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Application of TNFRSF25 agonists for prophylaxis and treatment of graft versus host disease

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI149916-01
Agency Tracking Number: R41AI149916
Amount: $224,713.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA18-575
Solicitation Year: 2018
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-01-07
Award End Date (Contract End Date): 2020-12-31
Small Business Information
San Antonio, TX 78229-3272
United States
DUNS: 116831128
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (919) 797-9746
Business Contact
Phone: (919) 797-9746
Research Institution
CORAL GABLES, FL 33146-2926
United States

 Nonprofit college or university

Graft-vs-Host-Disease (GVHD) is a frequent and life-threatening complication of hematopoietic stem cell
transplantation (HSCT), a procedure that often represents the best treatment option for patients suffering from
hematological malignancies. Even when HLA-matched family or unrelated donors are available, an
unsatisfactorily high frequency (30-40%) of transplant recipients still develop GVHD. Thus, there remains an
urgent need to develop strategies to treat and prevent GVHD for patients receiving either matched or unmatched
donor-recipient HSCT. Recently, CD4+FoxP3+ regulatory T cells (Tregs), which provide non-redundant function
to maintain peripheral immune self-tolerance, have demonstrated potential in pre-clinical models to promote
allograft acceptance. However, translation of such an approach to the clinic remains hampered by the practical
and economic hurdles associated with adoptive transfer of sufficient numbers of donor Tregs to patients. In this
regard, Pelican Therapeutics has developed a novel reagent that takes advantage of the natural ligand of a key
receptor, TNFRSF25, expressed on Tregs. Stimulation of TNFRSF25 using a fusion protein consisting of the
ligand TL1A (TL1A-Ig), in combination with IL-2, induces a dramatic and selective expansion of Tregs that
effectively reduces GVHD in mice following allogeneic HSCT. These initial studies utilized a model in which
Tregs were expanded in vivo with TL1A-Ig/IL-2 and then adoptively transferred to murine recipients. In this Phase
I STTR, Pelican will evaluate the potential for TL1A-Ig to be directly administered to recipients undergoing HSCT,
obviating the need to expand Tregs in donors prior to transplant. To verify and corroborate efficacy, two
independent murine models of aHSCT will be utilized, one involving complete MHC-mismatch and an MHC-
matched minor antigen-mismatched donor/recipient pair reflecting genetic disparities in clinical HSCT. In vivo
effectiveness of TL1A-Ig administration for GVHD amelioration will be evaluated using established quantitative
metrics that include immune phenotyping, levels of Treg expansion, analyses of immune competence and
reduction in clinical signs of GVHD. Pharmacokinetics and target engagement will be characterized as part of
these studies to determine suitability of TL1A-Ig as a drug candidate. To begin to translate these findings to
humans, a humanized TL1A-Ig (hTL1A-Ig) reagent will be characterized first, with regard to identification of
expression and kinetics of endogenous TNFRSF25 presence in human primary peripheral blood mononuclear
cell (PBMC) populations. Secondly, hTL1A-Ig target engagement and downstream signaling will be examined in
human PBMCs to further establish and characterize translational potential. Completion of this Phase I proof-of-
concept will establish rationale for advancing this molecule into further preclinical and IND-enabling
Every year, over 20,000 people with hematological malignancies undergo hematopoietic stem cell
transplantation. A significant proportion of these patients, even among so-called “matched” donor-recipient pairs,
develop graft-vs-host-disease (GVHD), a severe multi-organ inflammatory condition that often leads to patient
morbidity and mortality. Pelican Therapeutics has developed a new therapeutic strategy to ameliorate GVHD in
transplant recipients that utilizes their novel biomolecule, TL1A-Ig, which selectively expands tolerance-inducing
regulatory T cells by targeting a key receptor.

* Information listed above is at the time of submission. *

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