Novel Thrombolytic Drug Based on Thrombin Cleavable Microplasminogen Coupled to a Single‐Chain Antibody Specific for Activated GPIIb/IIIa

Bonnard, Thomas; Tennant, Zachary; Niego, Be׳eri; Kanojia, Ruchi; Alt, Karen; Jagdale, Shweta; Law, L. S.; Rigby, Sheena; Medcalf, Robert L.; Peter, Karlheinz; Hagemeyer, Christoph E.

doi:10.1161/jaha.116.004535

Cited by 22 publications

(22 citation statements)

References 62 publications

(88 reference statements)

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“…Studies have increasingly focused on the ScFv region only, which binds antigen(s), especially for cancer treatment and immunotherapy. 22,23 For example, the CTLA-4 antibody ScFv is projected to be an effective new antibody-type drug. 24 We not only isolated a therapeutic antibody fragment clone with therapeutic effects on a mouse MAAV vasculitis model, but also identified its VAP2 target antigen molecule.…”

Section: Discussionmentioning

confidence: 99%

<p>Efficacy of a recombinant single-chain fragment variable region, VasSF, as a new drug for vasculitis</p>

Kameoka¹,

Kishi²,

Koura

et al. 2019

DDDT

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Background: Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis is a pauci-immune disease with the inflammation of the small blood vessels. The efficacies of antibody drugs for induction therapies of vasculitis vary among cases. Here, we developed a novel clone of a single chain Fv region (ScFv) with vasculitis-specific therapeutic potential. Materials and methods: The clone, termed VasSF, was selected from our Escherichia coli expression library of recombinant human ScFv based on the therapeutic efficacy in an SCG/ Kj mouse model of MPO-ANCA-associated vasculitis (MAAV), such as improvement of the urinary score and decreased crescent formation in glomeruli, granulomatous in lung, MPO-ANCA biomarkers, the anti-moesin antibody, and some cytokine levels. Results: We identified vasculitis-associated apolipoprotein A-II (VAP2) as a target molecule of the clone and confirmed the independently-established VAP2 antibodies were also therapeutic in SCG/Kj mice. In MAAV, MPO-ANCA and cytokines stimulate neutrophils by facilitating heterodimer formation of VAP2 with apolipoprotein A-I in HDL. Conclusion: VasSF would constitute a novel antibody drug for vasculitis by suppressing the heterodimer formation of the apolipoproteins.

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Section: Discussionmentioning

confidence: 99%

<p>Efficacy of a recombinant single-chain fragment variable region, VasSF, as a new drug for vasculitis</p>

Kameoka¹,

Kishi²,

Koura

et al. 2019

DDDT

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“…• Fusion construct of targeting antibody against activated platelet and thrombin-activatable microplasminogen. 115 • Improvement of other existing thrombolytics.…”

Section: Nanoengineering Of New Thrombolytic Agentsmentioning

confidence: 99%

“…Of note, nonmagnetic metal conjugates, like fibrin-targeted, chitosan-coated gold nanoparticles, can serve as a monitoring tool for progression of t-PA-mediated thrombolysis by CT. 77 Finally, nanoengineering plays a major role in the ongoing search for improved thrombolytic agents. One such innovative construct fuses a targeting antibody against activated platelet to microplasminogen, engineered to be activated by thrombin instead of rt-PA. 115 This alteration of the plasminogen activating enzyme implies plasmin generation primarily around the thrombus site, but not systemically, potentially reducing the drug dose and alleviating the risk of sICH. Others have encapsulated urokinase (a cheaper, but less fibrin-specific alternative to rt-PA) in functionalized liposomes.…”

Section: Clot Removalmentioning

confidence: 99%

Applications of Nanotechnology in the Diagnosis and Therapy of Stroke

Landowski

Niego

Sutherland

et al. 2019

Semin Thromb Hemost

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Stroke is a leading cause of death and disability worldwide. The classification of stroke subtypes is difficult but critical for the prediction of clinical course and patient management, and limited treatment options are available. There is an urgent need for improvements in both diagnosis and therapy. Strokes have rapidly evolving phases of damage involving unique compartments of the brain, which imposes severe limitations for current diagnostic and treatment procedures. The rapid development of nanotechnology in other areas of modern medicine has ignited a widespread interest in its potential for the field of stroke. An important feature of nanoparticles is the relative ease in which their structures and surface chemistries can be modified for specific and potentially multiple, simultaneous purposes. Nanoparticles can be synthesized to carry and deliver therapeutics to specific cellular or subcellular compartments; they can be engineered to provide enhanced contrast for imaging based on the detection of changes in the blood flow; or possess ligand-specific chemistries which can facilitate diagnosis and monitor the treatment response. More specifically for a stroke, nanoparticles can be engineered to release their payload in response to the distinct extracellular processes occurring around the clot and in the ischemic penumbra, as well as aid in the detection of pathological hallmarks present at various stages of stroke progression. These capacities allow targeted release of disease-modifying agents in the affected brain tissue, increasing treatment efficacy, and limiting unwanted side effects. While nanospheres, liposomes, and mesoporous nanostructures all emerge as future prospects for stroke treatment and diagnosis, much of this potential is yet to be clinically realized. This review outlines aspects of nanotechnology identified as having potential to revolutionize the field of stroke.

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“…81 In further refinement, platelet α IIb β 3 -directed scFv was conjugated to a recombinant microplasminogen engineered to be activated by thrombin, such that thrombin-triggered release of platelet-targeted microplasminogen could enable local plasmin generation and clot lysis in mouse models of mesenteric thrombosis and PE. 82 An alternate "clot-targeted triggerable release" design for fibrinolytic agent tPA was also recently reported, where tPA was camouflaged by albumin by two different strategies, one by conjugating anionically modified tPA (modified by low-molecular-weight heparin [LMWH]) with cationically modified albumin (modified by protamine) and the other by conjugating albumin to tPA via a thrombin-cleavable peptide linker sequence GFPRGFPAGGC. 83 An additional component of this design was potential decoration of the albumin-based camouflage shell with clot-homing ligands (e.g., the platelet α IIb β 3 targeting peptide CQQHHLGGAK-QAGDV derived from fibrinogen) such that upon homing to the clot, the shedding of the albumin camouflage shell could be rendered by heparin dosing (to reverse heparin-protamine association) or thrombin-triggered cleavage of the linker, leading to clot-localized release of tPA.…”

Section: Direct Modification Of Therapeutic Agentsmentioning

confidence: 99%

Vascular Nanomedicine: Current Status, Opportunities, and Challenges

Sun

Gupta

2019

Semin Thromb Hemost

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The term “nanotechnology” was coined by Norio Taniguchi in the 1970s to describe the manipulation of materials at the nano (10−9) scale, and the term “nanomedicine” was put forward by Eric Drexler and Robert Freitas Jr. in the 1990s to signify the application of nanotechnology in medicine. Nanomedicine encompasses a variety of systems including nanoparticles, nanofibers, surface nano-patterning, nanoporous matrices, and nanoscale coatings. Of these, nanoparticle-based applications in drug formulations and delivery have emerged as the most utilized nanomedicine system. This review aims to present a comprehensive assessment of nanomedicine approaches in vascular diseases, emphasizing particle designs, therapeutic effects, and current state-of-the-art. The expected advantages of utilizing nanoparticles for drug delivery stem from the particle's ability to (1) protect the drug from plasma-induced deactivation; (2) optimize drug pharmacokinetics and biodistribution; (3) enhance drug delivery to the disease site via passive and active mechanisms; (4) modulate drug release mechanisms via diffusion, degradation, and other unique stimuli-triggered processes; and (5) biodegrade or get eliminated safely from the body. Several nanoparticle systems encapsulating a variety of payloads have shown these advantages in vascular drug delivery applications in preclinical evaluation. At the same time, new challenges have emerged regarding discrepancy between expected and actual fate of nanoparticles in vivo, manufacturing barriers of complex nanoparticle designs, and issues of toxicity and immune response, which have limited successful clinical translation of vascular nanomedicine systems. In this context, this review will discuss challenges and opportunities to advance the field of vascular nanomedicine.

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Novel Thrombolytic Drug Based on Thrombin Cleavable Microplasminogen Coupled to a Single‐Chain Antibody Specific for Activated GPIIb/IIIa

Cited by 22 publications

References 62 publications

<p>Efficacy of a recombinant single-chain fragment variable region, VasSF, as a new drug for vasculitis</p>

<p>Efficacy of a recombinant single-chain fragment variable region, VasSF, as a new drug for vasculitis</p>

Applications of Nanotechnology in the Diagnosis and Therapy of Stroke

Vascular Nanomedicine: Current Status, Opportunities, and Challenges

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