Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Rα1 and IL-13Rα2

Popović, Bojana; Breed, J.; Rees, Dianne; Gardener, Matthew J.; Vinall, Lisa; Kemp, Ben; Spooner, Jennifer; Keen, J.M.; Minter, Ralph; Uddin, Ferzan; Colice, Gene; Wilkinson, T.; Vaughan, Tristan J.; May, Richard

doi:10.1016/j.jmb.2016.12.005

Cited by 142 publications

(121 citation statements)

References 35 publications

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“…A structural characterization showed that tralokinumab inhibits the cytokine by binding to its heterodimeric receptor, composed of IL-4Rα (targeted by dupilumab) and IL-13Rα1 [114], as well as to its decoy receptor, IL-13Rα2 (Fig. 1) [115]. Tralokinumab is in clinical trials for asthma, idiopathic pulmonary fibrosis (IPF), IBD, AD, and AA (NCT02684097, Table 1).…”

Section: Th2 Antagonismmentioning

confidence: 99%

The Changing Landscape of Alopecia Areata: The Therapeutic Paradigm

Renert‐Yuval

Guttman‐Yassky

2017

Adv Ther

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Alopecia areata (AA), a prevalent inflammatory cause of hair loss, lacks FDA-approved therapeutics for extensive cases, which are associated with very poor rates of spontaneous hair regrowth and major psychological distress. Current treatments for severe cases include broad immune-suppressants, which are associated with significant adverse effects, precluding long-term use, with rapid hair loss following treatment termination. As a result of the extent of the disease in severe cases, topical contact sensitizers and intralesional treatments are of limited use. The pathogenesis of AA is not yet fully understood, but recent investigations of the immune activation in AA skin reveal Th1/IFN-γ, as well as Th2, PDE4, IL-23, and IL-9 upregulations. Tissue analyses of both animal models and human lesions following broad-acting and cytokine-specific therapeutics (such as JAK inhibitors and ustekinumab, respectively) provide another opportunity for important insights into the pathogenesis of AA. As reviewed in this paper, numerous novel therapeutics are undergoing clinical trials for AA, emphasizing the potential transformation of the clinical practice of AA, which is currently lacking. Dermatologists are already familiar with the revolution in disease management of psoriasis, stemming from better understanding of immune dysregulations, and atopic dermatitis will soon follow a similar path. In light of these recent developments, the therapeutic arena of AA treatments is finally getting more exciting. AA will join the lengthening list of dermatologic diseases with mechanism-targeted drugs, thus changing the face of AA.

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Section: Th2 Antagonismmentioning

confidence: 99%

The Changing Landscape of Alopecia Areata: The Therapeutic Paradigm

Renert‐Yuval

Guttman‐Yassky

2017

Adv Ther

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“…Fig. 6B highlights the structural paratope evident from this structure (50), which reveals that the positions of the insertions are on the periphery of the antigen-binding site ( Fig. 6), with residues G68 in VL FWR3 loop and T93 in VL CDR3 constituting part of the paratope.…”

Section: Analysis Of the Kd Values Of Igg Variantsmentioning

confidence: 94%

“…6. Sites of affinity-enhancing mutations modelled on the tralokinumab::IL-13 complex crystal structure (50). (a) Insertions with large beneficial effect on BAK1 affinity were found in two different loops, the VL FWR3 loop (G68) and the VL CDR3 (D92-S95), in close proximity to the antigen, IL-13 (brown cartoon/surface).…”

Section: Fig 5 Correlations Of Functional and Structural Features Wmentioning

confidence: 99%

In vitroEvolution of Antibody Affinity via Insertional Mutagenesis Scanning of an Entire Antibody Variable Region

Skamaki

Emond

Chodorge

et al. 2020

Preprint

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We report the first systematic combinatorial exploration of affinity enhancement of antibodies by insertions and deletions (InDels). Transposon-based introduction of InDels via the method TRIAD was used to generate large libraries with random in-frame InDels across the entire scFv gene that were further recombined and screened by ribosome display. Knowledge of potential insertion points from TRIAD libraries formed the basis of exploration of length and sequence diversity of novel insertions by insertional-scanning mutagenesis (ISM). An overall 256-fold affinity improvement of an anti-IL-13 antibody BAK1 as a result of InDel mutagenesis and combination with known point mutations validates this approach and suggests that the results of this InDel approach and conventional exploration of point mutations can synergize to generate antibodies with higher affinity.SignificanceInsertion/deletion (InDel) mutations play key roles in genome and protein evolution. Despite their prominence in evolutionary history, the potential of InDels for changing function in protein engineering by directed evolution remains unexplored. Instead point mutagenesis is widely used. Here we create antibody libraries containing InDels and demonstrate that affinity maturation can be achieved in this way, establishing an alternative to the point mutation strategies employed in all previous in vitro selections. These InDels mirror the observation of considerable length variation in loops of natural antibodies originating from the same germline genes and be combined with point mutations, making both natural sources of functional innovation available for artificial evolution in the test tube.

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“…Two IL‐13–targeting antibodies, tralokinumab and lebrikizumab, are the most advanced IL‐13–specific biologics in clinical development for the treatment of AD (Figure ). Tralokinumab, an IgG4λ anti–IL‐13 monoclonal antibody derived from a human phage display library, prevents IL‐13 from binding to both IL‐13Rα1 and IL‐13Rα2 . The latter receptor has a short cytoplasmic tail and no known signalling motifs, and is thought to have an anti‐inflammatory, decoy function via internalization of excess IL‐13 .…”

Section: The Era Of Biologics and Emerging Therapeutic Approachesmentioning

confidence: 99%

Understanding the immune landscape in atopic dermatitis: The era of biologics and emerging therapeutic approaches

Moyle¹,

Cevikbas

Harden

et al. 2019

Experimental Dermatology

120

146

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Atopic dermatitis (AD) is a chronic, systemic, inflammatory disease that affects the skin and is characterized by persistent itch and marked redness. AD is associated with an increased risk of skin infections and a reduced quality of life. Most AD treatment options to date were not designed to selectively target disease‐causing pathways that have been established for this indication. Topical therapies have limited efficacy in moderate‐to‐severe disease, and systemic agents such as corticosteroids and immunosuppressants present with tolerability issues. Advances in the understanding of AD pathobiology have made possible a new generation of more disease‐specific AD therapies. AD is characterized by the inappropriate activation of type 2 T helper (Th2) cells and type 2 innate lymphoid (ILC2) cells, with a predominant increase in type 2 cytokines in the skin, including interleukin (IL)‐13 and IL‐4. Both cytokines are implicated in tissue inflammation and epidermal barrier dysfunction, and monoclonal antibodies targeting each of these interleukins or their receptors are in clinical development in AD. In March 2017, dupilumab, a human anti–IL‐4Rα antibody, became the first biologic to receive approval in the United States for the treatment of moderate‐to‐severe AD. The anti–IL‐13 monoclonal antibodies lebrikizumab and tralokinumab, which bind different IL‐13 epitopes with potentially different effects, are currently in advanced‐stage trials. Here, we briefly review the underlying pathobiology of AD, the scientific basis for current AD targets, and summarize current clinical studies of these agents, including new research to develop both predictive and response biomarkers to further advance AD therapy in the era of precision medicine.

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Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Rα1 and IL-13Rα2

Cited by 142 publications

References 35 publications

The Changing Landscape of Alopecia Areata: The Therapeutic Paradigm

The Changing Landscape of Alopecia Areata: The Therapeutic Paradigm

In vitroEvolution of Antibody Affinity via Insertional Mutagenesis Scanning of an Entire Antibody Variable Region

Understanding the immune landscape in atopic dermatitis: The era of biologics and emerging therapeutic approaches

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