Linker Length Matters, Fynomer-Fc Fusion with an Optimized Linker Displaying Picomolar IL-17A Inhibition Potency

Silacci, Michela; Baenziger-Tobler, Nadja; Lembke, Wibke; Zha, Wenjuan; Batey, Sarah; Bertschinger, Julian; Grabulovski, Dragan

doi:10.1074/jbc.m113.534578

Cited by 47 publications

(37 citation statements)

References 30 publications

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“…Therefore, we expect that tumor independent T cell activation and cytokine release-related syndromes induced by COVA420 through cross-linking of T cells with FcR-bearing accessory cells is unlikely to impede further development of COVA420. As the Fynomer technology offers a broad range of formatting flexibility [20], one could consider the possibility to generate scFv and/or Fab-based Fynomer fusions in order to further minimize the risk of cytokine release-related syndromes upon administration.…”

Section: Discussionmentioning

confidence: 99%

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Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

et al. 2015

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CD3 bispecific therapies retargeting T cells to tumors have recently demonstrated striking activity in patients. Several CD3 bispecific antibodies directed against various tumor targets are currently being investigated in the clinic across different tumors. One limitation of these therapies is the risk of target-related toxicity due to low-level expression of tumor antigen in normal tissue. In this study we have engineered a bispecific CD3/HER2 FynomAb, COVA420, which redirects T cells with high potency and selectivity to tumor cells with high HER2 expression in vitro and in vivo. COVA420 activity depends on high HER2 density as no activity was observed on cells with lower HER2 levels as found in human normal tissue. These results suggest that COVA420 may spare normal tissue expressing low levels of HER2 while still having uncompromised efficacy on tumor cells OPEN ACCESSAntibodies 2015, 4 427 with high HER2 expression. This concept may be applied to other cancer antigens that otherwise cannot be targeted by T cell redirecting approaches, and may therefore expand the applicability of CD3 bispecific FynomAbs to a larger number of solid tumors.

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Section: Discussionmentioning

confidence: 99%

“…Fynomers are small (6 kDa) engineered binding proteins that are derived from the SH3 domain of the Fyn kinase [16][17][18][19][20][21]. Fynomers can be genetically fused to different termini of antibodies resulting in bispecific proteins, termed FynomAbs, with different architecture, depending on the Fynomer fusion site.…”

Section: Introductionmentioning

confidence: 99%

Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

et al. 2015

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“…into C57BL/6 mice. Serum concentrations after 10 minutes, 6, 24, 48, 96, 120, 144, and 168 hours were determined by ELISA on immobilized HER2 (18).…”

Section: In Vivo Tumor Xenograft and Pharmacokinetic Studiesmentioning

confidence: 99%

A Bispecific HER2-Targeting FynomAb with Superior Antitumor Activity and Novel Mode of Action

Brack¹,

Attinger-Toller²,

Schade³

et al. 2014

Molecular Cancer Therapeutics

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Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2-targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-HER2 resistance. On the basis of the approved antibody pertuzumab, we have created a panel of bispecific FynomAbs, which target two epitopes on HER2. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. One bispecific FynomAb, COVA208, was characterized in detail and showed a remarkable ability to induce rapid HER2 internalization and apoptosis in vitro. Moreover, it elicited a strong inhibition of downstream HER2 signaling by reducing HER2, HER3, and EGFR levels in vitro and in vivo. Importantly, COVA208 demonstrated superior activity in four different xenograft models as compared with the approved antibodies trastuzumab and pertuzumab. The bispecific FynomAb COVA208 has the potential to enhance the clinical efficacy and expand the scope of HER2-directed therapies, and delineates a paradigm for designing a new class of antibody-based therapeutics for other receptor targets. Mol Cancer Ther; 13(8); 2030-9. Ó2014 AACR.

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“…Furthermore, in the same study it has been shown that in a mouse model of acute inflammation, the most potent 2C1-Fc fusion protein was able to efficiently inhibit IL-17A in vivo. According to these evidences, Fynomer-Fc fusion proteins represent new drug candidates for the treatment of IL-17A mediated inflammatory conditions including psoriasis [89].…”

Section: Bi-specific Monoclonal Antibodiesmentioning

confidence: 99%

Small molecules and antibodies for the treatment of psoriasis: a patent review (2010–2015)

Chiricozzi

Saraceno

Novelli

et al. 2016

Expert Opinion on Therapeutic Patents

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Though the recent introduction of new antipsoriatic agents has facilitated the management of long-term psoriasis, there is still a strong desire for alternative therapeutic options. Indeed, there remain unmet needs regarding safety and efficacy of psoriasis treatment that should be addressed. In this context, recently patented drugs may prove valid, interesting, and promising within the therapeutic paradigm.

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Linker Length Matters, Fynomer-Fc Fusion with an Optimized Linker Displaying Picomolar IL-17A Inhibition Potency

Cited by 47 publications

References 30 publications

Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

A Bispecific HER2-Targeting FynomAb with Superior Antitumor Activity and Novel Mode of Action

Small molecules and antibodies for the treatment of psoriasis: a patent review (2010–2015)

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