Aberrant Immune Response to EBV
Protein Triggers the Immune System to Attack and Destroy Myelin,
Leading to Onset and Progression of Multiple Sclerosis (MS)
Findings Reinforce Potential for ATA188 to
Treat the Cause of MS by Specifically Targeting EBV-Infected B
cells and Plasma Cells
Reinforces Recent Epidemiological Analysis in
Science of >10 Million Individuals Over Two Decades Providing
Compelling Evidence of Causality of EBV Infection and MS
Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leader in T-cell
immunotherapy, leveraging its novel allogeneic Epstein-Barr virus
(EBV) T-cell platform to develop transformative therapies for
patients with cancer and autoimmune diseases, today lauded the
second high impact study this month solidifying EBV as the primary
driver of the development of MS. The paper, titled, “Clonally
Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and
GlialCAM,” was published today in the journal Nature.
MS is a chronic neurological illness affecting an estimated 2.8
million people worldwide, including approximately 900,000 in the
U.S. MS is driven by abnormally activated immune cells and
subsequent inflammation which damages and ultimately destroys the
protective myelin sheath surrounding nerve fibers in the central
nervous system (CNS). While genetics and environmental factors play
a role, it has long been postulated that EBV triggers the patient’s
immune cells to erroneously attack myelin.
The Nature study adds to the known EBV-MS epidemiological
connection by providing a mechanistic basis for how EBV infection
can trigger the patient’s immune cells to attack self-tissue in the
CNS. These findings validate molecular mimicry as one of the
leading mechanisms of EBV-mediated MS, which occurs when fragments
of the virus share sequence or structural similarities with certain
brain proteins. The immune system may mistake these “self-proteins”
for EBV. These new data reveal how EBV infection can drive the
development of antibodies that target both EBV and CNS proteins,
potentially leading to MS.
The researchers identified a type of antibody isolated from MS
patients’ cerebrospinal fluid (CSF), which strongly binds an EBV
protein, EBNA1, and cross-reacts with the central nervous system
protein GlialCAM. GlialCAM is a cell adhesion molecule expressed in
a variety of brain cells, including oligodendrocytes that are
responsible for producing myelin, as well as on the outside of
myelin sheaths. This antibody cross-reactivity between EBV and
self-proteins was found to result from molecular mimicry due to key
similarities between GlialCAM and EBNA1. The group also
demonstrated that immunization with EBNA1 in a mouse model of MS
exacerbated the disease and generated a strong antibody response
against GlialCAM and EBNA1, enhancing immune cell infiltration and
demyelination that are two hallmark features of human MS
pathology.
“EBV may be the only risk factor required to develop MS, given
essentially 100 percent of people living with MS have been infected
with EBV. Until now, we didn’t have a step-by-step account of how
this drives the immune system to attack a person’s own myelin
sheath,” said Lawrence Steinman, MD, Professor of Neurology and
Neurological Sciences, Pediatrics and Genetics, Stanford
University, and author of the study. “This new research fills in
those gaps and provides clarity into how EBV infection can cause
MS. New therapies that specifically target this link are already in
development, including Atara’s ATA188 T-cell immunotherapy, which
is actively enrolling a Phase 2 clinical study.”
The Nature paper complements findings from a second publication,
“Longitudinal analysis reveals high prevalence of Epstein-Barr
virus associated with multiple sclerosis,” recently published in
the journal Science, and collectively provide new epidemiological
and molecular data confirming the role of EBV in triggering and
driving the pathophysiology of MS. The cohort-based study provided
compelling epidemiological evidence that EBV infection precedes the
onset of MS. The study analyzed 62 million serum samples and
followed >10 million individuals in the U.S. military over a
20-year period (1993-2013), showing a 32-fold increase in the risk
of MS after EBV infection. Out of the 801 MS cases identified, 35
were EBV negative at baseline with all but one becoming EBV
positive before the onset of their MS, yielding a 97 percent
seroconversion rate versus 57 percent among individuals who did not
develop MS. Serum concentrations of neurofilament light chain
(sNfL), a sensitive biomarker for nerve fiber damage, only
increased after EBV infection, indicating that EBV infection
preceded not only symptom onset but also the time of the first
detectable pathological mechanisms underlying MS. Other viral
infections, like CMV, were not found to increase the risk of MS and
were ruled out as a contributing factor in MS development.
“These studies identify EBV as the leading cause of MS and
provide a direct mechanistic link between the activation of the
immune system caused by EBV, and the autoimmune myelin pathology
observed in MS,” said AJ Joshi, MD, Chief Medical Officer at Atara.
“Specifically, these new data further link MS to EBV-infected B
cells and plasma cells, highlighting the role of EBV antigens,
including EBNA1 protein, in the development of the disease.
Importantly ATA188, Atara’s investigational MS therapy, targets key
epitopes of these antigens, including EBNA1, with the hope of
ultimately delivering a new treatment option for the millions of
people currently living with MS. The actively enrolling Phase 2
EMBOLD study, with a formal interim analysis planned for Q2 this
year, will be a major step toward that direction.”
The complete articles are available in digital format and can be
viewed via the following links:
- https://www.nature.com/articles/s41586-022-04432-7
- https://www.science.org/doi/10.1126/science.abj8222
About Progressive Multiple Sclerosis
Multiple sclerosis (MS) is a chronic, debilitating, and
potentially disabling autoimmune disease of the central nervous
system (CNS) that affects myelin, a protein that helps nerves in
the brain and spinal cord communicate. There are an estimated 2.8
million people living with MS worldwide, with up to ~1.2 million
living with progressive forms of the disease, marked by continuous
clinical decline and worsening disability. While the exact triggers
of MS are not fully established, inflammation driven by
environmental and genetic factors is suspected. There is growing
evidence that EBV, carried by more than 90 percent of the
population that infects a particular type of immune cell called the
B cell, may have a role in MS and in fact may be the only risk
factor identified necessary to cause MS. With few treatment options
available for progressive MS and the ability of these treatments to
fundamentally alter disease progression, there remains a critical
unmet need.
About Atara Biotherapeutics, Inc.
Atara Biotherapeutics, Inc. (@Atarabio) is a pioneer in T-cell
immunotherapy leveraging its novel allogeneic EBV T-cell platform
to develop transformative therapies for patients with serious
diseases including solid tumors, hematologic cancers and autoimmune
disease. With our lead program in Phase 3 clinical development and
currently under review to support registration in Europe, Atara is
the most advanced allogeneic T-cell immunotherapy company and
intends to rapidly deliver off-the-shelf treatments to patients
with high unmet medical need. Our platform leverages the unique
biology of EBV T cells and has the capability to treat a wide range
of EBV-associated diseases, or other serious diseases through
incorporation of engineered CARs (chimeric antigen receptors) or
TCRs (T-cell receptors). Atara is applying this one platform, which
does not require TCR or HLA gene editing, to create a robust
pipeline including: tab-cel in Phase 3 development for Epstein-Barr
virus-driven post-transplant lymphoproliferative disease (EBV+
PTLD) and other EBV-driven diseases; ATA188, a T-cell immunotherapy
targeting EBV antigens as a potential treatment for multiple
sclerosis; and multiple next-generation chimeric antigen receptor
T-cell (CAR-T) immunotherapies for both solid tumors and
hematologic malignancies. Improving patients’ lives is our mission
and we will never stop working to bring transformative therapies to
those in need. Atara is headquartered in South San Francisco and
our leading-edge research, development and manufacturing facility
is based in Thousand Oaks, California. For additional information
about the company, please visit atarabio.com and follow us on
Twitter and LinkedIn.
Forward-Looking Statements
This press release contains or may imply “forward-looking
statements” within the meaning of Section 27A of the Securities Act
of 1933 and Section 21E of the Securities Exchange Act of 1934. For
example, forward-looking statements include statements regarding:
the development, timing, progress and prospects of ATA188 and
clinical trials relating to ATA188, the potential benefits of
ATA188, the safety profile of ATA188, the potential for ATA188 to
treat multiple sclerosis, the potential market for ATA188, the
mechanistic link between EBV and multiple sclerosis and the ability
of ATA188 to specifically target such link. Because such statements
deal with future events and are based on Atara’s current
expectations, they are subject to various risks and uncertainties
and actual results, performance or achievements of Atara could
differ materially from those described in or implied by the
statements in this press release. These forward-looking statements
are subject to risks and uncertainties, including, without
limitation, risks and uncertainties associated with the costly and
time-consuming pharmaceutical product development process and the
uncertainty of clinical success; the COVID-19 pandemic, which may
significantly impact (i) our business, research, clinical
development plans and operations, including our operations in South
San Francisco and Southern California and at our clinical trial
sites, as well as the business or operations of our third-party
manufacturer, contract research organizations or other third
parties with whom we conduct business, (ii) our ability to access
capital, and (iii) the value of our common stock; the sufficiency
of Atara’s cash resources and need for additional capital; and
other risks and uncertainties affecting Atara’s and its development
programs, including those discussed in Atara’s filings with the
Securities and Exchange Commission (SEC), including in the “Risk
Factors” and “Management’s Discussion and Analysis of Financial
Condition and Results of Operations” sections of the Company’s most
recently filed periodic reports on Form 10-K and Form 10-Q and
subsequent filings and in the documents incorporated by reference
therein. Except as otherwise required by law, Atara disclaims any
intention or obligation to update or revise any forward-looking
statements, which speak only as of the date hereof, whether as a
result of new information, future events or circumstances or
otherwise.
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version on businesswire.com: https://www.businesswire.com/news/home/20220122005025/en/
Investors & Media: Investors Eric Hyllengren
805-395-9669 ehyllengren@atarabio.com
Media Alex Chapman 805-456-4772 achapman@atarabio.com
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