Preclinical Study Presented at 2017 AACR Annual
Meeting
Immunomedics, Inc., (NASDAQ:IMMU) (“the Company” or “we”) today
announced that its lead antibody-drug conjugate (ADC), sacituzumab
govitecan (IMMU-132), with a proprietary SN-38-delivery platform,
has the potential to provide clinical benefit both to
chemosensitive solid tumors with low Trop-2 expression, as well as
to chemoresistant tumors with high Trop-2 expression.
“This preclinical study demonstrated that using
IMMU-132 to deliver SN-38 to tumor cells is a unique way to accrete
enough SN-38 within the tumor to cause significant DNA damage and
overpower the DNA-repair systems within the targeted cells,”
remarked Cynthia L. Sullivan, President and Chief Executive
Officer.
The Company had previously reported that
exposure to sacituzumab govitecan may induce an increase in several
different proteins involved in the repair of DNA double strand
breaks resulting in resistance to therapy.1 Given that sacituzumab
govitecan mediated different antitumor responses in different tumor
types, despite the fact that some tumor lines expressed similar low
levels of Trop-2, DNA repair by some tumor cells may play an
important role in determining sensitivity to therapy with
sacituzumab govitecan. Furthermore, resistance to chemotherapy
(e.g., irinotecan) may also be due in part to increased expression
of proteins used to rescue the cell from ensuing DNA
damage.
However, we postulated that if enough drug, such
as SN-38, enters the cell, significant DNA damage will occur that
will overwhelm any repair mechanisms resulting in apoptosis and
cell death. We conducted a preclinical study to investigate
if sacituzumab govitecan, through its targeting of Trop-2 in solid
tumors, would be superior to irinotecan in overcoming the repair of
DNA breaks in triple-negative breast cancer (TNBC) cells with
moderate to high Trop-2 expression.
A TNBC cell line with very active DNA repair
pathways, and low Trop-2 expression, was genetically modified to
yield two new tumor lines with moderate and high Trop-2
expression. Mice bearing these three different tumor types
(low, moderate and high Trop-2) were randomized into various
treatment groups. In all three tumor types, irinotecan, at its
maximum tolerated dose (>35-fold more SN-38 than sacituzumab
govitecan dose), provided a modest survival benefit relative to the
control group, with no significant difference between tumor
types. However, in mice bearing tumors with moderate or high
Trop-2 expression, sacituzumab govitecan therapy mediated
significant antitumor effects compared to all other treatments,
including irinotecan and control ADC therapy. This greatly improved
antitumor activity of sacituzumab govitecan over irinotecan is
likely due to increased targeting and uptake of SN-38 in these
tumors by sacituzumab govitecan at levels capable of overcoming
induced DNA repair.
“If our hypothesis is correct, these preclinical
results may offer an explanation for our clinical observation that
moderate to strong Trop-2 expression measured by
immunohistochemistry in most cancers might not be useful in
predicting a patient’s response to sacituzumab govitecan treatment,
one of the key findings in our second poster presentation at this
year’s AACR conference, which focused on the pharmacokinetics of
this investigational ADC in patients with diverse solid tumors,”
added Ms. Sullivan.
The pharmacokinetics study, entitled
“Pharmacokinetics of Sacituzumab Govitecan (IMMU-132), an
Antibody-drug Conjugate (ADC), Targeting Trop-2, in Patients with
Diverse Solid Tumors,” was presented by Dr. Robert M. Sharkey, a
consultant of the Company. Other co-authors are Dr. Allyson J.
Ocean, Weill Cornell Medicine, New York, NY; Dr. Alexander N.
Starodub, Indiana University Health Center for Cancer Care, Goshen,
IN (current address, Parkview Cancer Institute, Fort Wayne, IN);
Dr. Aditya Bardia, Massachusetts General Hospital Cancer Center,
Harvard Medical School, Boston, MA; Dr. Michael Guarino, Helen F
Graham Cancer Center, Newark, DE; Dr. Wells A. Messersmith,
University of Colorado Cancer Center, Aurora, CO; Dr. Jordan D.
Berlin, Vanderbilt-Ingram Cancer Center, Nashville, TN; Dr. Vincent
J. Picozzi, Virginia Mason Cancer Center, Seattle, WA; Dr. Rebecca
Moroose, UF Health Cancer Center, Orlando, FL; and Immunomedics
employees, Drs. William A. Wegener, Pius Maliakal, Serengulam V.
Govindan and David M. Goldenberg.
Sacituzumab govitecan cleared in a predictable
manner based on in-vitro serum stability studies, with no
difference between the 8 and 10 mg/kg dose groups studied
clinically. While there was a gradual release of SN-38, more than
90% of the SN-38 in the serum at any given time stayed bound to the
antibody. Glucuronidated SN-38 concentrations were lower than
SN-38, a possible reason for the lower incidence of severe diarrhea
as compared to irinotecan. In addition, neither neutropenia nor
diarrhea was found to correlate with free SN-38 levels in serum.
With no difference in safety and pharmacokinetics, but improved
objective response rate and clinical benefit ratio favoring the 10
mg/kg group in TNBC, small-cell and non-small-cell lung cancer
indications, 10 mg/kg is selected as the starting dose for future
clinical studies in treating patients with multiple cancer
indications.
Reference
- Cardillo TM, Sharkey RM, Rossi DL, et al. Synthetic lethality
exploitation by an anti-Trop-2-SN-38 antibody-drug conjugate,
IMMU-132, plus PARP-inhibitors in BRCA1/2-wild-type triple-negative
breast cancer. Clin Cancer Res. Epub ahead of print. Jan 9,
2017.
About ImmunomedicsImmunomedics
(the “Company”) is a clinical-stage biopharmaceutical company
developing monoclonal antibody-based products for the targeted
treatment of cancer, autoimmune disorders and other serious
diseases. Immunomedics’ advanced proprietary technologies allow the
Company to create humanized antibodies that can be used either
alone in unlabeled or “naked” form, or conjugated with radioactive
isotopes, chemotherapeutics, cytokines or toxins. Using these
technologies, Immunomedics has built a pipeline of eight
clinical-stage product candidates. Immunomedics’ portfolio of
investigational products includes antibody-drug conjugates (ADCs)
that are designed to deliver a specific payload of a
chemotherapeutic directly to the tumor while reducing overall
toxicities that are usually found with conventional administration
of these chemotherapeutic agents. Immunomedics’ most advanced ADCs
are sacituzumab govitecan (IMMU-132) and labetuzumab govitecan
(IMMU-130), which are in Phase 2 trials for a number of solid
tumors and metastatic colorectal cancer, respectively. IMMU-132 has
received Breakthrough Therapy Designation from the FDA for the
treatment of patients with triple-negative breast cancer who have
failed at least two prior therapies for metastatic disease.
Immunomedics has a research collaboration with Bayer to study
epratuzumab as a thorium-227-labeled antibody. Immunomedics has
other ongoing collaborations in oncology with independent cancer
study groups. The IntreALL Inter-European study group is conducting
a large, randomized Phase 3 trial combining epratuzumab with
chemotherapy in children with relapsed acute lymphoblastic leukemia
at clinical sites in Australia, Europe, and Israel. Immunomedics
also has a number of other product candidates that target solid
tumors and hematologic malignancies, as well as other diseases, in
various stages of clinical and preclinical development. These
include combination therapies involving its antibody-drug
conjugates, bispecific antibodies targeting cancers and infectious
diseases as T-cell redirecting immunotherapies, as well as
bispecific antibodies for next-generation cancer and autoimmune
disease therapies, created using its patented DOCK-AND-LOCK®
protein conjugation technology. The Company believes that its
portfolio of intellectual property, which includes approximately
310 active patents in the United States and more than 400 foreign
patents, protects its product candidates and technologies. For
additional information on the Company, please visit its website at
www.immunomedics.com. The information on its website does not,
however, form a part of this press release.
This release, in addition to historical
information, may contain forward-looking statements made pursuant
to the Private Securities Litigation Reform Act of 1995. Such
statements, including statements regarding clinical trials
(including the funding therefor, anticipated patient enrollment,
trial outcomes, timing or associated costs), regulatory
applications and related timelines, out-licensing arrangements
(including the timing and amount of contingent payments under the
licensing and development agreement with Seattle Genetics),
forecasts of future operating results, potential collaborations,
and capital raising activities, involve significant risks and
uncertainties and actual results could differ materially from those
expressed or implied herein. Factors that could cause such
differences include, but are not limited to, the Company’s
dependence on business collaborations or availability of required
financing from capital markets, or other sources on acceptable
terms, if at all, in order to further develop our products and
finance our operations, new product development (including clinical
trials outcome and regulatory requirements/actions), the risk that
we or any of our collaborators may be unable to secure regulatory
approval of and market our drug candidates, risks associated with
the outcome of pending litigation and competitive risks to marketed
products, and the Company’s ability to repay its outstanding
indebtedness, if and when required, as well as the risks discussed
in the Company’s filings with the Securities and Exchange
Commission. The Company is not under any obligation, and the
Company expressly disclaims any obligation, to update or alter any
forward-looking statements, whether as a result of new information,
future events or otherwise.
For More Information:
Dr. Chau Cheng
Senior Director, Investor Relations & Corporate Secretary
(973) 605-8200, extension 123
ccheng@immunomedics.com
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