- Zanidatamab preclinical data reveals additional differentiated
mechanisms of action including unique ability to induce complement
dependent cytotoxicity
- ProTECT™ (PROgrammed Tumor Engagement &
Checkpoint/Co-stimulation Targeting), the first
conditionally-active antibody technology that simultaneously
addresses both ends of the therapeutic window
- Preclinical IL-12 and 4-1BB programs represent future
therapeutic opportunities
Zymeworks Inc. (NYSE: ZYME), a clinical-stage biopharmaceutical
company developing multifunctional biotherapeutics, today announced
five presentations at the American Association for Cancer Research
(AACR) Annual Meeting. The presentations highlight preclinical data
that reveal new insights into the unique mechanisms of action of
lead clinical candidate, zanidatamab, introduce Zymeworks’ fourth
therapeutic platform, ProTECT™, and describe two new preclinical
assets focused on the cytokine, IL-12, and the immune-oncology
target, 4-1BB.
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Presentations are now available to registrants of the AACR
Annual Meeting and will also be archived on the Zymeworks
website.
Zanidatamab Presentations
Super-resolution imaging studies of zanidatamab: providing
insights into its bispecific mode of action
Abstract: 1032 Session Category: Experimental
and Molecular Therapeutics Session Title: Cellular Responses to
Anticancer Drugs
The bispecific antibody zanidatamab’s (ZW25’s) unique mechanisms
of action and durable anti-tumor activity in HER2-expressing
cancers
Abstract: 1005 Session Category: Experimental
and Molecular Therapeutics Session Title: Cellular Responses to
Anticancer Drugs
Zanidatamab, Zymeworks’ lead clinical candidate, is currently
enrolling in a pivotal trial for refractory HER2-amplified biliary
tract cancer (HERIZON-BTC-01) as well as several Phase 2 trials for
HER2-expressing gastroesophageal and breast cancers. Zanidatamab is
a bispecific antibody that simultaneously binds two distinct sites
on HER2 resulting in multiple mechanisms of action. Research
presented today at AACR continues to demonstrate that zanidatamab
induces the formation of HER2 receptor clusters and receptor
internalization resulting in their downregulation, inhibits growth
factor-dependent and -independent tumor cell proliferation, and
potently activates the immune system via antibody-dependent
cellular cytotoxicity (ADCC) and antibody-dependent cellular
phagocytosis (ADCP). New findings from this research have revealed
that zanidatamab can form complexes with HER2 with distinct higher
order geometry on the cell surface. The potential for
zanidatamab-induced HER2 localization may promote C1q engagement
and is consistent with the additional finding that zanidatamab has
the unique ability to promote complement dependent cytotoxicity
(CDC). This was not observed with either of the HER2-targeted
monospecific antibodies, trastuzumab and pertuzumab, or their
combination and may contribute to zanidatamab’s promising clinical
activity.
“In addition to the broad clinical validation of zanidatamab, we
continue to value ongoing research designed to better understand
its unique biparatopic mechanisms of action,” said Ali Tehrani,
Ph.D., Zymeworks’ President & CEO. “These findings provide
important insights for our clinical development strategy and
support our goal of developing zanidatamab in earlier lines of
therapy where the combination of trastuzumab and pertuzumab are the
backbone of the current standard of care.”
ProTECT™ Presentation
ProTECT™, a novel antibody platform for integrating
tumor-specific immune modulation and enhancing the therapeutic
window of targeted multispecific biologics
Abstract: 924 Session Category: Experimental
and Molecular Therapeutics Session Title: Antibody Technologies
The ProTECT™ platform is the first conditionally-active antibody
technology that can simultaneously address both ends of the
therapeutic window by potentially reducing toxicity and increasing
efficacy. Functional, natural heterodimers (e.g. PD-1/PD-L1) are
introduced to sterically block antigen binding outside the tumor.
As a result, therapeutics utilizing ProTECT™ have limited activity
in normal healthy tissue, avoiding on-target, off-tumor toxicities.
Once in the tumor microenvironment, proteases cleave and release
one half of the functional block activating both the targeting
antibody and the immunomodulatory function. The resulting activated
multifunctional therapeutic enables immune modulation in concert
with antigen binding, leading to an overall increase in the
therapeutic window through selective tumor activity and enhanced
potency. This platform is also transferable with minimal
engineering so it can be easily applied to different therapeutic
targets. Data presented today at AACR showcase the utility of the
ProTECT™ platform for the generation of a first-in-class
CD3-redirecting multispecific that also comprises PD-L1 checkpoint
blockade.
IL-12 and 4-1BB Presentations
Increasing the therapeutic index of IL-12 by engineering for
tumor-specific protease activation
Abstract: 1788 Session Category: Immunology
Session Title: Modifiers of the Tumor Microenvironment
IL-12 is a cytokine produced by innate immune cells that
potently stimulates anti-tumor cytotoxic T cell, T helper cell, and
natural killer cell-mediated immunity. The use of IL-12 as a
therapeutic approach has historically been limited by systemic
toxicity observed in clinical trials, and current approaches to
address this toxicity have focused on reducing the potency of
IL-12, which may also limit its anti-tumor activity. To broaden the
therapeutic window of this highly potent cytokine, systemic IL-12
activity was blocked with an anti-IL-12 antibody which was designed
to be cleaved and released by proteases in the tumor
microenvironment. Data presented at AACR show that the therapeutic
window of IL-12 may be increased by the combination of antibody
blockade and cytokine modifications that synergize to localize
activity to the tumor.
Understanding the geometry and valency of bispecific antibodies
in the optimization of tumor-dependent activation of 4-1BB
Abstract: 1737 Session Category: Immunology
Session Title: Immunomodulatory Agents and Interventions
4-1BB is a receptor expressed on the surface of
tumor-infiltrating T cells that when activated, can enhance T cell
function leading to tumor regression. Unfortunately, the clinical
development of several 4-1BB targeting antibodies has been plagued
by dose-limiting liver toxicity and subsequent lack of anti-tumor
activity. To address this liability, multiple formats of 4-1BB x
TAA (tumor associated antigen) bispecific candidates were developed
to identify those that could selectively activate T cells within
the tumor microenvironment. A promising bispecific format with
bivalent 4-1BB targeting and monovalent TAA targeting demonstrated
the highest potential for tumor selectivity across several
different TAAs and was subsequently evaluated in an in vivo
xenograft model where it showed robust anti-tumor activity.
“The presentations highlighted at the AACR Annual Meeting
showcase Zymeworks’ proprietary protein engineering capabilities
and how they are being used to develop solutions for a broad set of
therapeutic modalities,” said Tony Polverino, Ph.D., Executive Vice
President, Early Development and Chief Scientific Officer of
Zymeworks. “Leveraging different approaches to achieve tumor
selective activity, from the functional block of the ProTECT™
platform, to the antibody block used in our IL-12 cytokine
candidates, to the use of format and valency in our 4-1BB program,
we’ve demonstrated several versatile ways to increase the
therapeutic window of our drug candidates. We continue to exploit
these approaches along with our bispecific, antibody-drug
conjugate, and immunomodulatory platforms to build a diverse
therapeutic pipeline.”
About Zanidatamab
Zanidatamab is a bispecific antibody, based on Zymeworks’
Azymetric™ platform, that can simultaneously bind two
non-overlapping epitopes of HER2, known as biparatopic binding.
This unique design results in multiple mechanisms of action
including dual HER2 signal blockade, increased binding, and removal
of HER2 protein from the cell surface, and potent effector function
leading to encouraging antitumor activity in patients. Zymeworks is
developing zanidatamab in multiple Phase 1, Phase 2, and pivotal
clinical trials globally as a targeted treatment option for
patients with solid tumors that express HER2. The FDA has granted
Breakthrough Therapy designation for zanidatamab in patients with
previously treated HER2 gene-amplified Biliary Tract Cancer (BTC),
and two Fast Track designations to zanidatamab, one as a single
agent for refractory BTC and one in combination with standard of
care chemotherapy, for first-line gastroesophageal adenocarcinoma
(GEA). These designations mean zanidatamab is eligible for
Accelerated Approval, Priority Review and Rolling Review, as well
as intensive FDA guidance on an efficient drug development program.
Zanidatamab has also received Orphan Drug designations for the
treatment of biliary tract, gastric and ovarian cancers, as well as
Orphan Drug designation for the treatment of gastric cancer from
the European Medicines Agency.
About Zymeworks Inc.
Zymeworks is a clinical-stage biopharmaceutical company
dedicated to the development of next-generation multifunctional
biotherapeutics. Zymeworks’ suite of therapeutic platforms and its
fully integrated drug development engine enable precise engineering
of highly differentiated product candidates. Zymeworks’ lead
clinical candidate, zanidatamab (ZW25), is a novel Azymetric™
bispecific antibody which has been granted Breakthrough Therapy
designation by the FDA and is currently enrolling in a pivotal
clinical trial for refractory HER2-amplified biliary tract cancer
(HERIZON-BTC-01) as well as several Phase 2 clinical trials for
HER2-expressing gastroesophageal and breast cancers. Zymeworks’
second clinical candidate, ZW49, is a novel bispecific
HER2-targeting antibody-drug conjugate currently in Phase 1
clinical development and combines the unique design and antibody
framework of zanidatamab with Zymeworks’ proprietary ZymeLink™
linker and cytotoxin. Zymeworks is also advancing a deep
preclinical pipeline in oncology (including immuno-oncology agents)
and other therapeutic areas. In addition, its therapeutic platforms
are being leveraged through strategic partnerships with nine
biopharmaceutical companies. For additional information about
Zymeworks, visit www.zymeworks.com and follow @ZymeworksInc on
Twitter.
Cautionary Note Regarding Forward-Looking Statements
This press release includes “forward-looking statements” within
the meaning of the U.S. Private Securities Litigation Reform Act of
1995 and “forward-looking information” within the meaning of
Canadian securities laws, or collectively, forward-looking
statements. Forward-looking statements in this news release
include, but are not limited to, statements that relate to
Zymeworks’ clinical and preclinical development of its product
candidates, related clinical trials, and other information that is
not historical information. When used herein, words such as “will”,
“continue”, “can”, “potential”, “may”, 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. All forward-looking
statements are based upon Zymeworks’ current expectations and
various assumptions. Zymeworks believes there is a reasonable basis
for its expectations and beliefs, but they are inherently
uncertain. Zymeworks 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 factors, including, without
limitation, market conditions and the factors described under “Risk
Factors” in Zymeworks’ Annual Report on Form 10-K for its fiscal
year ended December 31, 2020 (a copy of which may be obtained at
www.sec.gov and www.sedar.com). Consequently, forward-looking
statements should be regarded solely as Zymeworks’ current plans,
estimates and beliefs. Investors should not place undue reliance on
forward-looking statements. Zymeworks cannot guarantee future
results, events, levels of activity, performance or achievements.
Zymeworks does not undertake and specifically declines any
obligation to update, republish, or revise any forward-looking
statements to reflect new information, future events or
circumstances or to reflect the occurrences of unanticipated
events, except as may be required by law.
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version on businesswire.com: https://www.businesswire.com/news/home/20210410005031/en/
Investor Inquiries: Ryan Dercho, Ph.D. (604) 678-1388
ir@zymeworks.com
Tiffany Tolmie (604) 678-1388 ir@zymeworks.com
Media Inquiries: Mary Klem (604) 678-1388
media@zymeworks.com
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