# Exploring the mechanisms of action of anti-ADAMTS 13 antibodies in immune thrombotic thrombocytopenic purpura

> **NIH NIH K08** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2022 · $165,240

## Abstract

Project Summary/Abstract
Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by autoimmune
inhibition of the enzyme ADAMTS13. The only known substrate of ADAMTS13 is von Willebrand factor (VWF).
Cleavage of VWF by ADAMTS13 is needed to prevent accumulation of ultralarge VWF multimers in the
microvasculature, leading to end-organ damage and potentially life-threatening consequences. Anti-ADAMTS13
IgGs are responsible for the inhibition of the enzyme. The vast majority of inhibitory antibodies target a region of
ADAMTS13 that is principally responsible for binding to the domain of VWF cleaved by the enzyme. However,
the mechanism of inhibition of these antibodies is currently an area of active research, and it is not known if they
primarily prevent substrate binding or decrease catalytic turnover, or if different antibodies inhibit by different
mechanisms. Recent work has shown that ADAMTS13 in iTTP patient plasma exists primarily in a conformation
that exposes a cryptic epitope otherwise hidden when ADAMTS13 is in its latent state. The current paradigm of
ADAMTS13 activity defines this as a so-called “Open” state, and the latent state as “Closed”. A third state also
appears to exist in which ADAMTS13 has the cryptic episode exposed, but also is able to cleave VWF; this is
referred to here as the “Open and Primed” state. Anti-ADAMTS13 IgGs that target distal domains of the protein
appear capable of inducing both the “Open” and “Open and Primed” state. The role of the different conformations
of ADAMTS13 in the pathophysiology of iTTP is unclear, as is the potential role of the distal domain-targeting
IgGs in the disease. Lastly, it is not known if ADAMTS13 activity can be rescued by introducing moieties capable
of competing for the binding of anti-ADAMTS13 IgGs with ADAMTS13. This project aims to elucidate the
mechanism(s) of inhibition of anti-ADAMTS13 antibodies, characterize the role of distal domain-targeting anti-
ADAMTS13 antibodies in the pathophysiology of the disease, and explore molecular mimics of the binding
epitopes of anti-ADAMTS13 IgGs as a rescue strategy for the disease. My career goal is to become an
independent investigator as a physician scientist, with a focus on the pathophysiology of iTTP. I am currently on
the tenure-track as an Assistant Professor in the Department of Internal Medicine, Division of Hematologic
Malignancies and Cellular Therapeutics, at the University of Kansas Medical Center (KUMC), a large academic
center. My research mentor is Dr. X. Long Zheng, a world-renowned researcher in iTTP. I am afforded 80%
protected time for research under my agreement with the University. My career development plan includes
regular meetings with my Career Advisory Committee, hands-on training in the structural biology techniques
included in this proposal, and ongoing clinical responsibilities, including a half-day of clinic weekly where I see
patients with non-malignant hematologic disorders.

## Key facts

- **NIH application ID:** 10429277
- **Project number:** 1K08HL163471-01
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Konstantine Halkidis
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $165,240
- **Award type:** 1
- **Project period:** 2022-08-18 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10429277

## Citation

> US National Institutes of Health, RePORTER application 10429277, Exploring the mechanisms of action of anti-ADAMTS 13 antibodies in immune thrombotic thrombocytopenic purpura (1K08HL163471-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10429277. Licensed CC0.

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