Folate receptor alpha (FRA) is a membrane protein with high affinity for binding and transporting folate into cells. Overexpression of FRA may confer a growth advantage to tumors by increasing folate uptake and affecting cell proliferation via alternative cell signaling pathways (1). FRA levels have been found to be elevated in tumors of epithelial origin compared to normal tissue as cancers of the breast (including TNBC (2)), colon, lungs and ovary (3). In this study, we report the development of MORAb-202, an anti-FRA antibody-drug conjugate (ADC), consisting of a FRA-binding antibody (MORAb-003, farletuzumab) with a cathepsin-cleavable form of eribulin (eribulin mesylate, marketed as Halaven®), a highly potent anti-mitotic agent that induces cell-cycle arrest and cell death by targeting microtubules.* We first study expression of FRA on a large panel of tumors patient-derived xenograft (PDX) and Cancer Cell Line-derived Xenograft (CDX). Then, we performed in vitro and in vivo anti-proliferation assays and compare antitumor activity of MORAb-202 with free eribulin accordingly to the FRA expression level. FRA expression was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the ADC. Moreover, in case of high expression of FRA, MORAb-202 showed a higher antitumor activity compared with free eribulin. These results suggest that FRA expression could be used as a response-predictive biomarker for this targeted therapy. The ability to identify and treat patients with an effective therapy based on the known expression of the tumor marker is a key point in predictive medicine progress. These findings support the clinical development of MORAb-202 ADC as a novel targeted therapy for patients with FRA-expressing tumors. The ADC described in this abstract is investigational, as efficacy and safety have not been established. There is no guarantee that this ADC will be available commercially.

1. C. MIGNARDa, F. BICHATa, C. DURIXa, K. RYBINSKIb, X. CHENGb, K.FURUUCHIb, E. ALBONEb, T.UENAKAb,c M. HILLAIRET de BOISFERONa
a Oncodesign, Dijon (France), b MORPHOTEK Inc, 210 Welsh Pool Road, Exton, PA 19341, USA, c Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan
MORAB-202 A FOLATE RECEPTOR ALPHA-TARGETED ANTIBODY-DRUG CONJUGATE SHOWS A HIGHLY POTENT ACTIVITY AGAINST A PANEL OF FRΑ-EXPRESSING TUMORS #1770
INTRODUCTION
Conclusions and perspectives
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RESULTS
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A new biomarker of recent interest in the cancer field is folate receptor alpha (FRA), a membrane-
bound protein with high affinity for binding and transporting folate into cells. Overexpression of FRA
may confer a growth advantage to tumors by increasing folate uptake and affect cell proliferation via
alternative cell signaling pathways (1). FRA levels have been found to be elevated in tumors of
epithelial origin compared to normal tissue, including triple-negative breast cancer (TNBC) (2). Due
to an absence of potential targeted therapy for this breast cancer subtype, the finding that a
significant number of TNBCs express abundantly FRA suggests an important population of patients may
benefit from FRA-targeting therapy.
Eighty-five percent of preclinical agents entering oncology clinical trials fail to demonstrate sufficient
safety or efficacy to gain regulatory approval (3). This failure rate shows a weak understanding of the
complexity of human cancer, the continued limitations of the predictive value of existing preclinical
models and the scale at which cancer models are interrogated in the preclinical setting (4). There is
a need for new experimental models that better replicate the diversity of human tumor biology in a
preclinical setting. It is now evidenced that patient-derived xenograft (PDXs) recapitulate human
tumor biology and help predict patient drug response (5) by directly comparing drug responses in
patients and their corresponding xenografts. To extend such observations to a greater number of
human cancers, we have generated in collaboration with Eisai an extensive collection of breast PDXs.
In this study, MORAb-202, a novel folate receptor-targeting eribulin* conjugate created through a
Morphotek and Eisai collaboration, was tested in FRA-expressing TNBC PDXs and was compared to free
eribulin.
The national IMODI (Innovative MODels Initiative) consortium collection
 FRA expression could be used for MORAb-202 activity biomarker.
 Preclinical antitumor activity of MORAb-202 is dependent on FRA expression.
 At equivalent dose MORAb-202 showed a higher antitumor activity when
compared to free eribulin in preclinical studies. In highly expressive FRA
tumor, to observe similar antitumor activity in preclinical studies, the dose of
eribulin without vectorization would require to be enhanced by 32-fold
compared to targeted eribulin. At this dose of eribulin, a body weight loss is
observed and a tumor relapse occurred in all treated animals, whereas no
relapse was observed for mice treated with MORAb-202.
 TNBC that does not express estrogen, progesterone or the HER2 receptor are
refractory to available targeted therapies for breast cancer treatment, such as
HER2-directed therapy (trastuzumab, T-DM1) and endocrine therapies
(tamoxifen or letrozole) should be sensitive to MORAb-202 treatment in FRA-
expressing tumors.
References
1-Siu MK et al., PLoS One. 2012;7(11)
2-Nacela BM., PLoS One. 2015, 10(3)
3-Arrowsmith, J. & Miller, P. 2011–2012. Nat. Rev. Drug Discov. 12, 569 (2013).
4-Paul, S.M. et al. Nat. Rev. Drug Discov. 9, 203–214 (2010).
5-Hidalgo, M. et al. Cancer Discov. 4, 998–1013 (2014).
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IHC analysis
In vivo anti-proliferation activity
(PDX: OD-BRE-589 FRA-negative tumor)
0 10 20 30 40
0
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Time post tumor induction (days)
Mediantumourvolume±IQR(mm3)
Vehicle IV Q1Dx1
MORAb-202 1 mg/kg IV Q1Dx1 (0.02 mg/kg eq. eribulin)
MORAb-202 5 mg/kg IV Q1Dx1 (0.1 mg/kg eq. eribulin)
eribulin 0.1 mg/kg IV Q1Dx1
eribulin 3.2 mg/kg IV Q1Dx1
Vehicle IV Q1Dx1
MORAb-202-eribulin 5 mg/kg IV Q1Dx1 (0.1 mg/kg eq. eribulin)
eribulin 0.1 mg/kg IV Q1Dx1
eribulin 3.2 mg/kg IV Q1Dx1
0 20 40 60 80
0
250
500
750
1000
MediantumorvolumeIQR(mm3
)
Time post tumor induction (days)
Vehicle IV Q1Dx1 (A)
MORAb-202 5 mg/kg IV Q1Dx1 (0.1 mg/kg eq. eribulin, B)
eribulin 0.1 mg/kg IV Q1Dx1 (C)
eribulin 3.2 mg/kg IV Q1Dx1 (D)
In vivo anti-proliferation activity
(PDX: IM-BRE-563 FRA-positive tumor)
A B
C D
Time post tumor induction (days)Time post tumor induction (days)
Individualtumorvolume(mm3)
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1500
2000
0 20 40 60 80
0
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1500
20 40 60 80
PDX characterization
FRA expression
Preclinical Antitumor Efficacy
In FRA-negative tumor, a marginal antitumor activity was
observed for mice treated with MORAb-202.
IHC analysis
OD-BRE-589 was negative for FRA.
A moderate (and heterogenous) to high expression
of FRA was observed for OD-BRE-0631 and IM-BRE-
563.
Preclinical Antitumor Efficacy
In IM-BRE-563, a higher response was observed with MORAb-
202 at 0.1 mg/kg Eq. eribulin when compared to mice
treated with eribulin at 3.2 mg/kg. At this end of the
experiment, all mice treated with MORAb-202 were tumor
free.
A body weight loss was observed only for mice treated with
eribulin at the highest dose.
Patient derived
tumor
Histological analysis of the tumor
OD-BRE-589 TNBC Spindle cells carcinoma ER(-), PR(-), HER2(-)
OD-BRE-631 TNBC invasive ductal carcinoma ER(-), PR(-), HER2(-)
IM-BRE-563 TNBC invasive ductal carcinoma ER(-), PR(-), HER2(-)
Group Data D60
Vehicle IV Q1Dx1
Median (mm3) 920
T/C% 100
MORAb-202 1 mg/kg Q1Dx1 (0.02 mg/kg eq. eribulin)
Median (mm3) 1104
T/C% 120
MORAb-202 5 mg/kg Q1Dx1 (0.1 mg/kg eq. eribulin)
Median (mm3) 413
T/C% 45
eribulin 0.1 mg/kg IV Q1Dx1
Median (mm3) 1115
T/C% 121
eribulin 3.2 mg/kg IV Q1Dx1
Median (mm3) 73
T/C% 8
T/C%: ratio of the median tumor volume of treated group (T) versus vehicle treated group (C)
Group Data D28
Vehicle IV Q1Dx1
Median (mm3) 1257
T/C% 100
MORAb-202 5 mg/kg Q1Dx1 (0.1 mg/kg eq. eribulin)
Median (mm3) 656
T/C% 52
eribulin 0.1 mg/kg IV Q1Dx1
Median (mm3) 882
T/C% 70
eribulin 3.2 mg/kg IV Q1Dx1
Median (mm3) 25
T/C% 2
T/C%: ratio of the median tumor volume of treated group (T) versus vehicle treated group (C)
Group Data D57
Vehicle IV Q1Dx1
Median (mm3) 838
T/C% 100
MORAb-202 5 mg/kg Q1Dx1 (0.1 mg/kg eq. eribulin)
Median (mm3) 21
T/C% 2
eribulin 0.1 mg/kg IV Q1Dx1
Median (mm3) 1048
T/C% 99
eribulin 3.2 mg/kg IV Q1Dx1
Median (mm3) 94
T/C% 11
T/C%: ratio of the median tumor volume of treated group (T) versus vehicle treated group (C)
MORAb-202 : antibody-drug conjugate (ADC*) consisting of farletuzumab paired with a
cathepsin-cleavable form of eribulin.
Highlights:
• eribulin:MAb ratio of 4.0
• Low aggregate levels (< 1%)
• Highly cytotoxic to FRA-positive cells and low levels of
off-target killing
• Bystander effect in mixed tumor cell populations
• Serum-stable
• Highly efficacious in tumor cell xenograft models
In vitro anti-proliferation activity
In vivo anti-proliferation activity
(CDX: NCI-H2110 FRA-positive tumor)
*The ADC described in this poster is investigational, as efficacy and
safety have not been established. There is no guarantee that this
ADC will be available commercially.
Crystal Violet assay; EC50 (nM)
IGROV I
(FRA +++)
NIH-OVCAR-3
(FRA++)
NCI-H2110
(FRA++)
A431-A3
(FRA +/-)
0.01 0.16 0.73 23
In vivo anti-proliferation activity
(PDX: OD-BRE-631 FRA-positive tumor)
Preclinical Antitumor Efficacy
In FRA-positive tumor, a significant antitumor activity was
observed for mice treated with MORAb-202 at 0.1 mg/kg eq.
eribulin. At equivalent dose, no antitumor activity was observed
with eribulin without targeting vector.
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Time post tumor induction (days)
MediantumorvolumeIQR(mm3
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MORAb-202 1 mg/kg
MORAb-202 2.5 mg/kg
MORAb-202 5 mg/kg
0 10 20 30 40 50 60
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Time post tumor induction (days)
Medianbodyweight±IQR(g)
Time post tumor induction (days)
Mediantumorvolume±IQR(mm3)
0 10 20 30 40 50 60
0
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Time post tumor induction (days)
Medianbodyweight(g)
Group MBWC (D34-D28, %)
Vehicle IV Q1Dx1 5.4
MORAb-202 5 mg/kg Q1Dx1 (0.1 mg/kg eq. eribulin) 0.8
eribulin 0.1 mg/kg IV Q1Dx1 6.0
eribulin 3.2 mg/kg IV Q1Dx1 -8.4
MBWC (D34-D28)
Treatment initiation
*Eribulin mesylate (Halaven®) is approved in the U.S. for the treatment of patients with metastatic breast cancer who
have previously received at least two chemotherapeutic regimens for metastatic disease, including an anthracycline and
a taxane in either the adjuvant or metastatic setting.