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  • 1
    Online Resource
    Online Resource
    The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
    Springer Science and Business Media LLC ; 2022
    In:  Nature Biotechnology Vol. 40, No. 12 ( 2022-12), p. 1845-1854
    Details
    In: Nature Biotechnology, Springer Science and Business Media LLC, Vol. 40, No. 12 ( 2022-12), p. 1845-1854
    Abstract: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19).
    Type of Medium: Online Resource
    ISSN: 1087-0156 , 1546-1696
    URL: Article
    DOI: 10.1038/s41587-022-01382-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
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    Abstract 3752: Preclinical pharmacology of MP0310: A 4-1BB/FAP bispecific DARPin drug candidate promoting tumor-restricted T-cell costimulation
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3752-3752
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3752-3752
    Abstract: Agonistic antibodies against the T cell costimulatory receptor 4-1BB (CD137) have proved to be very efficacious anti-tumor agents in preclinical animal models. However, clinical development of 4-1BB agonistic antibodies has met with limited success thus far. Anti-4-1BB monoclonal antibodies have either been reported to cause significant dose-limiting hepatotoxicity or demonstrated limited efficacy as single agent therapeutics. Here we describe the generation of a tumor-targeted 4-1BB agonist aimed at inducing more effective triggering of 4-1BB without associated systemic toxicity. Tumor targeting is achieved via fibroblast activation protein (FAP) which is abundantly expressed by cancer associated fibroblasts present in many solid tumors. Drug candidate MP0310 comprises DARPin domains binding to 4-1BB and FAP and is devoid of an antibody Fc domain. Compared to first generation monoclonal antibodies targeting 4-1BB, MP0310 shows high potency in vitro and less systemic activation in vivo. In vitro reporter and T cell assays indicate that MP0310 is a potent T cell co-stimulator whose activity is restricted to the presence of FAP-expressing cells. In humanized mouse xenograft studies, FAP-targeted 4-1BB activation induced potent co-stimulation of CD8 T cells leading to tumor growth inhibition. On the other hand, the DARPin molecule did not induce effects associated with strong systemic activation such as hepatotoxicity or exacerbation of graft versus host disease observed in such models, unlike the first generation FcγR-dependent 4-1BB antibodies. In addition, no systemic activation of T cell proliferation was observed in the absence of FAP-positive tumors. In healthy cynomolgus monkeys, administration of MP0310 did not induce systemic stimulation of memory T cell proliferation in contrast to an anti-4-1BB antibody despite MP0310 being fully cross-reactive to cyno 4-1BB and binding effectively to cyno FAP. Therefore, we conclude that the tumor-restricted co-stimulation of 4-1BB may prevent toxicities caused by systemic 4-1BB activation and provide a safe and effective way to boost anti-tumor T cell responses. This could allow more effective dosing and better combination therapies with checkpoint inhibitors and other immune stimulating drugs. MP0310 is in preparation to enter clinical development. Citation Format: Alexander Link, Julia Hepp, Christian Reichen, Patricia Schildknecht, Ivana Tosevski, Joanna Taylor, Laurent Juglair, Alexander Titz, Mirela Matzner, Ralph Bessey, Christof Zitt, Guy Lemaillet, Joerg Herbst, Keith M. Dawson, Hong Ji, Victor Levitsky, Dan Snell, Michael T. Stumpp, Andreas Harstrick, Elmar vom Baur. Preclinical pharmacology of MP0310: A 4-1BB/FAP bispecific DARPin drug candidate promoting tumor-restricted T-cell costimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3752.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3752
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    Abstract 4552: Tumor-restricted immune modulation by multispecific molecules from the DARPin toolbox
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4552-4552
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4552-4552
    Abstract: During the last years, immune-modulating drugs became an important cornerstone in the treatment of cancer patients. In particular, the PD1/PDL-1 and CTLA-4 antagonists revolutionized the field. However, only a limited number of patients benefit from these antagonistic molecules and more combination therapies are on the way to increase the number of patients benefiting from these novel therapies. Among the combinations, drugs that are T-cell or myeloid cell agonists belonging to the TNFR-superfamily show first promising clinical results. However, systemic immune activation bears the risk of severe side effects that will not allow using these powerful drugs at an effective dose. We have developed a new class of DARPin molecules that enable tumor-restricted immune cell activation of TNFR-superfamily agonists in the tumor only, thereby preventing systemic immune-activation. We generated DARPin molecules that bind with high affinity to TNFR-superfamily members (CD134, CD137 and CD40) and DARPin molecules that bind to tumor-specific antigens such as HER2 and EGFR or targets restricted to the tumor stroma compartment like FAP and extra-domain B of fibronectin (ED-B). Using these building blocks from our DARPin toolbox, we constructed a variety of multi-specific molecules consisting of a TNFR-superfamily receptor targeting DARPin molecule and a tumor-localizing DARPin molecule. In reporter cell assays the multi-specific DARPin molecules activate the respective TNF-superfamily receptor only in the presence of a cell expressing the tumor-localizer; e.g. the FAP-CD134 molecule activates CD134 only in the presence of a stromal cell expressing FAP and not in its absence. Moreover, activation of CD134 was dependent on the density of FAP expression on cells, showing that CD134 only becomes activated if a certain level of the tumor-localizing target is expressed. These finding were confirmed in experiments with primary immune cells where we see immune-cell activation only upon binding to the tumor-localizing target. This could be shown for multiple combinations ( & gt;8) and supports the concept that multi-specific DARPin molecules are powerful drug-candidates allowing tumor-restricted immune cell activation. Citation Format: Ulrike Fiedler, Christian Reichen, Joanna Taylor, Patricia Schildknecht, Sophie Barsin, Clara Metz, Anja Schlegel, Simon Fontaine, Denis Villemagne, Julia Ahlskog, Yvonne Kaufmann, Alexander Link, Nicolo Rigamonti, Julia Hepp, Michael T. Stumpp. Tumor-restricted immune modulation by multispecific molecules from the DARPin toolbox [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4552.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-4552
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
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    Comparison of an FAP-targeted, CD137 activating DARPin drug candidate with a non-targeted, CD137 activating antibody in a human PBMC transplanted HT-29 mouse tumor model.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. e14626-e14626
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. e14626-e14626
    Abstract: e14626 Background: Urelumab (BMS-663513) is a humanized monoclonal antibody binding to CD137 which, upon Fc-clustering, leads to activation of T-cells. Urelumab is currently in Phase 2 clinical development and has been reported to cause significant hepatotoxicities (around 15% Grade ≥2 ALT and AST elevation) when given as infusion every 3 weeks at doses ≥0.3 mg/kg. Currently ongoing clinical trials report decreased systemic toxicity but limited efficacy at lower doses of urelumab. We hypothesized that more effective triggering of CD137 without associated systemic toxicity may be achieved by targeting a CD137 agonistic engager without Fc to fibroblast activation protein (FAP) which is abundantly expressed in the stroma of many solid tumors. To achieve this, a targeted molecule belonging to the DARPin family of binding proteins was composed of one FAP- and two CD137-binding domains in a “beads on a string” format and tested in a mouse model with human PBMCs. Methods: Human PBMCs were used to reconstitute the immune system in NOG mice implanted subcutaneously with HT-29 human colon cancer cells. Mice were monitored for survival, body weight, and tumor size during the treatment phase of two weeks. Results: None of the mice in the control group died and no significant body weight loss was observed. Six of ten (60%) mice in the CD137 antibody group showed strong signs of graft vs. host disease and either died or reached the termination criterion of ≥20% body weight loss and were sacrificed. One of 30 (3%) mice died in the DARPin drug candidate groups but none of the animals showed body weight loss of ≥20% (p 〈 0.001, Log-rank test). Tumor growth inhibition was comparable for all treatment groups (around 20-30% at Day 18, p 〈 0.05 vs. control, Mann Whitney Test). Conclusions: This study confirms the hypothesis that systemic toxicities caused by the urelumab mode of action can be circumvented by FAP-targeting of a CD137 agonistic DARPin drug candidate while achieving comparable tumor growth inhibition. Consequently, higher clinical doses of tumor stroma-targeted agonistic DARPin drug candidates might be possible, and may result in stronger tumor growth inhibition.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.e14626
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 5
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    Abstract 3029: FAP-mediated tumor accumulation of a T-cell agonistic FAP/4-1BB DARPin drug candidate analyzed by SPECT/CT and quantitative biodistribution
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3029-3029
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3029-3029
    Abstract: Immunomodulating agents have revolutionized anti-cancer therapy. However, monotherapy is often not sufficient, and development of combination treatments is hampered by cumulative toxicity. In an attempt to overcome this challenge, a tumor-restricted agonistic 4-1BB/FAP DARPin drug candidate, which induces T-cell co-stimulation only when clustered by binding to fibroblast activation protein alpha (FAP) expressing cells, has been developed. FAP is a type II membrane-bound glycoprotein abundantly expressed in the stroma of many solid tumors by cancer-associated fibroblasts. As shown previously using in vitro and in vivo models (HT-29), co-stimulation induced by a FAP-targeted 4-1BB agonistic DARPin molecule leads to enhanced activation and expansion of CD8+ T-cells. To support clinical development of the drug candidate, tumor localization and accumulation were studied by whole-body SPECT/CT imaging and quantitative biodistribution using Indium-111 labeled DARPin molecules in a human colorectal adenocarcinoma (HT-29) xenograft model in CD1 nude mice. Immunohistochemical staining of tumor stroma confirmed local expression of FAP. Labeled 4-1BB/FAP DARPin molecules specifically accumulated in FAP-expressing tumor in vivo. SPECT/CT imaging and biodistribution revealed a maximum tumor accumulation of around 15% of the injected dose per gram of tissue around 72 h post injection. High tumor/blood ratios were observed one week post injection because the activity in the blood decreased according to the expected serum half-life of 26 h, determined in separate pharmacokinetic studies in BALB/c mice following single dose intravenous bolus injections. Based on the decrease of radioactivity in the tumor, a tumor residence half-life of approximately 4 days was calculated, indicating an extended tumor retention potentially due to FAP binding. No accumulation was observed in the muscle tissue that was choosen as a rather weakly-perfused control tissue. Taken together, FAP-targeting of a 4-1BB agonist DARPin molecule resulted in expected high tumor accumulation and retention compared to an untargeted version of the molecule, both relevant observations for further preclinical and clinical studies. These findings suggest that tumor-targeting via FAP has the potential to induce T-cell activation restricted to the tumor site, and thereby reducing toxicities caused by systemic 4-1BB activation. In conclusion, immunostimulatory drugs with tumor-targeted activity may have the potential to circumvent current limitations of immunotherapy and allow safe and effective use, in particular in combination therapy. Citation Format: Christian Reichen, Ralph Bessey, Christine DePasquale, Stefan Imobersteg, Martin Behe, Alain Blanc, Roger Schibli, Alexander Link, Laurent Juglair, Joanna Taylor, Patricia Schildknecht, Julia Hepp, Elmar vom Baur, Hong Ji, Christof Zitt, Victor Levitsky, Keith M. Dawson, Michael T. Stumpp, Dan Snell. FAP-mediated tumor accumulation of a T-cell agonistic FAP/4-1BB DARPin drug candidate analyzed by SPECT/CT and quantitative biodistribution [abstract]. In: Proceedings of the A merican Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3029.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3029
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    Abstract 2273: Selection of first-in-human clinical dose range for the tumor-targeted 4-1BB agonist MP0310 (AMG 506) using a pharmacokinetic/pharmacodynamics modeling approach
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2273-2273
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2273-2273
    Abstract: Following the clinical success of checkpoint inhibitors, cancer immunotherapy is rapidly expanding into combination treatments to enhance response rates and duration. Engagement of co-stimulatory molecules from the tumor necrosis factor receptor (TNFR) superfamily, including 4-1BB, may be a promising approach to enhance the benefits of cancer immunotherapy. Agonistic antibodies against the costimulatory receptor 4-1BB (CD137) have been shown to effectively enhance the anti-tumor activity of checkpoint inhibitors and other agents in preclinical animal models. However, the clinical development of 4-1BB agonistic antibodies has met with limited success thus far. Anti-4-1BB monoclonal antibodies have either been reported to cause significant dose-limiting hepatotoxicity or demonstrated limited efficacy as single agent therapeutics. We generated a DARPin® therapeutic candidate, MP0310 (AMG 506), which comprises domains binding to 4-1BB and fibroblast activation protein (FAP). MP0310 triggers 4-1BB activation only if bound and clustered via FAP which is abundantly expressed by cancer associated fibroblasts present in many solid tumors. In vitro functional assays indicate that MP0310 is a potent T cell co-stimulator in the presence of FAP-expressing cells. In vivo activity of tumor-targeted 4-1BB agonism was assessed in the HT-29 colon carcinoma xenograft model in PBMC humanized mice in combination with a T cell engager. Consistent with tumor targeting, MP0310 enhanced intra-tumoral CD8 T cell expansion while showing only limited systemic activity. We used a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to integrate in vitro and in vivo data to support the estimation of a minimal anticipated biological effect level (MABEL) and the relevant dose range for first in human (FIH) studies. In addition to a PK model describing the MP0310 concentrations over time in mouse and monkey, direct and indirect response models were used to describe receptor occupancy (RO), intra-tumoral CD8 T cell infiltration and peripheral CD8 count kinetics. Predictions from the combined PK and PD models using average intra-tumoral and peripheral drug concentrations (Cav) provide a MABEL dose with minimal expected systemic PD effects at 20% RO as well as the anticipated therapeutic dose range in humans. In conclusion, our PK/PD-modeling approach provides support for the selection of a safe starting dose for MP0310 (AMG506) in patients. It provides a rationale for selecting the maximum tested dose, and may help reduce the number of cancer patients receiving sub-therapeutic doses. MP0310 (AMG 506) is currently being evaluated in a Ph1 clinical study. Citation Format: Alexander Link, Laurent Juglair, Heïdi Poulet, Guy Lemaillet, Christian Reichen, Patricia Schildknecht, Ivana Tosevski, Joanna Robinson, Niina Veitonmäki, Jörg Herbst, Keith Dawson, Christof Zitt, Camila de Almeida, Rik de Greef, Victor Levitsky, Michael T. Stumpp, Hong Ji, Elmar Vom Baur. Selection of first-in-human clinical dose range for the tumor-targeted 4-1BB agonist MP0310 (AMG 506) using a pharmacokinetic/pharmacodynamics modeling approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2273.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2273
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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