Safe eradication of large established tumors using neovasculature‐targeted tumor necrosis factor‐based therapies

Huyghe, Leander; Parys, Alexander Van; Cauwels, Anje; Lint, Sandra Van; Munter, Stijn De; Bultinck, Jennyfer; Zabeau, Lennart; Hostens, Jeroen; Goethals, A.; Vanderroost, Nele; Verhee, Annick; Uzé, Gilles; Kley, Niko; Peelman, Frank; Vandekerckhove, Bart; Brouckaert, Peter; Tavernier, Jan

doi:10.15252/emmm.201911223

Cited by 34 publications

(38 citation statements)

References 38 publications

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“…This differential expression pattern with respect to healthy tissues makes of CD13 an attractive target for the selective delivery of drugs or cytokines. Indeed, a CD13-specific single monomeric variable antibody domain tagged to tumor necrosis factor (TNF) or interferon (IFN)-γ has been used to kill tumors by targeting the tumor neovasculature [41]. In addition, peptides based in the NGR motif, found out in a phage display exercise to selectively bind CD13 [42], have already been tested in "tumor homing" strategies for chemotherapeutic agents (compiled in [3]) directed towards CD13-expressing cells.…”

Section: Discussionmentioning

confidence: 99%

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

et al. 2020

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Background: In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. Methods: Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. Results: CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation.

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Section: Discussionmentioning

confidence: 99%

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

et al. 2020

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“…Theoretically, similar approaches inducing "immunological reaction towards connective tissue" could be applied to situations where scarring or fibrosis has ensued, and the breakage of the fibrosis is desirable without side effects in the rest of the body. Most recently, the technology to target powerful cytokines was further refined by generating novel "designer cytokines" that have reduced systemic toxicity to one afforded by the selective delivery to target organ [85,86]. Namely, these "designer cytokines", TNFα and interferon-γ (IFNγ) are delivered to the angiogenic vasculature by a separate vascular targeting domain [85].…”

Section: Systemically Administered Anti-fibrotic Molecule Car-decorinmentioning

confidence: 99%

“…Most recently, the technology to target powerful cytokines was further refined by generating novel "designer cytokines" that have reduced systemic toxicity to one afforded by the selective delivery to target organ [85,86]. Namely, these "designer cytokines", TNFα and interferon-γ (IFNγ) are delivered to the angiogenic vasculature by a separate vascular targeting domain [85]. In addition to that, they have a mutated receptor binding site in the therapeutic molecule, i.e.…”

Section: Systemically Administered Anti-fibrotic Molecule Car-decorinmentioning

confidence: 99%

“…In addition to that, they have a mutated receptor binding site in the therapeutic molecule, i.e. TNFα and IFNγ, to reduce their biological activity [85,86]. The reduced biological activity, in turn, reduces the systemic toxicity of the molecules and makes them viable, tolerated and safe drug option for systemic administration.…”

Section: Systemically Administered Anti-fibrotic Molecule Car-decorinmentioning

confidence: 99%

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Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

Järvinen

Pemmari

2020

Nanomaterials

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Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic blood vessels in the regenerating tissues have a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an appealing opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives to a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine.

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“…Earlier, we demonstrated that AcTakines based on type I interferon (IFN), targeted to type I cross-presenting dendritic cells (DCs) 30 or tumor cells 31 , induce tumor eradication in mice without systemic side effects. More recently, we showed that treatment with a tumor necrosis factor (TNF)-based AcTakine targeted to CD13 allows for destruction of large established tumors without detectable toxicity in vivo 32 .…”

Section: Introductionmentioning

confidence: 99%

Specific targeting of IL-1β activity to CD8+ T cells allows for safe use as a vaccine adjuvant

et al. 2020

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Annual administration and reformulation of influenza vaccines is required for protection against seasonal infections. However, the induction of strong and long-lasting T cells is critical to reach broad and potentially lifelong antiviral immunity. The NLRP3 inflammasome and its product interleukin-1β (IL-1β) are pivotal mediators of cellular immune responses to influenza, yet, overactivation of these systems leads to side effects, which hamper clinical applications. Here, we present a bypass around these toxicities by targeting the activity of IL-1β to CD8 + T cells. Using this approach, we demonstrate safe inclusion of IL-1β as an adjuvant in vaccination strategies, leading to full protection of mice against a high influenza virus challenge dose by raising potent T cell responses. In conclusion, this paper proposes a class of IL-1β-based vaccine adjuvants and also provides further insight in the mechanics of cellular immune responses driven by IL-1β.

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Safe eradication of large established tumors using neovasculature‐targeted tumor necrosis factor‐based therapies

Cited by 34 publications

References 38 publications

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

Specific targeting of IL-1β activity to CD8+ T cells allows for safe use as a vaccine adjuvant

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