Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells

Hutt, Meike; Fellermeier-Kopf, Sina; Seifert, Oliver; Schmitt, Lisa C.; Pfizenmaier, Klaus; Kontermann, Roland E.

doi:10.18632/oncotarget.24379

Cited by 11 publications

(9 citation statements)

References 45 publications

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“…Furthermore, the use of tetramerization domains, e.g., derived from p53 and GCN4, was applied to obtain dodecavalent fusion proteins with further improved crosslinking activity (Fischer et al, 2017). The use of Fc-regions or whole antibodies represents another option to generate hexavalent molecules and, in addition, allows to obtain targeted derivatives, e.g., as has been shown for scTRAIL fusion proteins (Hutt et al, 2018;Siegemund et al, 2018).…”

Section: Targeting Tnfr2mentioning

confidence: 99%

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Fischer

Kontermann

Pfizenmaier

2020

Front. Cell Dev. Biol.

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Tumor necrosis factor (TNF) is a central regulator of immunity. Due to its dominant proinflammatory effects, drugs that neutralize TNF were developed and are clinically used to treat inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. However, despite their clinical success the use of anti-TNF drugs is limited, in part due to unwanted, severe side effects and in some diseases its use even is contraindicative. With gaining knowledge about the signaling mechanisms of TNF and the differential role of the two TNF receptors (TNFR), alternative therapeutic concepts based on receptor selective intervention have led to the development of novel protein therapeutics targeting TNFR1 with antagonists and TNFR2 with agonists. These antibodies and bio-engineered ligands are currently in preclinical and early clinical stages of development. Preclinical data obtained in different disease models show that selective targeting of TNFRs has therapeutic potential and may be superior to global TNF blockade in several disease indications.

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Section: Targeting Tnfr2mentioning

confidence: 99%

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Fischer

Kontermann

Pfizenmaier

2020

Front. Cell Dev. Biol.

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159

146

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“…12 The fusion of cytokines to antibodies, capable of selective localization to the tumor mass, has been proposed as a means to increase the therapeutic index of these biopharmaceuticals. [13][14][15] Some antibody-cytokine fusions are currently being investigated in the clinic for the treatment of different types of malignancies. [16][17][18][19][20][21][22][23][24] Interleukin-12 (IL12) is a heterodimeric cytokine consisting of the p40 and p35 subunits, linked by a disulfide bond.…”

Section: Introductionmentioning

confidence: 99%

The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8⁺ T cell activity and synergizes with immune checkpoint inhibitors

Puca

Probst

Stringhini

et al. 2019

Intl Journal of Cancer

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We describe the cloning and characterization of a novel fusion protein (termed L19‐mIL12), consisting of murine interleukin‐12 in single‐chain format, sequentially fused to the L19 antibody in tandem diabody format. The fusion protein bound avidly to the cognate antigen (the alternatively spliced EDB domain of fibronectin), retained the activity of the parental cytokine and was able to selectively localize to murine tumors in vivo, as shown by quantitative biodistribution analysis. L19‐mIL12 exhibited a potent antitumor activity in immunocompetent mice bearing CT26 carcinomas and WEHI‐164 sarcomas, which could be boosted by combination with checkpoint blockade, leading to durable cancer eradication. L19‐mIL12 also inhibited tumor growth in mice with Lewis lung carcinoma (LLC), but in this case, cancer cures could not be obtained, both in monotherapy and in combination. A microscopic analysis and a depletion experiment of tumor‐infiltrating leukocytes illustrated the contribution of NK cells and CD8+ T cells for the anticancer activity observed in both tumor models. Upon L19‐mIL12 treatment, the density of regulatory T cells (Tregs) was strongly increased in LLC, but not in CT26 tumors. A FACS analysis also revealed that the majority of CD8+ T cells in CT26 tumors were specific to the retroviral AH1 antigen.

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“…The apparent discrepancy to the in vitro data, demonstrating superior activity of tumour targeted versus non targeted hexavalent TRAIL molecules, but similar therapeutic potency in this particular in vivo tumour model is currently not fully understood, but important parameters begin to emerge. Thus both, antigen density and affinity of the targeting antibody in relation to the affinity of TRAIL to its cognate death receptors appear to be important 19 . Further studies using other in vivo tumour models are necessary to conclude on the benefit of targeting TRAIL to tumour cells for a maximum therapeutic output and safety.…”

Section: Discussionmentioning

confidence: 99%

“…Such hexavalent TRAIL molecules fulfil the expected criteria of enhanced, tumour selective activity in vitro and in vivo 10 , 13 – 17 . The targeting of TRAIL to the cell surface of tumour or tumour stroma cells, as realized by antibody-mediated binding to specifically overexpressed antigens, e.g., growth factor receptors or cell adhesion molecules, has been shown to result in further enhanced bioactivity 1 , 18 , 19 .…”

Section: Introductionmentioning

confidence: 99%

IgG-single-chain TRAIL fusion proteins for tumour therapy

Siegemund

Schneider

Hutt

et al. 2018

Sci Rep

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Single-chain formats of TNF-related apoptosis inducing ligand (scTRAIL) can serve as effector components of tumour-associated antigen-targeted as well as non-targeted fusion proteins, being characterized by high tumour cell-specific induction of apoptosis through death receptor activation. We studied the suitability of immunoglobulin G as a scaffold for oligovalent and bispecific TRAIL fusion proteins. Thus, we developed novel targeted hexa- and dodecavalent IgG-scTRAIL molecules by fusing scTRAIL to the C-terminus of either light (LC-scTRAIL) or heavy immunoglobulin chain (HC-scTRAIL), or to both ends (LC/HC-scTRAIL) of the anti-EGFR IgG antibody hu225. The binding specificity to EGFR and death receptors was retained in all IgG-scTRAIL formats and translated into high antigen-specific bioactivity on EGFR-positive Colo205, HCT116 and WM1366 tumour cell lines, with or without sensitization to apoptosis by bortezomib. In vivo, therapeutic potential was assessed for one of the targeted variants, HC-scTRAIL, compared to the non-targeted Fc-scTRAIL. Both molecules showed a significant reduction of tumour volume and synergism with a Smac mimetic in a Colo205 xenograft tumour model. The IgG-scTRAIL format allows directing a defined, highly bioactive form of TRAIL to a wide variety of tumour antigens, enabling customized solutions for a patient-specific targeted cancer therapy with a reduced risk of side effects.

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Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells

Cited by 11 publications

References 45 publications

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8⁺ T cell activity and synergizes with immune checkpoint inhibitors

IgG-single-chain TRAIL fusion proteins for tumour therapy

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Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells

Cited by 11 publications

References 45 publications

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors

IgG-single-chain TRAIL fusion proteins for tumour therapy

Contact Info

Product

Resources

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The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8⁺ T cell activity and synergizes with immune checkpoint inhibitors