NORTH
CHICAGO, Ill. and SOUTH SAN
FRANCISCO, Calif., Oct. 4, 2023
/PRNewswire/ -- AbbVie (NYSE: ABBV), the Broad Institute of
MIT and Harvard, and Calico Life Sciences today announced
the publication in Nature of the discovery and
preclinical data that demonstrate investigational ABBV-CLS-484 is a
potential first-in-class, orally bioavailable, PTPN2/N1 phosphatase
inhibitor that enhances anti-tumor immunity. The findings, based on
research conducted by AbbVie in collaboration with the Broad
Institute and Calico, support the development of ABBV-CLS-484 as a
promising new strategy for cancer immunotherapy.
Titled "The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent
anti-tumour immunity," the paper highlights the novel structural
insights and design that led to the discovery of ABBV-CLS-484 and
its dual mechanism of action that targets tumor cells and
suppresses their growth, as well as promotes the activation of
several immune cell types to increase their anti-tumor
activity.1
Researchers at the Broad previously identified protein tyrosine
phosphatase non-receptor type 2 (PTPN2) and its closely related
paralog PTPN1 as potential targets for cancer immunotherapy through
an in vivo CRISPR screen.2 However, this
challenging target class had previously been deemed "undruggable".
AbbVie researchers overcame the challenges and discovered the dual
PTPN2/N1 inhibitor, ABBV-CLS-484, through structure-based drug
design and optimization of drug-like properties.
Discovery scientists at AbbVie, the Broad, and Calico further
uncovered the biology and mechanism of action of ABBV-CLS-484.
Preclinical findings presented demonstrate that ABBV-CLS-484
treatment amplifies the tumor intrinsic response to interferon and
increases the activation and function of several immune cell
subsets promoting cellular pathways including JAK-STAT signaling in
animal models. In murine cancer models resistant to PD-1 blockade,
monotherapy ABBV-CLS-484 treatment generates robust anti-tumor
immunity. Through in vivo studies and single cell
transcriptional profiling of tumor-infiltrating lymphocytes from
ABBV-CLS-484 treated mice, the team revealed that ABBV-CLS-484
inflames the tumor microenvironment and promotes NK and CD8+ T-cell
function. In T cells, mechanistically, ABBV-CLS-484 induces
epigenetic and metabolic changes resulting in a unique functional
state causing increased cytotoxicity and reduced T-cell exhaustion
and dysfunction.
"Immunotherapies like PD-1 blockade have revolutionized cancer
treatment; however, many patients do not respond well to them, and
a significant unmet need remains," said Christina Baumgartner, Ph.D., co-first author
and senior principal research scientist, AbbVie. "Through the
extraordinary efforts of AbbVie's medicinal chemistry team to drug
the undruggable, we now have a potential first-in-class PTPN2/N1
inhibitor. We're excited to share its biology and mechanism of
action, and look forward to further evaluating it in the
clinic."
"This study is a powerful demonstration of how collaboration can
bring together diverse expertise to advance our understanding of
disease biology and lead to discoveries that support new treatment
strategies for people living with cancer," said Marcia Paddock, M.D., Ph.D., co-author and
director of oncology new target development at Calico. "We are
proud to be working with both AbbVie and the Broad Institute and
look forward to sharing additional progress from our clinical
studies of this novel immunotherapy."
ABBV-CLS-484 is the first active-site phosphatase inhibitor to
enter clinical evaluation as a cancer therapy and is currently in
an AbbVie and Calico-led Phase 1 clinical trial in solid tumors
(NCT04777994).
"This is an unprecedented opportunity to evaluate how immune
responses work," said Robert
Manguso, Ph.D., co-senior author on the study, associate
member at the Broad, and assistant professor at the Massachusetts
General Hospital Center for Cancer Research and Harvard Medical School. "The ability to further
explore this signaling pathway in clinical studies is really
important."
About AbbVie
AbbVie's mission is to discover and deliver innovative medicines
and solutions that solve serious health issues today and address
the medical challenges of tomorrow. We strive to have a remarkable
impact on people's lives across several key therapeutic areas –
immunology, oncology, neuroscience, and eye care – and products and
services in our Allergan Aesthetics portfolio. For more information
about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on
LinkedIn, Facebook, Instagram, X (formerly Twitter), and
YouTube.
Forward-Looking Statements
Some statements in this news release are, or may be
considered, forward-looking statements for purposes of the Private
Securities Litigation Reform Act of 1995. The words "believe,"
"expect," "anticipate," "project" and similar expressions and uses
of future or conditional verbs, generally identify forward-looking
statements. AbbVie cautions that these forward-looking statements
are subject to risks and uncertainties that may cause actual
results to differ materially from those expressed or implied in the
forward-looking statements. Such risks and uncertainties include,
but are not limited to, challenges to intellectual property,
competition from other products, difficulties inherent in the
research and development process, adverse litigation or government
action, and changes to laws and regulations applicable to our
industry. Additional information about the economic, competitive,
governmental, technological and other factors that may affect
AbbVie's operations is set forth in Item 1A, "Risk Factors," of
AbbVie's 2022 Annual Report on Form 10-K, which has been filed with
the Securities and Exchange Commission, as updated by its
subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no
obligation, and specifically declines, to release publicly any
revisions to forward-looking statements as a result of subsequent
events or developments, except as required by law.
About Calico
Calico (Calico Life Sciences LLC) is an Alphabet-founded
research and development company whose mission is to harness
advanced technologies and model systems to increase our
understanding of the biology that controls human aging. Calico will
use that knowledge to devise interventions that enable people to
lead longer and healthier lives. To learn more about Calico,
visit www.calicolabs.com. Follow @calico
on LinkedIn, X (formally
Twitter) and YouTube.
References:
- Baumgartner C. K., et al. The PTPN2/PTPN1 inhibitor
ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature.
Published October 4, 2023. doi:
10.1038/s41586-023-06575-7.
- Manguso, R. T., et al. In vivo CRISPR screening identifies
Ptpn2 as a cancer immunotherapy target. Nature.
2017;547(7664):413-418. doi: 10.1038/nature23270.
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SOURCE AbbVie