The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity

Lin, Jianbo; Spidel, Jared L.; Maddage, Christopher; Rybiński, K; Kennedy, Rina; Krauthauser, Candice; Park, Young Chul; Albone, Earl F.; Jacob, Sara; Goserud, Matthew T; Martinez, Bryon; Chao, Qimin; Zhou, Yuhong; Nicolaides, Nicholas C.; Kline, J. Bradford; Grasso, Luigi

doi:10.4161/cbt.26106

Cited by 45 publications

(35 citation statements)

References 27 publications

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“…Lead BaCa antibody showed high in vivo stability with a t 1/2 of ~15 days (Figure S5B, C). To test the tumor selectivity of BaCa antibody, we intravenously (IV) injected infrared dye IR800-labeled antibodies (25 μg) into the tumor bearing mice to monitor tissue localization as described (Figure 5A) (Lin et al, 2013). It was also confirmed that IR800 labeling did not change the affinities against the respective receptors (Figure S5D).…”

Section: Resultsmentioning

confidence: 99%

A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer

et al. 2018

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Therapeutic antibodies targeting ovarian cancer (OvCa)-enriched receptors have largely been disappointing due to limited tumor-specific antibody-dependent cellular cytotoxicity. Here we report a symbiotic approach that is highly selective and superior compared with investigational clinical antibodies. This bispecific-anchored cytotoxicity activator antibody is rationally designed to instigate "cis" and "trans" cytotoxicity by combining specificities against folate receptor alpha-1 (FOLR1) and death receptor 5 (DR5). Whereas the in vivo agonist DR5 signaling requires FcγRIIB interaction, the FOLR1 anchor functions as a primary clustering point to retain and maintain a high level of tumor-specific apoptosis. The presented proof of concept study strategically makes use of a tumor cell-enriched anchor receptor for agonist death receptor targeting to potentially generate a clinically viable strategy for OvCa.

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Section: Resultsmentioning

confidence: 99%

A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer

et al. 2018

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“…Farletuzumab utilizes ADCC as a critical component of its pharmacologic mechanism for anti-tumor activity [Lin et al, 2013]. Based on this activity, polymorphisms within the FCGR2A and/or FCGR3A receptors that lower their binding affinity/avidity to farletuzumab could affect its clinical activity against FRA-positive cancers.…”

Section: Resultsmentioning

confidence: 99%

FCGR2A and FCGR3A Genotypes Correlate with Farletuzumab Response in Patients with First-Relapsed Ovarian Cancer Exhibiting Low CA125

Wang

Somers²,

Ross³

et al. 2017

Cytogenet Genome Res

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Farletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha and elicits an anti-tumor response via immune effector activity. Recent studies from a global phase 3 trial in ovarian cancer patients treated with carboplatin/taxane plus farletuzumab found that the tumor-produced CA125 protein can suppress farletuzumab function via perturbing its engagement to the activating Fc-γ receptors CD32a (FCGR2A) and CD16a (FCGR3A). Previous reports have indicated that naturally occurring polymorphisms in both of these receptors may play a role in their ability to engage therapeutic antibodies and elicit an optimal immune response via antibody-dependent cellular cytotoxicity (ADCC). In light of the importance of farletuzumab ADCC function for optimal tumor cell killing, we evaluated the frequency of FCGR2A-131H/R and FCGR3A-158V/F polymorphisms in 461 consenting patients from this global clinical study and their association with clinical outcome to placebo versus farletuzumab treatment. Here, we show that farletuzumab has enhanced binding to FCGR3A-158V high-affinity receptor and has an enhanced clinical outcome in patients with low baseline CA125 levels and at least 1 high-affinity allele of FCGR2A or FCGR3A.

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“…It has been shown to inhibit cell growth and activate antibody-dependent, cell-mediated cytotoxicity (5, 8, 9). Although MORAB-003 has been shown to act through antibody-dependent cellular cytotoxicity in vitro (10), additional mechanisms underlying its function are likely. Herein, we reported that sustained treatment with MORAB-003 antibody in xenograft models of human ovarian cancers or in 3-D cultured ovarian cancer models expressing high levels of FRα induced enrichment of late-stage autophagic events, eventually leading to cell death and tumor growth inhibition.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer

Wen

Graybill

Previs

et al. 2015

Clinical Cancer Research

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Purpose Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized monoclonal antibody against FRα, in ovarian cancer models. Experimental Design We first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003–induced cell death. Results MORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In add, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cystadenocarcinoma. Conclusions MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation.

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The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity

Cited by 45 publications

References 27 publications

A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer

A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer

FCGR2A and FCGR3A Genotypes Correlate with Farletuzumab Response in Patients with First-Relapsed Ovarian Cancer Exhibiting Low CA125

Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer

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