- essay titled 'Discuss monoclonal antibodies and antibody-drug conjugate therapeutic strategies targeting the tumour-associated antigen Folate Receptor alpha (FRα) in ovarian cancer'
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conjugate therapeutic strategies targeting the tumour-
associated antigen Folate Receptor alpha (FRα) in
ovarian cancer
By Isabella Hampson K21053811
Kings College London
Biomedical Sciences
6BBI0305 Immunology and Immunotherapy of Cancer (23~24)
Word count: 2177
,Abstract
Ovarian cancer (OC) is the leading cause of gynaecologic cancer mortality worldwide.
Existing therapies have failed to adequately meet the needs of women, who often suffer
chronic episodes of recurrent disease and chemoresistance. In addressing this major unmet
clinical need, folate receptor alpha (FRα) has attracted considerable interest due to its high
expression in approximately 80% of OC tumours. In this review, we discuss the use of
monoclonal antibodies (mAbs) and antibody-drug conjugates (ADC) targeting the tumour-
associated antigen, FRα, in treatment of OC. Of note, ADC are the only FRα-targeting therapy
in clinical use.
Introduction
The clinical challenge of ovarian cancer
OC is a highly heterogenous disease at the molecular level and can be classified based on its
potential origin from the epithelium, stroma, or germinal cells of the ovary 1,2. Epithelial
ovarian cancers (EOC) make up approximately 90% of all malignant ovarian tumours in adult
women. EOC represent a diverse group of tumours; these neoplasms can be classified into
distinct histological subtypes based on morphological appearance of tumour cells (figure 1)
and specific genetic alterations3. Taking into account the clinic-pathological heterogeneity in
EOC, tailored treatment approaches should be implemented in management of the disease.
Figure 1. Histological slides of the main subtypes of epithelial ovarian cancer, showing morphological
appearance of tumour cells. HE-saffron. a High-grade serous carcinoma. ×10. b Low-grade serous carcinoma.
×20. c Clear-cell carcinoma. ×10. d Mucinous carcinoma. ×20. d Endometrioid carcinoma. ×20. Taken from 4.
, As a consequence of approximately 70% of patients receiving a diagnosis at late-stage
disease, OC has a high mortality rate relative to other gynaecologic cancer types 5. This is
partly due to early stage OC presenting asymptomatically, and even at late-stage OC,
symptoms are vague6. Moreover, in up to 90% of women, early-stage disease is curable7,8,
emphasising the importance of early detection of OC and the crucial need for a reliable
serum biomarker and accessible screening method.
Current therapies
Cytoreductive surgery followed by adjuvant platinum-taxane chemotherapy has remained
the mainstay of OC treatment for a quarter of a century9. Recently, poly (ADP-ribose)
polymerase (PARP) inhibitors have emerged in front-line maintenance therapy of OC,
exhibiting significant clinical efficacy. However, their benefits are greatest in high-grade
serous OC with underlying homologous recombination deficiency and thus far, an
improvement in overall survival has only been demonstrated in women with BRCA mutated
EOC10-12. Moreover, with the increasingly extensive clinical use of PARP inhibitors, the
potential for acquiring drug resistance is significant13.
Vascular endothelial growth factor (VEGF) is a key promoter of angiogenesis and disease
progression in EOC. Bevacizumab, a humanized mAb against VEGF, has been shown to
improve progression-free survival, in particular in poor-prognosis patients 14-16.
While the initial response to platinum-based chemotherapy can be as high as 80%, acquired
drug resistance is common and most women will develop many episodes of recurrent
disease, wherein these chronic episodes culminate in chemoresistance and death. 80% of
women treated with cytoreductive surgery and adjuvant chemotherapy have been shown to
relapse17. Furthermore, bevacizumab and PARP inhibitors provide benefits for only a subset
of patients and can only delay the relapse of platinum-resistant (PR) EOC 18. This exemplifies
the crucial need for development of novel therapeutics in treatment of OC, in particular for
those who develop resistance to therapies.
FRα in health
FRα is encoded by the FOLR1 gene and is one of four glycopolypeptide members of folate
receptors19. FRα has the essential function of facilitating uptake of extracellular folate
obtained from dietary sources via potocytosis20.
FRα is primarily expressed on the plasma membrane of epithelial cells in various tissues. In
the kidneys, FRα is expressed on the apical surface of proximal tubular cells to maintain
folate homeostasis within the body21,22. While in the brain, FRα is selectively expressed in the
choroid plexus mediating transcellular 5-mTHF transport into cerebrospinal fluid. Mutations
in the FOLR1 gene are associated with cerebral folate transport deficiency and childhood-
onset neurodegeneration, as reported in a number of studies23-25. Moreover, folic acid is an
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