Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency.
OBJECTIVE
The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of Notch signaling has been reported in several human tumor types. In this report, we describe the development of an antibody, OMP-59R5 (tarextumab), which blocks both Notch2 and Notch3 signaling.


METHODS
We utilized patient-derived xenograft tumors to evaluate antitumor effect of OMP-59R5. Immunohistochemistry, RNA microarray, real-time PCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts.


RESULTS
We found that anti-Notch2/3, either as a single agent or in combination with chemotherapeutic agents was efficacious in a broad spectrum of epithelial tumors, including breast, lung, ovarian, and pancreatic cancers. Notably, the sensitivity of anti-Notch2/3 in combination with gemcitabine in pancreatic tumors was associated with higher levels of Notch3 gene expression. The antitumor effect of anti-Notch2/3 in combination with gemcitabine plus nab-paclitaxel was greater than the combination effect with gemcitabine alone. OMP-59R5 inhibits both human and mouse Notch2 and Notch3 function and its antitumor activity was characterized by a dual mechanism of action in both tumor and stromal/vascular cells in xenograft experiments. In tumor cells, anti-Notch2/3 inhibited expression of Notch target genes and reduced tumor-initiating cell frequency. In the tumor stroma, OMP-59R5 consistently inhibited the expression of Notch3, HeyL, and Rgs5, characteristic of affecting pericyte function in tumor vasculature.


CONCLUSIONS
These findings indicate that blockade of Notch2/3 signaling with this cross-reactive antagonist antibody may be an effective strategy for treatment of a variety of tumor types.
OncoMed Pharmaceuticals, Inc., Redwood City, California. jean.yen@oncomed.com.
Wan-Ching
WC
Yen
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Marcus M
MM
Fischer
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Fumiko
F
Axelrod
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Christopher
C
Bond
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Jennifer
J
Cain
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Belinda
B
Cancilla
OncoMed Pharmaceuticals, Inc., Redwood City, California.
William R
WR
Henner
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Rene
R
Meisner
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Aaron
A
Sato
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Jalpa
J
Shah
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Tracy
T
Tang
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Breanna
B
Wallace
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Min
M
Wang
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Chun
C
Zhang
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Ann M
AM
Kapoun
OncoMed Pharmaceuticals, Inc., Redwood City, California.
John
J
Lewicki
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Austin
A
Gurney
OncoMed Pharmaceuticals, Inc., Redwood City, California.
Timothy
T
Hoey
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D051883:Receptor, Notch2 / Q000037:antagonists & inhibitors*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C497764:NOTCH2 protein, human; C499374:NOTCH3 protein, human; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C000606143:tarextumab