Targeting cytokines to inflammation sites

Adams, Gill; Vessillier, Sandrine; Dreja, Hanna; Chernajovsky, Yuti

doi:10.1038/nbt888

Cited by 61 publications

(79 citation statements)

References 45 publications

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“…The remaining 4 linkers contained an MMP‐cleavable site (PLGLWA) 25, either alone or in the presence of G 4 S‐flanking regions, and a scrambled MMP‐cleavable sequence (AGPLLW). To test the ability of the MMP enzyme to access, cleave, and activate the internal anti‐TNF domain, the aDVD constructs where incubated with physiologically relevant concentrations of recombinant MMP enzyme.…”

Section: Resultsmentioning

confidence: 99%

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

Onuoha

Ferrari

Sblattero

et al. 2015

Arthritis & Rheumatology

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ObjectiveBiologic drugs, such as the anti–tumor necrosis factor (anti‐TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies.MethodsActivatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM‐1), which is up‐regulated at sites of inflammation, and anti‐TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM‐1 and an internal arm that comprises the therapeutic domain of an anti‐TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)–cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets.ResultsIntact aDVD constructs demonstrated significantly reduced binding and anti‐TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti‐TNF inhibitory capacities as the parent molecules.ConclusionThe design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off‐target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of RA and other inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

Onuoha

Ferrari

Sblattero

et al. 2015

Arthritis & Rheumatology

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“…It has been shown in previous work with cytokines that IFN fusion with LAP has a longer halflife (13). By fusion with the LAP domain, melittin could have a longer half-life, especially if delivered via recombinant adenovirus, but still behave as a fast-acting compound once released by MMP2 cleavage.…”

Section: Discussionmentioning

confidence: 99%

“…Upon activation, the active TGF-ß is released from this shell by proteolytic cleavage of the LAP domain (12). Taking advantage of this natural LAP protective shell, a hybrid IFN-ß with a LAP domain and an MMP cleavage site has been successfully engineered to target inflammation sites (13). This latent IFN-ß will only be activated by MMP cleavage.…”

Section: Introductionmentioning

confidence: 99%

In vitro- and in vivo-targeted tumor lysis by an MMP2 cleavable melittin-LAP fusion protein

Holle

Song²,

Holle³

et al. 2009

Int J Oncol

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Abstract. Chemotherapy is one of the main treatment options for cancer, but the effectiveness of chemotherapeutic drugs is severely limited due to their systemic toxicity. Therefore, the need for a more targeted approach in tumor treatment is obvious. A tumor-activated agent would decrease systemic toxicity as well as increase the efficacy of the treatment. It has previously been shown that the latency of pro-TGF-ß is conferred by dimerization of two latency-associated peptides (LAP) that form a protective shield, which is cleaved off upon activation by matrix metalloproteinases (MMPs). It has also been shown that the fusion of this LAP peptide with other cytokines can confer their latency. In the present study, a recombinant adenovirus with a fusion gene encoding a tumor-activated pro-cytolytic peptide was made in which the LAP domain of TGF-ß was fused with melittin, a potent cytolytic toxin, with an MMP2 cleavage site in between the two. In vitro studies show that the melittin-MMP2-LAP recombinant adenovirus can be activated by MMP2 which leads to the release of free melittin to lyse the target cells. In vivo studies show approximately a 70% decrease in B16 tumor volume in melittin-MMP2-LAP recombinant adenovirustreated mice as compared to control mice. No significant systemic toxicity was observed in the treated mice.

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“…Whether this approach is sufficiently safe has not been thoroughly investigated and it is of concern that in cases of an infectious pathogen constitutive expression of a systemic nature could be detrimental. Advances in protein engineering, such as the development of novel TNF inhibitors, 77 latent cytokines that become activated at sites of disease, 101 and the targeting of cytokines to specific sites via fusion to scFv moieties (immunocytokines), 102 hold promise that systemic gene therapy can be made safer, targeted, and very effective.…”

Section: Current Status and Future Directionsmentioning

confidence: 99%