OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage
biopharmaceutical company focused on discovering and developing
novel anti-cancer therapeutics, presented preclinical data during
the American Association for Cancer Research (AACR) Annual Meeting
related to two of its therapeutic candidates, anti-TIGIT
(OMP-313M32), currently in the Phase 1a portion of a Phase 1a/b
study, and GITRL-Fc trimer (OMP-336B11), currently in a Phase 1a
study. In addition, preclinical data was presented exploring the
ability of OncoMed’s Wnt antagonist vantictumab (anti-FZD,
OMP-18R5) to potentiate immune responses to checkpoint agents.
TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an
inhibitory checkpoint receptor that binds to PVR ligand, a protein
broadly expressed on tumor cells and tumor-infiltrating cells, and,
in doing so, blocks T-cell activation. OncoMed’s presentation
(Abstract 5627) showed that anti-TIGIT treatment
reduced the abundance of regulatory T-cells (Tregs) within tumors
in animal models, and mechanistic studies demonstrated an important
contribution of effector function for anti-tumor efficacy. “These
investigations highlight the potential of our anti-TIGIT antibody,”
said Ann Kapoun, Ph.D., OncoMed’s Vice President of Translational
Medicine. “These translational research efforts inform our
biomarker strategies and may help us identify patients whose tumors
are most likely to benefit from our therapeutic candidates.”
A series of preclinical studies (Abstract 70, Abstract
2726, Abstract 3826) from OncoMed highlighted the ability
of GITRL-Fc, a novel linkerless ligand trimer that binds to the
co-stimulatory receptor GITR (glucocorticoid-induced TNF receptor
family-related protein), to function as a robust GITR agonist by
both stimulating T-cell and NK responses and reducing the abundance
of Tregs in tumors. The studies also investigated the impact of
aging on anti-tumor immune response, an important and often
underappreciated parameter impacting the efficacy of
immuno-oncology strategies.
Another preclinical study (Abstract 1733)
examined the synergistic impact of OncoMed’s Wnt pathway antagonist
vantictumab on the ability of checkpoint agents to promote an
effective anti-tumor immune response. These data add to a growing
recognition of the importance of the Wnt pathway in shaping immune
function.
“The data detailed in these AACR presentations exemplify the
ongoing extensive efforts to deepen our understanding of the
mechanisms of action of our agents” said Austin Gurney Ph.D.,
OncoMed's Senior Vice President of Research and Chief Scientific
Officer. “With both our anti-TIGIT and GITRL-Fc programs advancing
in Phase 1 studies, these research efforts will have direct impact
on informing our clinical programs.”
Below are additional highlights from the OncoMed poster
presentations:
Abstract 5627 - Anti-TIGIT biomarker study:
Inhibition of TIGIT induces loss of Tregs from tumors and requires
effector function for tumor growth inhibition
Using a surrogate anti-TIGIT antibody, potent single-agent
dose-dependent anti-tumor efficacy was demonstrated on large
established CT26 WT tumors. Anti-TIGIT efficacy was shown to
require effector function for tumor growth inhibition and biomarker
analysis demonstrated reduction of Treg frequency and activation of
T-cells and NK cells as part of the mechanism of action of
anti-TIGIT. CD226, a co-receptor for TIGIT’s ligands PVR and PVRL2,
was significantly upregulated in T-cells, Tregs and NK cells,
reflecting a feedback loop activated by the inhibition of TIGIT
activity. Anti-TIGIT gene signatures in tumors and in blood were
identified from multiple syngeneic models and may be potential
biomarkers for measuring anti-TIGIT activity. Additionally in a
human tissue study, TIGIT expression on Tregs was found to be
considerably higher than on CD8+ T-cells in multiplexed IHC panels
across a panel of multiple solid tumors types.
Abstract #70 - Effect of aging on the antitumor
activity of GITRL-Fc
It is now appreciated that the immune system changes in response
to aging. In this study, the activity of GITRL-Fc protein was
compared in both young and older mice. Compared to young mice,
tumors grew faster in older mice. This may be due in part to an
observed greater prevalence of myeloid-derived suppressor cells
(MDSC) in older mice. GITRL-Fc significantly inhibited tumor growth
in both older and younger mice with efficacy more pronounced in
young mice. In older mice, GITRL-Fc (mIgG2a) was still able to
deplete Tregs in tumor and increase Tregs in the spleen as has been
previously shown with GITRL-Fc in young mice. A GITRL-Fc protein
deficient in effector function (mIgG2a (N297A)) did not deplete
Tregs in the tumor but did retain anti-tumor growth activity.
Collectively, these data demonstrate that Treg depletion and
activation of GITR signaling contribute to the anti-tumor efficacy
of GITRL-Fc in older mice.
Abstract #2726 - In vitro functional activity
of OMP-336B11, a GITRL-Fc fusion protein, on primary human immune
cells
In this study, functional characterization of OMP-336B11 in
various human immune cell assays was presented. OMP-336B11 enhanced
activated human T-cell proliferation and augmented IL-2 induced
IFNγ from human NK cells. Notably, OMP-336B11 demonstrated superior
activity compared to agonist anti-GITR antibodies. OMP-336B11 is
designed with an IgG1 Fc domain in order to elicit NK-mediated
cytotoxicity of high GITR-expressing cells (i.e., Tregs).
Co-incubation of primary human NK cells (effector) and GITR
expressing cells (target) resulted in an OMP-336B11 dependent
dose-titratable increase in target cytotoxicity.
Abstract #3826 - GITRL-Fc biomarker and
mechanism study: GITRL-Fc reduces Treg frequency in tumors and
requires effector function for inhibition of tumor growth
Using a surrogate GITRL-Fc molecule, potent single agent
dose-dependent anti-tumor efficacy was demonstrated on large
established CT26.WT tumors. Biomarker analysis showed that loss of
Tregs, activation of T-cells and Fc-mediated effector function are
key elements in the mechanism of action of the molecule.
Immuno-phenotyping of tumor-associated immune cells revealed a
reduction in Treg frequency in the tumor by 24 hours post-dose that
was maintained at 7 and 14 days. GITRL-Fc treatment increased
proliferation and activation markers on tumor-associated CD4+ and
CD8+ T-cells, suggesting an increased cytotoxic environment within
the tumor. GITRL-Fc gene signatures were identified in tumors and
blood from multiple syngeneic models and may be used as potential
biomarkers along with multiplexed IHC panels (e.g. GITR+CD4+
T-cells, GITR+CD8+ T-cells) that were developed. Additional studies
comparing intratumoral (IT) vs intraperitoneal GITRL-Fc injection
demonstrated both routes of administration produced similar
efficacy, suggesting IT administration may be an alternative route
of administration.
Abstract #1733 - Wnt antagonists synergize with
immune checkpoint inhibitors to enhance anti-tumor responses
While enhanced Wnt signaling has been shown to play a major role
in cancer stem cell biology, more recent studies have implicated
Wnt in the development of resistance to anti-tumor immune
responses. In murine tumor models, targeting Wnt signaling using
the Fzd receptor monoclonal antagonist antibody vantictumab in
combination with immune checkpoint inhibitors anti-CTLA-4 or
anti-PD1 induces enhanced anti-tumor responses leading to decreased
tumor volume and increased infiltration of activated CD8+ T-cells
into the tumor microenvironment. In addition, the data showed that
combined Wnt and immune checkpoint inhibition decreased Tregs and
immune suppressive myeloid cell populations, enhanced cytotoxic
T-cell activity and increased antigen presentation by APCs. These
results suggest that co-targeting Wnt and immune checkpoint
proteins may provide valuable opportunities for novel combination
strategies for immunotherapeutic clinical development.
These posters are available on the Pipeline section of OncoMed’s
website, www.oncomed.com.
Additional information on the meeting can be found on the AACR
website www.aacr.org.
About OncoMed PharmaceuticalsOncoMed
Pharmaceuticals is a clinical-stage biopharmaceutical company
focused on discovering and developing novel anti-cancer
therapeutics. OncoMed has internally discovered a broad pipeline of
investigational drugs intended to address the fundamental biology
driving cancer's growth, resistance, recurrence and metastasis.
Anti-TIGIT (OMP-313M32), navicixizumab (anti-DLL4/VEGF bispecific,
OMP-305B83), and rosmantuzumab (anti-RSPO3, OMP-131R10) are part of
OncoMed's strategic alliance with Celgene Corporation. OncoMed is
independently developing GITRL-Fc (OMP-336B11), as well as
continuing to pursue new drug discovery research. For further
information about OncoMed Pharmaceuticals, please see
www.oncomed.com.
Forward Looking StatementsTo the extent that
statements contained in this press release are not descriptions of
historical facts regarding OncoMed Pharmaceuticals, they are
forward-looking statements reflecting the current beliefs and
expectations of management made pursuant to the safe harbor
provisions of the Private Securities Litigation Reform Act of 1995,
including, without limitation, the mechanisms of action and
potential of OncoMed’s anti-TIGIT and GITRL-Fc; the importance of
effector function to the anti-tumor activity of anti-TIGIT and
GITRL-Fc; the advancement of OncoMed’s anti-TIGIT and GITRL-Fc
programs in Phase 1; OncoMed’s use of biomarkers to measure the
activity of anti-TIGIT and GITRL-Fc in patients; the ability of
OncoMed’s translational research efforts to help identify patients
most likely to benefit from its therapeutic candidates; the
potential for IT administration of GITRL-Fc; and the benefits of
co-targeting Wnt and immune checkpoint proteins. Such
forward-looking statements involve substantial risks and
uncertainties that could cause OncoMed's clinical development
programs, future results, performance or achievements to differ
significantly from those expressed or implied by the
forward-looking statements. Such risks and uncertainties include,
among others, the uncertainties inherent in the preclinical and
clinical development process; OncoMed's ability to raise additional
capital to support the development of its unpartnered programs; and
OncoMed's dependence on its key executives. OncoMed undertakes no
obligation to update or revise any forward-looking statements. For
a further description of the risks and uncertainties that could
cause actual results to differ from those expressed in these
forward-looking statements, as well as risks relating to OncoMed's
business in general, see OncoMed's Annual Report on Form 10-K filed
with the U.S. Securities and Exchange Commission (SEC) on March 9,
2018 and OncoMed's other current and periodic reports filed with
the SEC.
Investor Relations Contact:
Matthew BeckSolebury Troutmbeck@troutgroup.com(646) 378-2933
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