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A Novel Prediction Platform to Enhance the Design of Therapeutic SERPINs

1Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands, 2Laboratory for Haemostasis, Inflammation and Thrombosis, Institut Nationale de la Santé et de la Recherche Médicale (Inserm), Paris, France, 3Utrecht University, Utrecht, Netherlands, 4Department of Medicine, College of Medicine, University of North Carolina, North Carolina, United States

Abstract Number: OC 05.3

Meeting: ISTH 2021 Congress

Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors

Background: Serine proteases are an essential driving force behind many physiological processes. As such, their activity needs to be tightly regulated. To prevent excessive activity, activated serine proteases are targeted by serine protease inhibitors (SERPINs). Under physiological conditions, there is a balance between the protease activity and the potency of the SERPIN. Changes in this balance may lead to pathology.
SERPIN specificity is mainly determined by its reactive center loop (RCL) and can be easily altered to change the SERPIN specificity or potency. As such, predicting the effects of RCL mutagenesis has substantial therapeutic potential. Currently, there is limited insight into how mutagenesis affects SERPIN behaviour, which is hampering the design of therapeutic SERPINs. This knowledge gap is further complicated by the sheer amount of mutants required to screen all possibilities within the RCL.

Aims: To develop a SERPIN specificity prediction platform and to apply this in the design of novel therapeutic SERPINs.

Methods: We developed a SERPIN specificity prediction platform by generating insights into RCL specificity per key position (P4-P4’). With these 160 variants, RCL contribution to the inhibition of seven coagulation proteases was identified and confirmed in separate test-cohorts.

Creation of α1-antitrypsin reactive center loop libraries spanning the P4-P4’ area.

 

Results: Significant correlation was found for five out of the seven targeted proteases. To further validate our platform, a third generation of APC-specific SERPINs were designed with improved efficacy and specificity. This translated into increased efficacy compared to the published 357KRK359 variant1 in in vitro coagulation assays, which was further validated in an in vivo model of Hemophilia A.

Conclusions: Based upon these insights, we conclude that the library-based approach offers unique insight into SERPIN RCL-specificity that will improve design of therapeutic SERPINs.
1Polderdijk, S.G., Adams, T.E., Ivanciu, L., Camire, R.M., Baglin, T.P. and Huntington, J.A. Design and characterization of an APC-specific serpin for the treatment of hemophilia. Blood 2017; 129:105-113.

To cite this abstract in AMA style:

Sanrattana W, Sefiane T, Smits S, Fens M, Monroe D, Lenting P, Maas C, de Maat S. A Novel Prediction Platform to Enhance the Design of Therapeutic SERPINs [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-novel-prediction-platform-to-enhance-the-design-of-therapeutic-serpins-2/. Accessed December 6, 2023.

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