, resulting in cellular transformation and malignant outgrowth. Epigenetic enzymes are recognized as promising therapeutic targets for the treatment of cancer. Inventiva has several research programs in epigenetics, with specific focus on histone lysine methyltransferases (HKMTs). Emerging evidence suggests that G9a, a HKMT, able to mono and dimethylate H3K9 leading to the inactivation of tumor suppressor genes, plays a predominant role in lung and ovarian cancers. To identify novel G9a inhibitors, we used an AlphaLisa assay, with a histone H3-derived peptide and a specific antibody against H3K9me2. The assay, in 384-well format, displayed a robust Z-factor (0.84) with a signal to noise ratio around 800. We screened Inventiva's proprietary compound library using this assay. Three hundred thirty-six hits inhibited G9a by more than 60% (Hit rate: 0.14%). Despite the advantages offered by AlphaLisa technology, such as high S/N ratios and straightforward automation, this technology has been reported to generate a high number of false positives. In order to confirm the activity of our hits, we used a different technology, the methyltransferase Glo (MT-Glo) assay, which measures the reaction product SAH by luminescence read-out. Out of the 336 identified compounds, 75 were confirmed by this orthogonal screening (Hit confirmation rate: 22%). Additional compound characterization is ongoing to allow the selection of the best hit series for chemical optimization. In conclusion, the AlphaLisa assay, coupled with MT-Glo assay allowed the identification and confirmation of potent hits against G9a, as chemical starting points for our hit-to-lead optimization program. Citation Format: Claudia Fromond, Xavier Espanel, Laurent Chene, Philippe Masson, Benaïssa Boubia, Christian Montalbetti, Pierre Broqua. Identification of G9a inhibitors by AlphaLisa™ technology and hit confirmation using MT-Glo™. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 99. doi:10.1158/1538-7445.AM2015-99
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-99
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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