Claudin-6 (CLDN6) and Folate Receptor Alpha (FRα) Targeted Antibody-Drug Conjugates: Bypassing Platinum Resistance and Tumor Heterogeneity in High-Grade Serous Ovarian Carcinoma
Keywords:
High-Grade Serous Ovarian Carcinoma, Folate Receptor Alpha, Mirvetuximab, Soravtansine, Platinum ResistanceAbstract
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy, and predicting its outcomes is complicated by two interlinked adversaries: the near-inevitable development of platinum resistance that depletes the most successful drug class against the disease and a profound molecular and antigenic heterogeneity that defies targeted therapy. Antibody-drug conjugates (ADCs) directed against tumor-associated antigens offer a strategically attractive answer to both because they kill through a cytotoxic mechanism of microtubule disruption by a delivered payload that is wholly independent of the DNA-repair and drug-handling pathways that confer platinum resistance and because the bystander effect of their membrane-permeable payloads can reach antigen-negative cells within a heterogeneous tumor. This review examines two complementary antigens that researchers are pursuing in HGSOC. Folate receptor alpha (FRα), overexpressed in the great majority of these tumors, is the target of mirvetuximab soravtansine, the first agent of any class to demonstrate an overall-survival benefit in platinum-resistant ovarian cancer and the first ADC approved for this disease. Claudin-6 (CLDN6), an oncofetal tight-junction protein essentially absent from normal adult tissue and expressed in roughly half of HGSOC, is the target of the first-in-class ADC TORL-1-23, which has shown encouraging response rates in platinum-resistant disease in early-phase testing. We detail the biology and resistance mechanisms of HGSOC; the rationale by which antigen-directed payload delivery bypasses platinum resistance; the design, clinical validation, and pipeline of FRα- and CLDN6-targeted ADCs; the way bystander killing, complementary antigen coverage, and biomarker-guided selection address heterogeneity; the safety; and resistance.
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