NIH grant: Structural and functional characterization of autoimmune antibodies against NMDAR (1R01AI194245-01A1)

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NIH grant 1R01AI194245-01A1: Structural and functional characterization of autoimmune antibodies against NMDAR
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Hiroyasu  Furukawa. Award: $929257.
Start: 2026-06-18T00:00:00.
Project Summary. The goal of this project is to understand the origins and molecular mechanisms underlying
the anti-cancer autoimmune response against the N-methyl-D-aspartate receptor (NMDAR) and its correlation
with anti-N-methyl-D-aspartate receptor autoimmune encephalitis (NMDARAE). While anti-cancer immune
responses can promote tumor elimination, they may also lead to the production of self-reactive antibodies that
trigger autoimmune diseases. NMDARAE is the most common form of immune-mediated encephalitis, which
results in prominent neuropsychiatric symptoms, including seizures, psychosis, and memory deficits. NMDARs
belong to a family of ligand-gated ion channels expressed exclusively in the central nervous system. They are
involved in various aspects of brain development and function, including learning and memory. They respond to
the neurotransmitter glutamate and a co-agonist, glycine or D-serine, to mediate excitatory neurotransmission,
which plays a central role in synaptic plasticity. NMDARAE is associated with ovarian teratomas, where aberrant
NMDAR expression is believed to trigger an autoimmune response. In NMDARAE, anti-NMDAR antibodies, as
well as B cells and antibody-secreting cells, cross the blood-brain barrier via unknown mechanisms, resulting in
the presence of anti-NMDAR antibodies at high titers within the brain and cerebrospinal fluid (CSF). These
antibodies target NMDARs, modulating their function and contributing to disease pathology. Emerging evidence,
supported by our preliminary data, suggests that NMDARs are also expressed in triple-negative breast cancer
(TNBC), extending the relevance of anti-NMDAR autoimmunity beyond ovarian teratomas. In our TNBC mouse
model, which ectopically expresses NMDARs (TNBC-NMDAR), we observed the onset of anti-NMDAR
autoimmunity, where the produced antibodies cause both anti-tumor activity and symptoms such as lowered
seizure threshold, mirroring key features of NMDARAE. Here, we will establish this TNBC mouse model as we
develop molecular methods to characterize it. Aim 1 will focus on establishing and characterizing the TNBC-
NMDAR mouse model. We will develop a detection method utilizing the intact tetrameric NMDAR channel
proteins and a method to isolate B cells expressing B cell receptors against NMDAR from biological samples by
using fluorescently labeled intact NMDAR proteins, followed by single-cell RNA sequencing. Aim 2 will utilize
single-particle cryo-electron microscopy (cryo-EM) to investigate the interactions between NMDAR and the
cloned antibodies, providing insights into epitope recognition, NMDAR subtype specificity, and conformational
changes induced by antibody binding. Aim 3 will assess the impact of the cloned antibodies on NMDAR channel
activity using electrophysiology. We will also assess anti-tumor activity and NMDARAE onset by each antibody
clone. Together, the proposed research will gain insights into the link between anti-cancer anti-NMDAR
autoimmunity and NMDARAE. It will also elucidate which functional properties of the cloned antibodies promote
anti-tumor activity while contributing to NMDARAE, thereby informing potential therapeutic strategies.

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