iTolerance, Inc. Pre-Clinical Non-Human
Primate Study Demonstrates Long-Term Success of Allogeneic Islet
Implantation Without Chronic Immunosuppression for the Treatment of
Diabetes
May 16, 2022
Data published in peer-reviewed journal, Science Advances
Co-implantation of allogeneic islets and streptavidin
(SA)-FasL-presenting microgels sustained long-term (>6 months)
survival of pancreatic islet cells and provided excellent glycemic
control in non-human primates (NHPs) with diabetes without chronic
immunosuppression
Following islet implantation, prompt glycemic control was
achieved and maintained by all animals receiving SA-FasL-presenting
microgels
Success in NHP model, the gold standard translational
model for allogeneic transplantation, provides validation for
advancement into human clinical studies
MIAMI, FL / May 16, 2022 / iTolerance, Inc.
(“iTolerance” or the “Company”), an early-stage regenerative medicine
company developing technology to enable tissue, organoid or cell therapy
without the need for life-long immunosuppression, today announced the
publication of positive pre-clinical results from a non-human primate
(NHP) study evaluating co-implantation of allogeneic islets and
SA-FasL-presenting microgels for the treatment of diabetes.
The manuscript titled, FasL-microgels induce immune acceptance of islet allografts in nonhuman primates[1], was published in the peer-reviewed Journal, Science Advances. The
corresponding authors for the published manuscript are the Company’s
Scientific Founders and Advisory Board members, Andrés J. García, PhD,
F.B.S.E., Haval Shirwan, PhD, and James F. Markmann MD, PhD.
Anthony Japour, MD, Chief Executive Officer of iTolerance, commented,
“The NHP data and its publication is a landmark milestone for
iTolerance. Chronic immunosuppression carries significant long-term
morbidity and mortality risks, including potential for cancer, decline
in kidney function, and beta cell toxicity. Eliminating chronic
immunosuppression could obviate the need for chronic prophylactic
antiviral, antifungal, and antimicrobial agents prescribed to prevent
serious infections with immunosuppression regimens. Therefore,
demonstrating sustained long-term survival of pancreatic islet cells and
glycemic control in non-human primates with diabetes without chronic
immunosuppression is potentially game changing in the advancement of a
possible cure for Type 1 Diabetes.”
Dr. Japour added, “We are grateful to our team of scientists for
their work, the JDRF for providing valuable resources and support for
the study, and Science Advances for publishing this important
data. Now more than ever, we are dedicated to translating these findings
to the clinic and are in ongoing discussions with the U.S. FDA to
progress toward human clinical trials.”
Dr. García, the Company’s Scientific Co-Founder and Executive
Director, Parker H. Petit Institute for Bioengineering and Bioscience
Petit Director’s Chair in Bioengineering and Bioscience Regents
Professor, George W. Woodruff School of Mechanical Engineering Georgia
Institute of Technology, stated, “We are incredibly pleased with the
results from this study. Achieving long-term survival of allogeneic
grafts without chronic immunosuppression was, until now, an elusive
goal. In this very stringent model of islet implantation, we were able
to successfully demonstrate a reliable and safe tolerogenic regimen for
diabetes without the use of chronic immunosuppression – an exciting
finding. We believe this major advancement enables us to take a step
toward developing a potential cure for Type 1 Diabetes.”
“The use of long-term immunosuppression medications remains the major
hurdle for the use of cell and regenerative therapies,” added Camillo
Ricordi, MD, Chief Scientist of iTolerance. “The data generated through
this NHP study establishes that the approach we have developed may
eliminate the need for chronic immunosuppression, a revolutionary
approach that I believe will change the way that the scientific research
community approaches regenerative medicine.”
Summary of Pre-Clinical Non-Human Primate Study for the Treatment of Diabetes
The NHP study investigated the immunomodulatory potential of the
SA-FasL microgel technology in a pre-clinical streptozotocin
(STZ)-induced diabetes NHP model in which allogeneic islets and SA-FasL
microgels are co-implanted into the omentum, an area of fatty tissue
attached to the stomach.
Results demonstrated robust glycemic control, sustained C-peptide
levels, and graft survival in non-human primates with diabetes for >6
months. Surgical extraction of the graft resulted in prompt
hyperglycemia. In contrast, animals receiving microgels without SA-FasL
under the same rapamycin regimen rejected islet grafts acutely.
Graft survival was associated with increased number of regulatory
FoxP3+ cells in the graft site with no significant changes in T cell
systemic frequencies or responses to donor and third-party antigens,
indicating localized tolerance.
Immunostaining analyses of the graft site demonstrated the presence
of FoxP3+ (a marker of Treg) cells at a higher frequency (cell count,
intensity) in SA-FasL Microgel treated NHPs compared to Microgel
subjects (FoxP3+ cell counts: p-value=0.0143; FoxP3+ intensity:
p-value=0.043). This finding parallels studies conducted in mice with
diabetes demonstrating a pivotal role for Treg in establishing
SA-FasL-microgel-induced immune acceptance.
NHPs treated with SA-FasL-presenting microgels did not reveal
changes between pre- and post-transplant IFN-γ secreting cell numbers
and anti-donor major histocompatibility complex (MHC) antibodies. In
contrast, subjects that received control microgels generated antibodies
against donor MHC molecules and exhibited increased CD8+ T cell
proliferative responses to donor and third-party antigens.
Subjects receiving allogeneic islets and SA-FasL microgels exhibited
normal liver and kidney metabolic function and organ histology and
continued to gain weight.
This localized immunomodulatory strategy succeeded with unmodified
islets and does not require long term immunosuppression, showing
translational potential in β-cell replacement for treating diabetes.
Dr. Shirwan, from the Department of Child Health and Molecular
Microbiology and Immunology and Director, Immunomodulation and
Translational Research Program at the University of Missouri and a
Scientific Co-Founder of the Company, commented, “The Fas receptor/Fas
ligand (FasL) pathway plays a crucial role in activation-induced cell
death and tolerance to self-antigens. In previously conducted mouse
models, we demonstrated that co-implantation of SA-FasL-presenting
microgels with unmodified allogeneic islets with a short course of
rapamycin resulted in long-term engraftment and function in mice with
diabetes. I am thrilled that we were able to translate that pre-clinical
success to a NHP model, a model I believe is much more reflective of
the potential outcome in humans. I look forward to helping advance this
noteworthy breakthrough and unlocking its full potential for the
treatment of Type 1 Diabetes and beyond.”
Dr. Ricordi added, “Most importantly, this biomaterial-based strategy
offers off-the-shelf immunomodulatory capability without modification
of donor islets, increasing its clinical relevance and breadth of
potential clinical applicability. These findings are a major achievement
that justifies the moving this technology forward towards clinical
application in the most expedient and efficient way possible.”
Dr. Markmann, Scientific Co-Founder of iTolerance and Chief, Division
of Transplantation Surgery and Director, Liver, Pancreas and Islet
Transplant Programs and Director of Clinical Operations, MGH Transplant
Center, said, “It is unusual to demonstrate such long-term success of
allogeneic islet implantation in a non-human primate without the need
for chronic immunosuppression. The simple, minimally invasive strategy
used and encouraging results provide added confidence in the
translatability of this technology to the clinic. Additionally, with the
data seen to date, we believe this platform technology could be
utilized in other areas of cell therapy and bring potential solutions to
patients and physicians.”
The NHP study was made possible by funding and support from the JDRF.
Study protocols were approved by the Institutional Animal Care and Use
Committee at the Massachusetts General Hospital Research Institute.
About iTOL-100
The Company’s iTOL-100 platform technology is a biotechnology-derived
Strepavidin-FasL fusion protein, a synthetic form of the naturally
occurring protein FasL, mixed with a biotin-PEG microgel (SA-FasL
microgel) that potentially allows convenient and effective
co-administration with implanted cells or organoids to induce local
immune tolerance without the need for life-long immunosuppression. In
pre-clinical studies, iTOL-100 has been shown to establish durable,
localized immune tolerance, allowing the implanted tissue, organoid or
cell therapy to function as a replacement for damaged native cells.
About iTolerance, Inc.
iTolerance is an early stage privately held regenerative medicine
company developing technology to enable tissue, organoid or cell therapy
without the need for life-long immunosuppression. Leveraging its
proprietary biotechnology-derived Strepavidin-FasL fusion
protein/biotin-PEG microgel (SA-FasL microgel) platform technology,
iTOL-100, iTolerance is advancing a pipeline of programs using both
allogenic pancreatic islets and stem cells that have the potential to
cure diseases. The Company’s lead program, iTOL-101 is being developed
for Type 1 Diabetes and in a pre-clinical non-human primate study,
pancreatic islet cells co-implanted with iTOL-101 exhibited long-term
function with control of blood glucose levels and restoration of insulin
secretion without the use of chronic immune suppression. The Company’s
second lead candidate, iTOL-102, is leveraging significant advancements
in stem cells to derive pancreatic islets which allows an inexhaustible
supply of insulin-producing cells. Utilizing iTOL-100 to induce local
immune tolerance, iTOL-102 has the potential to be a cure for Type 1
Diabetes without the need for life-long immunosuppression. Additionally,
the Company is developing iTOL-201 for liver failure and iTOL-301 as a
potential regenerative protein and cell therapy that leverages stem cell
sources to produce proteins or hormones in the body in conditions of
high unmet need without the need for life-long immunosuppression. For
more information, please visit itolerance.com.
Forward-Looking Statements
This press release contains “forward-looking statements” within the
meaning of the “safe-harbor” provisions of the Private Securities
Litigation Reform Act of 1995. When used herein, words such as
“anticipate”, “being”, “will”, “plan”, “may”, “continue”, and similar
expressions are intended to identify forward-looking statements. In
addition, any statements or information that refer to expectations,
beliefs, plans, projections, objectives, performance or other
characterizations of future events or circumstances, including any
underlying assumptions, are forward-looking.
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expectations and various assumptions. The Company believes there is a
reasonable basis for its expectations and beliefs, but they are
inherently uncertain. The Company may not realize its expectations, and
its beliefs may not prove correct. Actual results could differ
materially from those described or implied by such forward-looking
statements as a result of various important factors, including, without
limitation, anticipated levels of revenues, future national or regional
economic and competitive conditions, and difficulties in developing the
Company’s platform technology. Consequently, forward-looking statements
should be regarded solely as the Company’s current plans, estimates and
beliefs. Investors should not place undue reliance on forward-looking
statements. The Company cannot guarantee future results, events, levels
of activity, performance or achievements. The Company does not undertake
and specifically declines any obligation to update, republish, or
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events or circumstances or to reflect the occurrences of unanticipated
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BioFlorida is the voice of Florida's life sciences industry, representing 8,600 establishments and research organizations in the BioPharma, MedTech, Digital Health and Health Systems that collectively employ nearly 107,000 Floridians. Source: TEConomy/BIO (released 2022)
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