Asunto(s)
Receptor 1 de Folato , Inmunoconjugados , Neoplasias Ováricas , Medicina de Precisión , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Medicina de Precisión/métodos , Inmunoconjugados/uso terapéutico , Inmunoconjugados/administración & dosificación , Receptor 1 de Folato/antagonistas & inhibidores , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/patologíaRESUMEN
Platinum-resistant ovarian cancer (PROC) refers to disease progression within 6 months after the completion of platinum-based chemotherapy. Historically, treatment options for PROC were limited with a poor prognosis and non-platinum single agent plus bevacizumab has been the mainstay of treatment. Fortunately, there have been notable advancements in recent years, leading to an advance in treatment paradigms for this challenging disease. Various combinations of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, and immunotherapy are being explored for an improved treatment outcome. Antibody-drug conjugates targeting folate receptor alpha, which deliver a cytotoxic payload directly to cancer cells, have emerged as a promising therapeutic approach for PROC. WEE1 inhibitors, such as adavosertib, function by inhibiting the WEE1 kinase activity, leading to premature entry of a cell into mitosis phase and thus increased DNA damage. It has been observed that cancer cells with TP53 mutations may be more sensitive to WEE1 inhibitors. Biomarker testing such as analysis of the expression level of folate receptor alpha or mutation in TP53 may be applicable for identifying patients who are more likely to respond to the specific therapy, enabling a more personalized treatment approach. This overview summarizes key clinical findings on the efficacy and safety of theses novel biomarker-driven therapeutic approaches.
Asunto(s)
Resistencia a Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Receptor 1 de Folato/antagonistas & inhibidores , Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia/métodos , Inmunoconjugados/uso terapéutico , Pirazoles/uso terapéutico , Proteína p53 Supresora de Tumor , Pirimidinonas/uso terapéuticoRESUMEN
BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).
Asunto(s)
Carcinoma Epitelial de Ovario , Maitansina , Neoplasias Ováricas , Femenino , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Maitansina/administración & dosificación , Maitansina/efectos adversos , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Receptor 1 de Folato/antagonistas & inhibidores , Receptor 1 de Folato/genética , Resistencia a Antineoplásicos/genética , Compuestos de Platino/farmacologíaRESUMEN
Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRß), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRß-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1ß release by FRß+ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.
Asunto(s)
Aminopterina/farmacología , Síndrome de Liberación de Citoquinas/prevención & control , Receptor 2 de Folato/genética , Antagonistas del Ácido Fólico/farmacología , Ácido Fólico/metabolismo , Macrófagos/efectos de los fármacos , Animales , Antígenos CD19/genética , Antígenos CD19/inmunología , Células CHO , Cricetulus , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Femenino , Receptor 1 de Folato/antagonistas & inhibidores , Receptor 1 de Folato/genética , Receptor 1 de Folato/inmunología , Receptor 2 de Folato/antagonistas & inhibidores , Receptor 2 de Folato/inmunología , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Ratones , Modelos Biológicos , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/patología , Células RAW 264.7 , Ratas , Ratas Endogámicas Lew , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
Alpha folate receptor (FRα) is currently under investigation as a target for the treatment of patients with non-small-cell lung cancer (NSCLC), since it is highly expressed in tumor cells but is largely absent in normal tissue. In this study, a novel human variable domain of a heavy-chain (VH) antibody fragment specific to FRα was enriched and selected by phage bio-planning. The positive phage clone (3A102 VH) specifically bound to FRα and also cross-reacted with FRß, as tested by ELISA. Clone 3A102 VH was then successfully expressed as a soluble protein in an E. coli shuffle strain. The obtained soluble 3A102 VH demonstrated a high affinity for FRα with affinity constants (Kaff) values around 7.77 ± 0.25 × 107 M-1, with specific binding against both FRα expressing NSCLC cells and NSCLC patient-derived primary cancer cells, as tested by cell ELISA. In addition, soluble 3A102 VH showed the potential desired property of a targeting molecule by being internalized into FRα-expressing cells, as observed by confocal microscopy. This study inspires the use of phage display to develop human VH antibody (Ab) fragments that might be well suited for drug targeted therapy of NSCLC and other FRα-positive cancer cells.
Asunto(s)
Bacteriófagos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptor 1 de Folato/antagonistas & inhibidores , Fragmentos de Inmunoglobulinas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Línea Celular Tumoral , Humanos , Fragmentos de Inmunoglobulinas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Antibody-drug conjugates (ADCs) hold great therapeutic promise for cancer indications; however, treating tumors with intratumor heterogeneity remains challenging. We hypothesized that ADCs that can simultaneously target two different cancer antigens could address this issue. Here, we report controlled production and evaluation of bispecific ADCs chemically functionalized with tumor-targeting small molecules. Enzyme-mediated conjugation of bi-functional branched linkers and following sequential orthogonal click reactions with payload and tumor targeting modules (folic acid or RGD peptide) afforded homogeneous bispecific ADCs with defined ligand/drug-to-antibody ratios ranging from 4 + 4 to 16 + 4 (ligand/payload). Most bispecific ADCs were stable under physiological conditions for 14 days. Functionalization with the cancer-specific ligands did not impair cathepsin B-mediated payload release from ADCs. Bispecific ADCs targeting the folate receptor (FR)/human epidermal growth factor receptor 2 (HER2) demonstrated specific binding and high cell killing potency only in cells expressing either antigen (FR or HER2). Integrin/HER2 bispecific ADCs equipped with RGD peptides also showed target-specific binding and cytotoxicity in integrin- or HER2-positive cells. These findings suggest that our small-molecule based bispecific ADCs have the potential to effectively treat tumors with heterogeneous antigen expression.
Asunto(s)
Antineoplásicos/farmacología , Receptor 1 de Folato/antagonistas & inhibidores , Inmunoconjugados/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptor 1 de Folato/metabolismo , Humanos , Inmunoconjugados/química , Estructura Molecular , Receptor ErbB-2/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
RNA interference (RNAi) applications have evolved from experimental tools to study gene function to the development of a novel class of gene-silencing therapeutics. Despite decades of research, it was not until August 2018 that the US FDA approved the first-ever RNAi drug, marking a new era for RNAi therapeutics. Although there are many limitations associated with the inherent structure of RNA, delivery to target cells and tissues remains the most challenging. RNAs are unable to diffuse across cellular membranes due to their large size and polyanionic backbone and, therefore, require a delivery vector. RNAi molecules can be conjugated to a targeting ligand or packaged into a delivery vehicle. Alnylam has used both strategies in their FDA-approved formulations to achieve efficient delivery to the liver. To harness the full potential of RNAi therapeutics, however, we must be able to target additional cells and tissues. One promising target is the folate receptor α, which is overexpressed in a variety of tumors despite having limited expression and distribution in normal tissues. Folate can be conjugated directly to the RNAi molecule or used to functionalize delivery vehicles. In this review, we compare both delivery strategies and discuss the current state of research in the area of folate-mediated delivery of RNAi molecules.
Asunto(s)
Sistemas de Liberación de Medicamentos , Receptor 1 de Folato/genética , Silenciador del Gen , ARN Interferente Pequeño/uso terapéutico , Receptor 1 de Folato/antagonistas & inhibidores , Ácido Fólico/genética , Ácido Fólico/metabolismo , Terapia Genética/tendencias , Humanos , Ligandos , Interferencia de ARN , ARN Interferente Pequeño/genéticaRESUMEN
BACKGROUND: The development of biocompatible tumor-targeting delivery systems for anticancer agents is essential for efficacious cancer chemotherapy. Nanoparticles, as drug delivery cargoes for cancer therapy, are rapidly improving to overcome the limitations of conventional chemotherapeutic agents. Heparin-modified nanoparticles are currently being considered as one of the favorable carriers for the delivery of chemotherapeutics to cancer tissues. OBJECTIVE: This study was aimed at evaluating the in vitro and in vivo antitumor activity of a novel targeted, pH-sensitive, heparin-based polymeric micelle loaded with the poorly water-soluble anticancer drug, docetaxel (DTX). The micelles could overcome the limited water solubility, non-specific distribution, and insufficient drug concentration in tumor tissues. METHODS: DTX-loaded folate targeted micelles were prepared and evaluated for physicochemical properties, drug release, in vitro cellular uptake and cytotoxicity in folate receptor-positive and folate receptor-negative cells. Furthermore, the antitumor activity of DTX-loaded micelles was evaluated in the tumor-bearing mice. Some related patents were also studied in this research. RESULTS: The heparin-based targeted micelles exhibited higher in vitro cellular uptake and cytotoxicity against folate receptor over-expressed cells due to the specific receptor-mediated endocytosis. DTX-loaded micelles displayed greater antitumor activity, higher anti-angiogenesis effects, and lower systemic toxicity compared with free DTX in a tumor-induced mice model as confirmed by tumor growth monitoring, immunohistochemical evaluation, and body weight shift. DTX-loaded targeting micelles demonstrated no considerable toxicity on major organs of tumor-bearing mice compared with free DTX. CONCLUSION: Our results indicated that DTX-loaded multifunctional heparin-based micelles with desirable antitumor activity and low toxicity possess great potential as a targeted drug delivery system in the treatment of cancer.
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Docetaxel/farmacología , Endosomas/efectos de los fármacos , Receptor 1 de Folato/antagonistas & inhibidores , Ácido Fólico/metabolismo , Heparina/química , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Docetaxel/química , Endosomas/metabolismo , Femenino , Fibrinolíticos/química , Receptor 1 de Folato/metabolismo , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos BALB C , Micelas , Nanopartículas/química , Neoplasias/metabolismo , Neoplasias/patología , Patentes como AsuntoRESUMEN
We developed a STAT3 silencing siRNA to both tumor cells and M2 macrophages. The dual-targeting system prepared by electronic self-assembly was composed of folic acid-conjugated carboxymethyl chitosan for targeting and cationic chitosan derivatives for siRNA package. The effects of siRNA delivery was investigated in M2 macrophages and Lewis lung cancer cells (LLC). Due to the enhanced delivery efficiency, the dual-targeting delivery system exhibited a higher efficacy compared with non-targeting nanoparticles, resulting in a dramatically reduction of STAT3 expression in both cells, and a successful shift from M2 phenotypes (pro-tumor) to M1 phenotypes (anti-tumor) for macrophages. Additionally, the influence of the nanoparticles on LLC cells co-cultured with M2 macrophages was also investigated. The increased apoptosis and inhibition of proliferation of LLC cells were observed. In vivo therapeutic effect was also evaluated in s.c. tumor models, tumor growth was effectively inhibited and the level of M2 macrophages in tumor tissues was dramatically reduced.
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Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Receptor 1 de Folato/genética , Nanopartículas/química , Factor de Transcripción STAT3/genética , Animales , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quitosano/química , Quitosano/farmacología , Receptor 1 de Folato/antagonistas & inhibidores , Ácido Fólico/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , ARN Interferente Pequeño/química , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Tratamiento con ARN de Interferencia/métodos , Factor de Transcripción STAT3/antagonistas & inhibidores , Macrófagos Asociados a Tumores/efectos de los fármacosRESUMEN
Actively targeted nanomedicines have promised to revolutionize cancer treatment; however, their clinical translation has been limited by either low targetability, use of unsafe materials, or tedious fabrication. Here, we developed CD44 and folate receptor (FR) dually targeted nanoparticulate doxorubicin (HA/FA-NP-DOX) based on a direct conjugate of two purely natural ligands, hyaluronic acid and folic acid (FA), for safe, highly specific, and potent treatment of ovarian tumors in vivo. HA/FA-NP-DOX had a small size and high DOX loading, wherein the particle size decreased from 115, 93, to 89 nm with increasing degree of substitution of FA from 6.4, 8.5, to 11.1, while increased from 80, 93, to 103 nm with increasing DOX loading from 15.0, 23.1, to 31.4 wt %. Interestingly, HA/FA-NP-DOX exhibited excellent lyophilization redispersibility and long-term storage stability with negligible drug leakage while it released 91% of DOX in 48 h at pH 5.0. Cellular studies corroborated that HA/FA-NP-DOX possessed high selectivity to both CD44 and FR, resulting in strong killing of CD44- and FR-positive SKOV-3 ovarian cancer cells while low toxicity against CD44- and FR-negative L929 fibroblast cells. In vivo studies revealed a long elimination half-life of 5.6 h, an elevated tumor accumulation of 12.0% ID/g, and an effective inhibition of the SKOV-3 ovarian tumor for HA/FA-NP-DOX, leading to significant survival benefits over free DOX·HCl and phosphate-buffered saline controls. These dually targeted nanomedicines are simple and safe, providing a potentially translatable treatment for CD44- and FR-positive malignancies.
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Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Neoplasias Ováricas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Doxorrubicina/química , Femenino , Receptor 1 de Folato/antagonistas & inhibidores , Receptor 1 de Folato/genética , Humanos , Receptores de Hialuranos/antagonistas & inhibidores , Receptores de Hialuranos/genética , Ligandos , Ratones , Nanomedicina/métodos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Maternal folate (vitamin B9) status is the largest known modifier of neural tube defect risk, so we evaluated folate-related mechanisms of action for dolutegravir (DTG) developmental toxicity. DESIGN: Folate receptor 1 (FOLR1) was examined as a target for DTG developmental toxicity using protein and cellular interaction studies and an animal model. METHODS: FOLR1 competitive binding studies were used to test DTG for FOLR1 antagonism. Human placenta cell line studies were used to test interactions with DTG, folate, and cations. Zebrafish were selected as an animal model to examine DTG-induced developmental toxicity and rescue strategies. RESULTS: FOLR1 binding studies indicate DTG is a noncompetitive FOLR1 antagonist at therapeutic concentrations. In-vitro testing indicates calcium (2âmmol/l) increases FOLR1-folate interactions and alters DTG-FOLR1-folate interactions and cytotoxicity. DTG does not inhibit downstream folate metabolism by dihydrofolate reductase. Early embryonic exposure to DTG is developmentally toxic in zebrafish, and supplemental folic acid can mitigate DTG developmental toxicity. CONCLUSION: Folates and FOLR1 are established modifiers of risk for neural tube defects, and binding data indicates DTG is a partial antagonist of FOLR1. Supplemental folate can ameliorate increased developmental toxicity due to DTG in zebrafish. The results from these studies are expected to inform and guide future animal models and clinical studies of DTG-based antiretroviral therapy in women of childbearing age.
Asunto(s)
Receptor 1 de Folato/antagonistas & inhibidores , Ácido Fólico/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/toxicidad , Proteínas de Pez Cebra/antagonistas & inhibidores , Pez Cebra/embriología , Animales , Línea Celular , Suplementos Dietéticos , Desarrollo Embrionario/efectos de los fármacos , Femenino , Receptor 1 de Folato/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/toxicidad , Humanos , Modelos Animales , Oxazinas , Piperazinas , Embarazo , Piridonas , Pruebas de Toxicidad , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
As synthetic small interfering RNA (siRNA) against antitumoral gene targets show promise for cancer treatment, different siRNA delivery systems have sparkled intense investigations. To develop tumor-specific carriers for cytosolic and systemic siRNA delivery, our laboratory has recently generated folate-conjugated targeted combinatorial siRNA polyplexes based on sequence-defined oligomer platform compatible with solid-phase-supported synthesis. These polyplexes presented efficient siRNA-mediated gene silencing in folate receptor-expressing tumors in vitro and in vivo. In this chapter, we provide a brief background on the formulation design and detailed protocols to evaluate polyplex formation, gene silencing efficiency, and receptor-directed cell killing in cancer cells using targeted combinatorial siRNA polyplexes.
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Sistemas de Liberación de Medicamentos/métodos , Receptor 1 de Folato/genética , Neoplasias/genética , ARN Interferente Pequeño/genética , Línea Celular Tumoral , Receptor 1 de Folato/antagonistas & inhibidores , Receptor 1 de Folato/química , Ácido Fólico/genética , Silenciador del Gen , Humanos , Neoplasias/terapia , Polietilenglicoles/química , Polímeros/química , ARN Interferente Pequeño/química , ARN Interferente Pequeño/uso terapéuticoRESUMEN
Antibody drug conjugates (ADCs) are an exciting class of oncologic therapeutics. ADCs have been FDA approved in hematologic malignancies and breast cancer and are a growing area of study in numerous solid malignancies. The desire for tumor-specific therapies with decreased systemic toxicity has driven over a decade of research into the design and optimization of ADCs, which are now in a third generation of development. Gynecologic malignancies in particular suffer a dearth of novel therapies. This review will examine the field of ADCs in gynecologic cancers, focusing on ADCs targeting folate receptor alpha (FRα), mesothelin, tissue factor, MUC16 (CA125), NaPi2B, and Trop2.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Maitansina/análogos & derivados , Antígenos de Neoplasias , Antígeno Ca-125 , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Moléculas de Adhesión Celular/antagonistas & inhibidores , Diseño de Fármacos , Femenino , Receptor 1 de Folato/antagonistas & inhibidores , Proteínas Ligadas a GPI/antagonistas & inhibidores , Humanos , Maitansina/uso terapéutico , Proteínas de la Membrana/antagonistas & inhibidores , Mesotelina , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/antagonistas & inhibidores , Tromboplastina/antagonistas & inhibidoresRESUMEN
The glycoprotein FRα is a membrane-attached transport protein that is shielded from the immune system in healthy cells. However, it is upregulated in various malignancies, involved in cancer development and is also immunogenic. Furthermore, FRα is a tumor-associated antigen endowed with unique properties, thus rendering it a suitable target for immunotherapeutic development in cancer. Various anti- FRα immunotherapeutic strategies are thus currently being developed and clinically assessed for the treatment of various solid tumors. These approaches include passive anti-FRα immunotherapies, such as monoclonal antibodies, or active immunotherapies, such as CART, folate haptens and vaccines. In this review, we will explore the advances in the field of FRα-based immune therapies and discuss both their successes and shortcomings in the clinical setting.
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Receptor 1 de Folato/antagonistas & inhibidores , Receptores de Folato Anclados a GPI/inmunología , Inmunoterapia/métodos , Neoplasias/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Ensayos Clínicos como Asunto , Femenino , Receptor 1 de Folato/inmunología , Receptores de Folato Anclados a GPI/genética , Humanos , Ratones , Neoplasias/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapiaRESUMEN
Prognosis for women with epithelial ovarian cancer remains poor. One new molecular target in epithelial ovarian cancer is folate receptor alpha (FRα). This commentary discusses the characteristics that contribute to its attractiveness as a candidate for therapeutic intervention.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Receptor 1 de Folato/antagonistas & inhibidores , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Ensayos Clínicos como Asunto , Femenino , Humanos , Terapia Molecular Dirigida , PronósticoRESUMEN
PURPOSE OF REVIEW: Antibody drug conjugates (ADC) are a novel class of cancer therapeutics, delivering cytotoxic therapy directly to cancer cells, and show promise in the management of platinum-resistant ovarian cancer. Herein we summarize the ADC landscape currently in clinical study. RECENT FINDINGS: Mirvetuximab Soravtansine, IMGN853, is an ADC targeting the folate receptor alpha (FRα) and has demonstrated promising single agent activity and a favorable toxicity profile in FRα-positive, platinum-resistant, epithelial ovarian cancer (EOC). The antitumor effect is seen primarily in less heavily pretreated EOC patients with moderate-to-high FRα tumor expression. A phase III study, randomizing patients to either IMGN853 or the physician's choice of single-agent chemotherapy has completed accrual. Additional ADC are being evaluated in ovarian cancer including agents that target NaPiB2, Trop2, mesothelin, and MUC16 are in phase 1 clinical trials. SUMMARY: ADC bind antigens overexpressed on cancer cells and provide site-selective drug delivery, with the goal to increase therapeutic efficacy of cytotoxics while decreasing the off-target toxicity of the payloads. With appropriate antigen selection and adequate, measurable antigen threshold targets, these new agents may provide an improved strategy for overcoming resistance to standard chemotherapy in ovarian cancer.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/efectos adversos , Ensayos Clínicos Fase III como Asunto , Desarrollo de Medicamentos , Femenino , Receptor 1 de Folato/antagonistas & inhibidores , Humanos , Inmunoconjugados/efectos adversos , Maitansina/efectos adversos , Maitansina/análogos & derivados , Maitansina/farmacología , Maitansina/uso terapéutico , Neoplasias Ováricas/patologíaRESUMEN
The study is focused on description of folate and several antifolates at physiological conditions. Knowledge of the molecular structure and dynamics is important for understanding their biological activity and therapeutic application. They are modelled in saline by atomistic molecular dynamics simulations and characterized in detail. In addition, quantum chemical calculations are used for determining the electronic structure of the six compounds. All molecules are highly flexible and have similar interactions with water. Specifics are found in some of their local backbone conformations, in the molecular shape, and in the electron density distribution. Most of the ligands have fairly folded geometry and prefer U- and Z-shapes. Two of them are quasi-linear. Key to the molecular shape are the bicyclic fragment, its bridge, and the charge of the terminal amino acid residue. Docking into the active site of folate receptor-α predicts a similar best binding pose for four of the ligands, which requires stretching of pterin and bending of glutamate/ornithine relative to the geometry in saline. The chemical modifications in the antifolates induce local electron density redistribution in comparison to folate, leading to increase of the positive charges of the neighboring fragments. The obtained results would help better tuning of the potential usage of the molecules in new bioactive materials, e.g., as vector-ligands for drug delivery.
Asunto(s)
Antagonistas del Ácido Fólico/química , Antagonistas del Ácido Fólico/farmacología , Ácido Fólico/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Sitios de Unión , Receptor 1 de Folato/antagonistas & inhibidores , Receptor 1 de Folato/química , Enlace de Hidrógeno , Ligandos , Conformación Molecular , Estructura Molecular , Unión Proteica , Solventes , Relación Estructura-ActividadRESUMEN
PURPOSE: Reversible, low-grade ocular adverse events (AE) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeted antibody-drug conjugate undergoing phase III clinical evaluation in platinum-resistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine. PATIENTS AND METHODS: Target expression in the human eye was determined by IHC. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a phase I clinical study, patients with ovarian cancer were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle. RESULTS: FRα expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients, respectively; no grade 3/4 ocular events were observed. Compared with those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% vs. 15%) and none discontinued due to ocular AEs. CONCLUSIONS: Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend toward symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Enfermedades de la Córnea/prevención & control , Glucocorticoides/administración & dosificación , Inmunoconjugados/efectos adversos , Maitansina/análogos & derivados , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Córnea/efectos de los fármacos , Córnea/patología , Enfermedades de la Córnea/inducido químicamente , Enfermedades de la Córnea/patología , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Femenino , Receptor 1 de Folato/antagonistas & inhibidores , Receptor 1 de Folato/metabolismo , Humanos , Inmunoconjugados/administración & dosificación , Infusiones Intravenosas , Masculino , Maitansina/administración & dosificación , Maitansina/efectos adversos , Persona de Mediana Edad , Soluciones Oftálmicas/administración & dosificación , Neoplasias Ováricas/patología , Conejos , Pruebas de Toxicidad Subaguda , Resultado del TratamientoRESUMEN
Photodynamic therapy (PDT) following lung-sparing extended pleurectomy for malignant pleural mesothelioma (MPM) has been investigated as a potential means to kill residual microscopic cells. High expression levels of folate receptor 1 (FOLR1) have been reported in MPM; therefore, targeting FOLR1 has been considered a novel potential strategy. The present study developed FOLR1targeting porphyrin-lipid nanoparticles (folate-porphysomes, FP) for the treatment of PDT. Furthermore, inhibition of activated epidermal growth factor (EGFR)-associated survival pathways enhance PDT efficacy. In the present study, these approaches were combined; FP-based PDT was used together with an EGFR-tyrosine kinase inhibitor (EGFR-TKI). The frequency of FOLR1 and EGFR expression in MPM was analyzed using tissue microarrays. Confocal microscopy and a cell viability assay were performed to confirm the specificity of FOLR1targeting cellular uptake and photocytotoxicity in vitro. In vivo fluorescence activation and therapeutic efficacy were subsequently examined. The effects of EGFR-TKI were also assessed in vitro. The in vivo combined antitumor effect of EGFR-TKI and FP-PDT was then evaluated. The results revealed that FOLR1 and EGFR were expressed in 79 and 89% of MPM samples, respectively. In addition, intracellular uptake of FP corresponded well with FOLR1 expression. When MPM cells were incubated with FP and then irradiated at 671 nm, there was significant in vitro cell death, which was inhibited in the presence of free folic acid, thus suggesting the specificity of FPs. FOLR1 targeting resulted in disassembly of the porphysomes and subsequent fluorescence activation in intrathoracic disseminated MPM tumors, as demonstrated by ex vivo tissue imaging. FP-PDT resulted in significant cellular damage and apoptosis in vivo. Furthermore, the combination of pretreatment with EGFR-TKI and FP-PDT induced a marked improvement of treatment responses. In conclusion, FP-based PDT induced selective destruction of MPM cells based on FOLR1 targeting, and pretreatment with EGFR-TKI further enhanced the therapeutic response.
Asunto(s)
Receptor 1 de Folato/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Fotoquimioterapia/métodos , Neoplasias Pleurales/tratamiento farmacológico , Adulto , Anciano , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Receptor 1 de Folato/metabolismo , Humanos , Lípidos/química , Neoplasias Pulmonares/patología , Masculino , Mesotelioma/patología , Mesotelioma Maligno , Ratones Desnudos , Persona de Mediana Edad , Nanopartículas/química , Neoplasias Pleurales/patología , Porfirinas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload.