# Clot-Targeted Antithrombotics for Venous Thromboprophylaxis

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $404,000

## Abstract

Project Summary
 We currently lack effective therapies that reduce the risk of venous thromboembolism without an
attendant risk of bleeding. The assembled investigative team has recently identified single chain antibodies
that selectively block activated platelets and enrich therapeutics at the site of a developing thrombus. In the
process, we have discovered that selective targeting of activated platelets allows a wide variety of
antithrombotic agents to be efficacious, well below systemic concentrations that cause bleeding. In this
proposal, we postulate that selective targeting to activated platelets provides a means to locally concentrate
antiplatelet, anticoagulant, and fibrinolytic agents at the site of a growing venous thrombus without disrupting
essential hemostatic processes. We believe that this strategy will enable the design of high potency agents for
venous thromboprophylaxis, but without an increased risk of major bleeding. In this proposal, we intend to:
(1) Define the ability of clot-targeted “dual pathway” antithrombotics to prevent venous thrombosis
and inhibit postthrombotic vein wall fibrosis without hemostatic disturbance. The efficacy of “dual
pathway” antithrombotics based on SCE5-TAP, a single chain antibody with both antiplatelet and anticoagulant
activity will be defined using murine models of venous thrombosis. These studies will evaluate the capacity of
SCE5-TAP and related new variants to prevent venous thrombosis, limit early and late inflammatory
responses, and inhibit thrombus-induced remodeling of the vein wall without hemostatic disturbance.
(2) Determine the capacity of clot-targeted antithrombotics that display anti-platelet and fibrinolytic
activity to inhibit venous thrombosis and postthrombotic vein wall remodeling. The effectiveness of
antithrombotics based on SCE5-scuPA, a single chain antibody with both antiplatelet and fibrinolytic activity will
be defined using murine models of venous thrombosis alone or in combination with SCE5-TAP or related new
variants. We will also design recombinant clot-targeted hybrid constructs (SCE5-TAP-scuPA) that display
antiplatelet, anticoagulant, and fibrinolytic activity. The ability of these agents to inhibit thrombosis, promote
thrombus resolution, and limit the development of vein wall fibrosis will be defined.
(3) Mitigate the immune response to clot-targeted antithrombotics with the design of functionally
deimmunized TAP variants through deletion of immunogenic T cell epitopes. The cellular
immunogenicity of TAP (tick anticoagulant peptide) will be assessed and T cell epitopes, which drive the
response mapped in naïve human peripheral blood mononuclear cells. Computational tools will be used to
design functionally deimmunized TAP variants that will be evaluated in vitro and ex vivo for their maintenance
of FXa inhibitory activity and their reduction of cellular immunogenicity. The wild type and resulting lead
candidate will be assessed for cellular and humoral immun...

## Key facts

- **NIH application ID:** 9986015
- **Project number:** 5R01HL147855-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Elliot Chaikof
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986015

## Citation

> US National Institutes of Health, RePORTER application 9986015, Clot-Targeted Antithrombotics for Venous Thromboprophylaxis (5R01HL147855-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986015. Licensed CC0.

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