Exploiting protease activation for therapy

Bleuez, Chloe; Koch, Wolfgang F.; Urbach, Carole; Hollfelder, Florian; Jermutus, Lutz

doi:10.1016/j.drudis.2022.03.011

Cited by 19 publications

(21 citation statements)

References 124 publications

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“…Current treatment of certain congenital coagulopathies is based on the use of extended half-life exogenous recombinant coagulation factors [ 127 ] capable of neutralizing the action of matrix-degrading proteases. They are also based on the activation and inactivation of the proteases involved in the maturation and activation of, for example, transforming growth factor, myostatin, complement C3 and C5, or IL-1b and IL-18 [ 128 ], and on the inactivation of the retroviral proteases of HIV [ 129 ] or SARS-CoV-2, both at the level of the intracellular life cycle of the virus (protease 3CL [ 130 , 131 ]) and by facilitating the entry of the virus into the cell (TMPRSS2 [ 132 ]).…”

Section: Homeostasis Of Hemostasismentioning

confidence: 99%

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

Pablo-Moreno

Serrano

Revuelta

et al. 2022

IJMS

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The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.

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Section: Homeostasis Of Hemostasismentioning

confidence: 99%

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

Pablo-Moreno

Serrano

Revuelta

et al. 2022

IJMS

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“…Chen et al . 22 designed a EGFR antibody masked by a latency-associated peptide whose EC 50 was boosted by 7.5-fold.…”

Section: Discussionmentioning

confidence: 99%

“… 21 The most widely used approach has been activation by hydrolysis with enzymes that are overexpressed in the tumor or organ of interest. 9 , 10 , 11 , 12 , 13 , 16 , 15 , 20 , 22 , 23 , 24 , 25 , 26 Alternatives have also been investigated, 21 such as photo-cleavable linkers, 17 pH-dependent peptide-DNA locks, 18 or pH-sensitive masking peptides. 27 A number of masked antibodies that effectively decrease binding to the target when not at the tumor site and improve therapeutic index (i.e., the ratio of maximal tolerated dose to therapeutic dose) have been successfully engineered.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into the rational design of masked antibodies

Orozco

Bersellini

Irving

et al. 2022

mAbs

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Although monoclonal antibodies have greatly improved cancer therapy, they can trigger side effects due to on-target, off-tumor toxicity. Over the past decade, strategies have emerged to successfully mask the antigen-binding site of antibodies, such that they are only activated at the relevant site, for example, after proteolytic cleavage. However, the methods for designing an ideal affinity-based mask and what parameters are important are not yet well understood. Here, we undertook mechanistic studies using three masks with different properties and identified four critical factors: binding site and affinity, as well as association and dissociation rate constants, which also played an important role. HDX-MS was used to identify the location of binding sites on the antibody, which were subsequently validated by obtaining a high-resolution crystal structure for one of the mask-antibody complexes. These findings will inform future designs of optimal affinity-based masks for antibodies and other therapeutic proteins.

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“…Proteases play pivotal roles in inflammation and are considered therapeutic targets and biomarkers for different pathologies. Different reviews can be found on this subject [ 28 , 39 , 40 ]. The correlation between DED and inflammation and the involvement of proteases in inflammatory events show the potential for proteases to become new drug targets or biomarkers for DED.…”

Section: Proteases and Dry Eye Diseasementioning

confidence: 99%

Proteases and Their Potential Role as Biomarkers and Drug Targets in Dry Eye Disease and Ocular Surface Dysfunction

Ramos-Llorca

Scarpellini

Augustyns

2022

IJMS

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Dry eye disease (DED) is a multifactorial disorder that leads to ocular discomfort, visual disturbance, and tear film instability. DED is accompanied by an increase in tear osmolarity and ocular surface inflammation. The diagnosis and treatment of DED still present significant challenges. Therefore, novel biomarkers and treatments are of great interest. Proteases are present in different tissues on the ocular surface. In a healthy eye, proteases are highly regulated. However, dysregulation occurs in various pathologies, including DED. With this review, we provide an overview of the implications of different families of proteases in the development and severity of DED, along with studies involving protease inhibitors as potential therapeutic tools. Even though further research is needed, this review aims to give suggestions for identifying novel biomarkers and developing new protease inhibitors.

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Exploiting protease activation for therapy

Cited by 19 publications

References 124 publications

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

Mechanistic insights into the rational design of masked antibodies

Proteases and Their Potential Role as Biomarkers and Drug Targets in Dry Eye Disease and Ocular Surface Dysfunction

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