Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade

Dakhel, Sheila; Ongaro, Tiziano; Gouyou, Baptiste; Matasci, Mattia; Villa, Alessandra; Neri, Dario; Cazzamalli, Samuele

doi:10.18632/oncotarget.27320

Cited by 12 publications

(10 citation statements)

References 46 publications

(59 reference statements)

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“…CSG targeting of TNFα is critical to induce vessel dilation and improve tumour perfusion [49]. This outcome is different from the anti-vascular effect of TNFα, where TNFα-targeted peptides bind to tumour blood vessels or ECM proteins that are primarily located around tumour blood vessels [29,65,66]. Whilst we are interested in developing TNFα-CSG as an anti-cancer therapeutic, as an imaging agent, CSG-IO-NP may be used for diagnostic screening to identify patients who may benefit from TNFα-CSG therapy.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Detection of Desmoplasia by Targeted Delivery of Iron Oxide Nanoparticles to the Tumour-Specific Extracellular Matrix

Chopra

Yeow

et al. 2021

Pharmaceutics

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Diagnostic imaging of aggressive cancer with a high stroma content may benefit from the use of imaging contrast agents targeted with peptides that have high binding affinity to the extracellular matrix (ECM). In this study, we report the use of superparamagnetic iron-oxide nanoparticles (IO-NP) conjugated to a nonapeptide, CSGRRSSKC (CSG), which specifically binds to the laminin-nidogen-1 complex in tumours. We show that CSG-IO-NP accumulate in tumours, predominantly in the tumour ECM, following intravenous injection into a murine model of pancreatic neuroendocrine tumour (PNET). In contrast, a control untargeted IO-NP consistently show poor tumour uptake, and IO-NP conjugated to a pentapeptide. CREKA that bind fibrin clots in blood vessels show restricted uptake in the angiogenic vessels of the tumours. CSG-IO-NP show three-fold higher intratumoral accumulation compared to CREKA-IO-NP. Magnetic resonance imaging (MRI) T2-weighted scans and T2 relaxation times indicate significant uptake of CSG-IO-NP irrespective of tumour size, whereas the uptake of CREKA-IO-NP is only consistent in small tumours of less than 3 mm in diameter. Larger tumours with significantly reduced tumour blood vessels show a lack of CREKA-IO-NP uptake. Our data suggest CSG-IO-NP are particularly useful for detecting stroma in early and advanced solid tumours.

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Section: Discussionmentioning

confidence: 99%

Enhanced Detection of Desmoplasia by Targeted Delivery of Iron Oxide Nanoparticles to the Tumour-Specific Extracellular Matrix

Chopra

Yeow

et al. 2021

Pharmaceutics

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“…Our group has previously shown that therapeutic index and anti-cancer activity of potent cytokines such as IL-2 [ 11 , 15 ], IL-12 [ 39 ] or TNF [ 12 , 40 ], can be improved by fusing them to the L19 antibody in various formats. In this study, the therapeutic activity and tolerability of the parental L19-TNF WT was directly compared to the L19-TNF I97A mutant in a syngeneic mice model study.…”

Section: Resultsmentioning

confidence: 99%

“…In our study, the single point mutation I97A (located at the interface between TNF subunits) reduced the binding affinity of TNF to its cognate receptor TNFR1, resulting in an approximately 50-fold faster dissociation rate when compared to the wild type protein ( Figure 4 ). The I97A mutation enabled dose escalation of the immunocytokine beyond the previously established MTD (i.e., 375 μg/Kg), with non-detectable toxicity in a preclinical model of cancer [ 40 ]. In contrast, the respective wild type TNF fusion protein showed lower tolerability when administered at an equimolar dose in the same tumor model ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

An Attenuated Targeted-TNF Localizes to Tumors In Vivo and Regains Activity at the Site of Disease

Dakhel

Lizak

Matasci

et al. 2021

IJMS

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Antibody-cytokine fusion proteins (immunocytokines) are gaining importance for cancer therapy, but those products are often limited by systemic toxicity related to the activity of the cytokine payload in circulation and in secondary lymphoid organs. Tumor necrosis factor (TNF) is used as a pro-inflammatory payload to trigger haemorrhagic necrosis and boost anti-cancer immunity at the tumor site. Here we describe a depotentiated version of TNF (carrying the single point mutation I97A), which displayed reduced binding affinity to its cognate receptor tumor necrosis factor receptor 1 (TNFR-1) and lower biocidal activity. The fusion of the TNF(I97A) mutant to the L19 antibody promoted restoration of anti-tumor activity upon accumulation on the cognate antigen, the alternatively spliced EDB domain of fibronectin. In vivo administration of high doses (375 μg/Kg) of the fusion protein showed a potent anti-tumor effect without apparent toxicity compared with the wild type protein. L19-TNFI97A holds promise for the targeted delivery of TNF activity to neoplastic lesions, helping spare normal tissues.

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“…Alternatively, small molecule inhibitors have been used to temporarily inhibit the respective signaling pathway of the cytokine receptor [ 147 ]. This attenuates payload-mediated toxicity in the circulation.…”

Section: Current Challenges and Routes Of Future Payload Developmentmentioning

confidence: 99%

The present and future of immunocytokines for cancer treatment

Gout

Groen

Egmond

2022

Cell. Mol. Life Sci.

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Monoclonal antibody (mAb) therapy has successfully been introduced as treatment of several lymphomas and leukemias. However, solid tumors reduce the efficacy of mAb therapy because of an immune-suppressive tumor micro-environment (TME), which hampers activation of effector immune cells. Pro-inflammatory cytokine therapy may counteract immune suppression in the TME and increase mAb efficacy, but untargeted pro-inflammatory cytokine therapy is limited by severe off-target toxicity and a short half-life of cytokines. Antibody-cytokine fusion proteins, also referred to as immunocytokines, provide a solution to either issue, as the antibody both acts as local delivery platform and increases half-life. The antibody can furthermore bridge local cytotoxic immune cells, like macrophages and natural killer cells with tumor cells, which can be eliminated after effector cells are activated via the cytokine. Currently, a variety of different antibody formats as well as a handful of cytokine payloads are used to generate immunocytokines. However, many potential formats and payloads are still left unexplored. In this review, we describe current antibody formats and cytokine moieties that are used for the development of immunocytokines, and highlight several immunocytokines in (pre-)clinical studies. Furthermore, potential future routes of development are proposed.

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Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade

Cited by 12 publications

References 46 publications

Enhanced Detection of Desmoplasia by Targeted Delivery of Iron Oxide Nanoparticles to the Tumour-Specific Extracellular Matrix

Enhanced Detection of Desmoplasia by Targeted Delivery of Iron Oxide Nanoparticles to the Tumour-Specific Extracellular Matrix

An Attenuated Targeted-TNF Localizes to Tumors In Vivo and Regains Activity at the Site of Disease

The present and future of immunocytokines for cancer treatment

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