FRα will become another hot target in ADC field. As with PD1, once it is successful in one indication, it can be replicated for more indications.

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FRα: Another Hot Target In The ADC Field
On May 3, 2023, ImmunoGen announced that its FRα-targeting antibody-drug
conjugates drug Elahere has successfully completed the phase III verification
clinical trial of MIRASOL, becoming the first new drug to prolong the survival of
patients with platinum-resistant ovarian cancer. Elahere is an antibody-drug
conjugate (ADC) targeting folate receptor-α (FRα), mainly indicated for the
treatment of adult patients with FRα-positive platinum-resistant epithelial
ovarian cancer, fallopian tube cancer or primary peritoneal cancer, and these
patients had previously received one to three systemic regimens.
In recent years, FRα targeting drug development continues to increase, and
Elahere successfully demonstrated FRα's potential in ovarian cancer. In China,
there were more than 60,000 new cases of ovarian cancer in 2020, and
hundreds of thousands of cases of recurrence and maintenance treatment
every year, but currently there is no specific therapy to meet the huge clinical
demand. Previously, it was difficult to develop drugs targeting FRα. Small
molecule conjugated drugs and monoclonal antibody drugs all encountered
failures. Elahere was only conditionally approved based on small-scale phase
III clinical data. This phase III clinical success means that FRα targets will
overcome twists and turns and usher in new breakthroughs.
Introduction to FRα Targets
Folate receptor alpha (FRα), encoded by FOLR1, is a cell surface glycoprotein
with a molecular weight of 38-40 kD. It was first discovered as a folate-binding
protein and cloned as a tumor-associated antigen in 1991. FRα is a member of
the high-affinity FRs family, which also includes FRβ, FRγ, and FRδ, encoded
by FOLR2, FOLR3, and FOLR4, respectively.
FRα has a high affinity for reductive folic acid (such as 5-methyltetrahydrofolic
acid and tetrahydrofolic acid) and folic acid, which is absorbed through
endocytosis. FRα is essential in embryonic development, folic acid
supplementation, and is an important strategy for the prevention of birth
defects. In addition to delivering folate, FRα is involved in the regulation of
tumor cell proliferation and metastasis.

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F1 Clinical application of FRα-targeted drugs in cancer diagnosis and treatment
Source: Nature Reviews Clinical Oncology
FRα is a potential therapeutic target for tumor therapy. In addition to
transporting folic acid, it is also involved in regulating the proliferation and
metastasis of tumor cells. FRα is almost not expressed in normal tissues.
However, FRα is widely and highly expressed in tumor tissues, especially
in non-small cell lung cancer (14-74%), triple-negative breast cancer (35-68%),
mesothelioma (72-100%), and epithelial ovarian cancer (76-89%). Therefore,
FRα is an ideal target for the development of tumor targeting drugs. A variety
of drugs targeting FRα through various mechanisms such as
ADC, CAR-T, and double antibody are currently under development.

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F2 FRa expression levels in different types of tumors
Source: https://doi.org/10.1038/s41571-020-0339-5
Mechanism of FRα in Tumor
There are four main mechanisms of frα-mediated folic acid internalization and
cancer cell signaling regulation:
1. Folate binding to FRα can induce STAT3 activation through a
JAK-dependent process mediated by GP130 co-receptors.
2. FRα can form a macromolecular complex with LYN tyrosine kinase to
regulate the phosphorylation of PEAK1 to promote the activation of ERK and
STAT3.
3. GPI-anchored FRα is internalized in caveolae vesicles, forming early
endosomes, which undergo acidification and subsequent degradation and fuse
with lysosomes to release FRα and folic acid. FRα is then translocated to the
nucleus and functions directly as a transcription factor.
4. FRα acts as a folate transporter; Rapidly proliferating cells require adequate
intake of folic acid for single-carbon metabolic reactions and DNA synthesis,
repair, and methylation.

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F3 Mechanism of FRα in tumor
Research on FRα Targeted Therapy
Potential FRα targeted therapies include folic acid derivatives, ADCs, small
molecules, vaccines, CAR-T, nuclides, and monoclonal antibodies. The six
mechanisms are briefly described below:
1. Folate drug-conjugates: chemotherapeutic agents, such as vintafolide, have
been conjugated to folate for FRα-targeted therapy.
2. Vaccines targeting FRα: autologous dendritic cells engineered with FRα
mRNA commence an anti-FRα immune response, mediated by T-cells.
3. Chimeric antigen receptor (CAR) T cells: CAR T cells recognizing FRα
trigger tumor cell killing.
4. Monoclonal antibodies (direct effects): Specific recognition of FRα lead to
inhibition of downstream signaling events that cause tumor cell death.
5. Monoclonal antibodies (immune effector cell engagement): antibodies link
FRα-expressing tumor cells with immune effector cells that bear Fc receptors,
potentiate effector cell activation and target-neutralizing functions by
engendering antibody-dependent effector cell-mediated cytotoxicity (ADCC),
phagocytosis (ADCP).
6. Killing cancer cells through complement-dependent cytotoxicity (CDC)
activation.

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F4 Research on FRα targeted therapy
FRα and Ovarian Cancer
Folate receptor alpha (FRα) is a potent anticancer drug target. It includes
limited expression in non-malignant tissues, combined with overexpression in
malignant tissues in some cancers, making FRα a potential target using
multiple platforms such as antibodies, antibody-drug conjugates (ADCs),
bispecific antibodies or chimeric antigen receptor (CAR) T cells.
F5 FRα as a therapeutic target in cancer patients
Source: https://www.nature.com/articles/s41571-020-0339-5

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In the 2023 V1 version of the NCCN Guidelines for Ovarian Cancer, the ADC
drug Mirvetuximab soravtansine-gynx is listed as a recommended drug for the
recurrent platinum-resistant diseases. It is a tumor target for FRα expression.
For the treatment of gynecological malignant tumors, surgery, chemotherapy,
radiotherapy mainly used in clinical comprehensive treatment measures,
postoperative adjuvant chemotherapy, can effectively control the tumor
subclinical micro tumor lesions, so as to improve the clinical cure rate of
tumors. From traditional small molecule chemotherapy drugs to antibody drugs,
and then to the newly developed antibody drug conjugate (ADC), the
development of chemotherapy is more and more tending to stronger
targeting, higher cytotoxicity, less adverse reactions and other therapeutic
measures.
In late 2022, the FDA accelerated approval of Mirvetuximab soravtansine-gynx
for Frα-positive, platinum-resistant ovarian, fallopian tube, or peritoneal
epithelial carcinoma.
The drug was approved based on an evaluation of study 0417 (NCT04296890),
a one-arm trial of 106 patients with FRα-positive, platinum-resistant ovarian
epithelial, fallopian tube, or primary peritoneal cancer. Among 104 patients
with platinum-resistant, measurable disease who received at least one dose,
the confirmed ORR was 31.7% (95%CI: 22.9, 41.6) and the median DOR was
6.9 months (95%CI: 5.6, 9.7).
Table 1 NCT04296890 Research data
Future Research Prospects of FRα in Gynecological
Tumors
FRα is a highly relevant and potentially available target for cancer therapy.
Differential expression of FRα on the surface of malignant cells in selected
tumors has enabled the development of antiboy-based therapeutic strategies,
including ADCs, BiTEs, and CAR T cells. In addition, FRα's affinity for
non-physiological substrates, such as higher levels of folic acid compared to
natural folic acid in the diet, enables folic acid conjugators associated with

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chemotherapy payloads, radioisotopes, and/or fluorescent molecules to further
facilitate the development of anticancer drugs and imaging agents.
At present, there is a general lack of effective biomarkers for diagnosis,
treatment and prognostic analysis of gynecological tumors in clinical practice.
Further studies on the expression and distribution of FRα on the surface of
tumor cells can promote the study of gynecological tumor-related antigens,
and perhaps FRα can be used as a novel tumor biomarker for gynecological
tumors.
Conclusion
FRα is a highly relevant target in cancer therapy. Although it has failed in
humanized monoclonal antibodies and small molecule folic acid conjugated
drugs due to insufficient single-drug activity, it cannot be denied that it has
natural advantages as an anti-cancer target.
It is less expressed in normal tissues, but overexpressed in non-small cell lung
cancer, mesothelioma, endometrial cancer and other solid tumors. Although
no FRα ADCs are currently available on the global market, positive clinical
results have been achieved in clinical trials of IMGN853, MORAb-202, and
STRO-002. FRα, as an ADC target with less competition but clear drug
potential, can avoid homogeneous competition and form differentiated
advantages.
FRα will become another hot target in ADC field. As with PD1, once it is
successful in one indication, it can be replicated for more indications. As a lead
PEG derivatives, Huateng Pharma is dedicated to being your most reliable
partner to provide chemical synthesis and high-quality PEG linkers for ADC
drugs.
References:
[1]. Exploiting the folate receptor α in oncology
[2]. Folate Receptor α - A New Target for an Old Enemy
[3]. NCCN Guidelines Version 1.2023 Ovarian Cancer/Fallopian Tube Cancer/Primary
Peritoneal Cancer
Related articles:
[1]. Top 2 Targets of ADC: HER2 & Trop2
[2]. Target And Clinical Trial Progress of ADC In Prostate Cancer
[3]. 5 ADC Targets And Representative Drugs For Non-Small Cell Lung Cancer (NSCLC)
[4]. Approved Antibody–Drug Conjugates (ADCs) and In Clinical Trials