New Preclinical Data Presented at the 2018
American Association for Cancer Research Annual Meeting Show
Potent T-Cell Directed Tumor Killing with Reduced Cytokine
Production Compared to a Competitor Bispecific Construct
Aptevo Therapeutics Inc. (Nasdaq:APVO), a biotechnology company
focused on developing novel oncology and hematology therapeutics,
today announced the presentation of new data for APVO436, a
bispecific antibody candidate targeting CD123 and CD3, at the
American Association for Cancer Research (AACR) 2018 Annual
Meeting. The preclinical data demonstrate potent T-cell
cytotoxicity of tumors expressing CD123 with limited cytokine
release and suggest that APVO436 has the potential for increased
clinical benefit and a favorable safety profile.
Cytokine release syndrome (CRS) is a significant
concern with T-cell activating therapies and has been associated
with severe complications in clinical trials. Aptevo has
previously published data on its first generation candidate,
APVO414, showing reduced cytokine release upon T-cell engagement
compared to another bispecific format (Mol Cancer Ther. 2016 Sep;
15(9); 2155-65).
New preclinical data presented at this year’s
AACR Annual Meeting compare Aptevo’s second generation bispecific,
APVO436, with an Aptevo-generated version of Macrogenics’ CD123 x
CD3 dual-affinity re-targeting (DART) molecule, MGD006, evaluating
T-cell activation, proliferation, cytotoxicity and cytokine
secretion.
The data show that APVO436 and the
Aptevo-generated version of MDG006 are both effective at
stimulating a tumor-directed immune response by inducing comparable
T-cell activation, proliferation and cytotoxicity. However,
in these preclinical studies, APVO436 induced lower levels of
several T-cell cytokines, including IFNγ, IL-2, IL-6, TNFα and
several additional cytokines, suggesting a potential safety
advantage with APVO436.
“We are especially excited about these latest
data for APVO436, which continue to show robust T-cell engagement
and cytotoxic activity with reduced levels of cytokine
release. Importantly, IFNγ, IL-6, and TNFα are considered to
be the most relevant cytokines responsible for dosing toxicities
observed in clinical studies with T-cell engaging molecules, which
suggests that APVO436 could offer the potential for reduced
toxicities compared to other CD123 x CD3 T-cell engagers at
comparable or higher doses,” said Jane Gross, Ph.D., Senior Vice
President and Chief Scientific Officer for Aptevo.
“The accumulating data for APVO436 showing
enhanced stability, extended half-life in rodents of up to 12.5
days, desirable manufacturing characteristics, and reduced cytokine
release in preclinical studies, support our assessment of APVO436
as a “Best-in-Class” anti-CD123 x anti CD3 immunotherapeutic.
We plan to file an IND for APVO436 in the upcoming weeks and
commence a Phase 1 clinical trial of APVO436 later this year in
acute myeloid leukemia and myelodysplastic syndrome,” noted Dr.
Gross.
Acute myeloid leukemia (AML) is a form of blood
and bone marrow cancer that is characterized by rapid disease
progression. While treatments for AML are available, there
remains a high unmet medical need for targeted therapies addressing
patients with relapsed and refractory disease, and patients who
cannot tolerate traditional chemotherapy. The American Cancer
Society estimates that approximately 20,000 new cases of AML are
diagnosed each year in the United States.
Myelodysplastic syndromes (MDS) are conditions
associated with abnormalities in the blood-forming cells in the
bone marrow. Approximately 1 in 3 patients with MDS will
progress to have AML. The American Cancer Society estimates
that approximately 10,000 new cases of MDS are diagnosed each year
in the United States.
AACR Data
In a poster session on Monday, April 16, 2018,
Aptevo scientists presented comprehensive data from a series of
preclinical studies of APVO436 showing it is a potent inducer of
redirected T-cell killing of AML tumor cells both in vitro and in
vivo through the dual targeting of CD123 (a cell surface receptor
highly expressed in several hematological malignancies) and CD3 (a
T-cell co-receptor that promotes cytotoxicity.)
The data presented show that APVO436:
- Binds human CD123 and CD3-expressing cells with EC50 values in
the low nM range and demonstrates potent target specific activity
against CD123 expressing tumor cell lines at low effector to target
ratios
- Potently induces endogenous T-cell activation and proliferation
accompanied by depletion of CD123 expressing cells in experiments
with primary AML subject samples and normal donor samples
- Demonstrates potent cytotoxic activity from antigen-expanded T
cells from both normal and AML subject samples in the presence of
CD123+ tumor cells upon re-exposure to APVO436
- Results in rapid and significant reduction in skeletal tumor
burden indicating migration and engagement of T cells at the tumor
site, in mice with established disseminated Molm-13 tumors and
IV-implanted human T cells in therapeutic preclinical animal
studies
- Induces lower levels of multiple cytokines compared to a
different CD123 x CD3 format, when T cells were stimulated in the
presence of CD123+ tumor cells
About APVO436 and the ADAPTIR Platform
APVO436 is an optimized, next generation
bispecific antibody candidate designed to simultaneously target
CD123 and CD3 and redirect T-cell cytotoxicity to the tumor.
APVO436 was built on Aptevo’s proprietary ADAPTIR protein
therapeutic platform. Focused on generating novel, targeted
bispecific antibody-based immunotherapies for cancer and autoimmune
diseases, the ADAPTIR platform offers key advantages over other
bispecific formats, derived in part from the flexible and modular
nature of the ADAPTIR structure. These advantages include: (i)
achieving potent biological activity and extended half-life while
retaining desirable manufacturing characteristics; (ii) unique
properties for redirecting T-cell cytotoxicity (RTCC) compared to
other bispecific platforms, including a favorable cytokine release
profile; (iii) ability to achieve target-dependent induction of
RTCC at lower concentrations than other bispecific antibody
formats; and (iv) flexibility to build ADAPTIR candidates with
diverse mechanisms of action, including RTCC, and targeted cytokine
release and others. Two ADAPTIR molecules are currently in clinical
development, with several more ADAPTIR bispecific immunotherapies
in preclinical development.
Aptevo Product Portfolio
Marketed Product:
- IXINITY (coagulation factor IX [recombinant])
– is a third-generation recombinant human coagulation factor IX
approved in the United States for the control and prevention of
bleeding episodes and for perioperative management in adults and
children 12 years of age or older with Hemophilia B.
ADAPTIR Clinical and Preclinical
Pipeline:
- Otlertuzumab – a monospecific ADAPTIR
candidate currently in Phase 2 clinical development for the
treatment of peripheral T-cell lymphoma (PTCL). A previous
Phase 2 clinical study evaluating otlertuzumab for the treatment of
chronic lymphocytic leukemia (CLL) showed that otlertuzumab in
combination with bendamustine, compared to bendamustine alone,
demonstrated a significant increase in median progression free
survival for the combination, from approximately 10 to 16
months.
- APVO414 – a bispecific ADAPTIR candidate,
currently in Phase 1 development, targeting prostate specific
membrane antigen (PSMA), an enzyme that is expressed on the surface
of prostate cancer cells, and, CD3, a component of the T cell
receptor complex expressed on all T cells. APVO414 redirects
T cells to specifically kill PSMA expressing tumors and is being
developed for metastatic castration-resistant prostate cancer,
which is advanced prostate cancer that has spread to other organs
and no longer responds to hormone blocking therapies.
- APVO436 – a bispecific ADAPTIR candidate
currently in preclinical development targeting CD123, a cell
surface receptor highly expressed on several hematological
malignancies and CD3, a component of the T cell receptor. APVO436
engages T cells to initiate killing of tumor cells. Aptevo
intends to file an IND and begin clinical development of APVO436 in
2018.
- ALG.APV-527 – a bispecific antibody candidate,
partnered with Alligator Bioscience, featuring a novel mechanism of
action designed to simultaneously target 4-1BB (CD137) and 5T4, a
tumor antigen widely overexpressed in a number of different types
of cancer. 4-1BB, a costimulatory receptor on T cells, is
known to enhance the immune response to cancer through activation
of tumor-specific T cells and is believed to be a promising target
for new immunotherapeutic approaches. ALG.APV-527 could potentially
have utility in the treatment of a broad spectrum of cancers
over-expressing the tumor antigen, including breast, cervical,
non-small-cell-lung, prostate, renal, gastric, colorectal and
bladder cancers.
- APVO210 – a bispecific ADAPTIR preclinical
candidate with a novel mechanism of action based on targeted
cytokine delivery. APVO210 is composed of a humanized
anti-CD86 antibody fused with a modified form of IL-10 that
specifically induces IL-10 signaling on antigen presenting cells,
but not on lymphoid populations. APVO210 functions by suppressing
immune responses and inducing certain tolerogenic responses and
therefore may have potential benefit for the treatment of
autoimmune and inflammatory diseases. Aptevo intends to file
an IND for APVO210 in 2018.
- ROR1 Bispecific – a proof-of-concept
bispecific candidate targeting ROR1, an antigen found on several
solid tumors and hematologic, or blood-related malignancies.
Initial preclinical data demonstrate redirected T cell killing of
tumors expressing ROR1 in vitro and in vivo in animal models.
About Aptevo Therapeutics
Inc.Aptevo Therapeutics Inc. is a clinical-stage
biotechnology company focused on novel oncology and hematology
therapeutics to meaningfully improve patients’ lives. Aptevo
has a commercial product, IXINITY® coagulation factor IX
(recombinant), approved and marketed in the United States for the
treatment of Hemophilia B, and a versatile core technology – the
ADAPTIR™ modular protein technology platform capable of generating
highly-differentiated bispecific antibodies with unique mechanisms
of action to treat cancer or autoimmune diseases. Aptevo has
two ADAPTIR antibody candidates currently in clinical development
and a broad pipeline of novel investigational-stage bispecific
antibody candidates focused in immuno-oncology and autoimmune
disease and inflammation. For more information, please visit
www.aptevotherapeutics.com
Safe Harbor StatementThis press
release includes forward-looking statements within the meaning of
the Private Securities Litigation Reform Act of 1995. Any
statements, other than statements of historical fact, including,
without limitation, statements regarding potential milestone
payments, Aptevo’s outlook, financial performance or financial
condition, Aptevo’s technology and related pipeline, collaboration
and partnership opportunities, commercial portfolio, milestones,
and any other statements containing the words “believes,”
“expects,” “anticipates,” “intends,” “plans,” “forecasts,”
“estimates,” “will” and similar expressions are forward-looking
statements. These forward-looking statements are based on Aptevo’s
current intentions, beliefs and expectations regarding future
events. Aptevo cannot guarantee that any forward-looking statement
will be accurate. Investors should realize that if underlying
assumptions prove inaccurate or unknown risks or uncertainties
materialize, actual results could differ materially from Aptevo’s
expectations. Investors are, therefore, cautioned not to place
undue reliance on any forward-looking statement. Any
forward-looking statement speaks only as of the date of this press
release, and, except as required by law, Aptevo does not undertake
to update any forward-looking statement to reflect new information,
events or circumstances.
There are a number of important factors that
could cause Aptevo’s actual results to differ materially from those
indicated by such forward-looking statements, including a
deterioration in Aptevo’s business or prospects; adverse
developments in research and development; adverse developments in
the U.S. or global capital markets, credit markets or economies
generally; and changes in regulatory, social and political
conditions. Additional risks and factors that may affect results
are set forth in Aptevo’s filings with the Securities and Exchange
Commission, including its most recent Annual Report on Form 10-K,
as filed on March 13, 2018 and its subsequent reports on Form 10-Q
and current reports on Form 8-K. The foregoing sets forth many, but
not all, of the factors that could cause actual results to differ
from Aptevo’s expectations in any forward-looking statement.
Source: Aptevo Therapeutics Stacey
JurchisonSenior Director, Investor Relations and Corporate
Communications206-859-6628 JurchisonS@apvo.com
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