A Novel Monoclonal Antibody for Detection of Folate Receptor Alpha in Paraffin-Embedded Tissues

5583 Background: Folate receptor alpha (FRA) is over-expressed in the majority of epithelial ovarian cancers (EOC) but largely absent from normal tissue. MORAb-003 (M3) is a humanized monoclonal antibody to FRA. Binding of M3 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-positive tumor cell killing; and suppresses tumor growth in xenograft models. High-dose M3 is non-toxic in monkeys. A phase 1 study showed no significant AEs and suggestions of efficacy in platinum-resistant EOC. This phase 2 efficacy study will determine the efficacy of M3 in platinum-sensitive EOC in first relapse, either as a single agent (SA) in asymptomatic relapse, or in combination with platinum and taxane (P/T) in symptomatic relapse, and to maintain a second response. Methods: Subjects with EOC in first relapse are eligible. For CA125 elevation without symptoms (± measurable disease) the subject receives SA M3 until progression. For symptomatic relapse the subject receives P/T and M3. Subjects with CR or PR receive SA M3 maintenance therapy with the objective of prolonging the second remission longer than the first. Endpoints include CA125 and CT scans. ORR and PFS will be determined for each arm. Results: To date, 15 subjects have been treated, 8 in combination therapy and 7 on single-agent M3. No significant drug-related adverse events have been reported. All subjects treated with the combination of M3 and P/T for symptomatic relapse who have reached at least the first evaluation point have achieved a normalization of CA125 and reduction of tumor size (CR or PR) by CT scan using RECIST criteria, including 3 of 3 subjects with first remissions of 6 to 9 months. Early responses have been observed in the SA M3 treatment arm. Conclusions: This first phase 2 study will determine the efficacy of M3, either as SA or in combination with P/T chemotherapy to achieve a meaningful response rate in EOC in first relapse, and to maintain the second remission longer than the subject’s own first remission. These data will be used to define the most effective phase of disease in which to use M3, and to focus a pivotal study on the area of greatest efficacy. The early results continue to demonstrate activity of M3 in EOC. No significant financial relationships to disclose.

Download Full-text

Phase I study of MORAb-003, a humanized anti-folate receptor-alpha monoclonal antibody, in platinum resistant ovarian cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.5027 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 5027-5027 ◽

Cited By ~ 5

Author(s):

J. A. Konner ◽

S. Ahmed ◽

S. Gerst ◽

N. Vander Els ◽

S. Pezzuli ◽

...

Keyword(s):

Monoclonal Antibody ◽

Folate Receptor ◽

Karnofsky Performance Status ◽

Performance Status ◽

Human Antibody ◽

Folate Receptor Alpha ◽

Receptor Alpha ◽

Platinum Resistant ◽

Human Dose ◽

Study Results

5027 Background: Folate receptor alpha (FRA) is over-expressed in the majority of epithelial ovarian cancers (EOC) but largely absent from normal tissue. MORAb-003 (M3) is a humanized monoclonal antibody (MAb) to FRA. Binding of M3 to FRA can prevent phosphorylation of substrates specific for the Lyn kinase; suppress proliferation of cells over-expressing FRA; mediate FRA-positive tumor cell killing via antibody-dependent cellular and complement-dependent mechanisms; and suppress tumor growth in vivo of FRA-expressing tumors in rodent xenograft models. Toxicology studies in non-human primates found no evidence of toxicity with M3 at supra-pharmacological doses. This open-label, multiple-infusion, first-in-human, dose-escalation trial evaluates the safety, pharmacokinetics (PK), and antitumor activity of M3 in patients with platinum-resistant EOC. Methods: Sequential cohorts of patients receive four weekly infusions at escalating dose levels of M3, from 12.5 mg/m2 to 100 mg/m2. Human anti-human antibody (HAHA) and PK analyses are performed. Eligible patients have EOC that relapsed < 6 months after platinum-based therapy, acceptable organ function, Karnofsky Performance Status ≥ 70%, and measurable disease by GOG-RECIST criteria. Patients undergo pulmonary function testing (PFT) at baseline, and at end of study. Results: To date, 7 women have been treated with M3: 3 at the 12.5 mg/m2 dose, 3 at 25 mg/m2, and 1 at 37.5 mg/m2. Median age was 60. Neither dose limiting toxicity nor HAHA has been observed. Grade 1 rash occurred in 1 patient. Grade 1/2 fever following drug administration occurred in 2 patients. Grade 2 FEV1 decrease was observed in a patient with likely pulmonary lymphangitic metastasis. One subject at 25 mg/m2 had radiographically stable disease. At low doses, the PK analysis demonstrated the half-life to be shorter than anticipated based on animal studies, possibly due to tumor binding. Radiolableled imaging studies are underway to determine the distribution of M3. Conclusions: The FRA-specific MAb MORAb-003 appears to be well tolerated in patients with EOC. Enrollment continues and updated results will be presented. No significant financial relationships to disclose.

Download Full-text

Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed platinum-sensitive ovarian cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2013.03.002 ◽

2013 ◽

Vol 129 (3) ◽

pp. 452-458 ◽

Cited By ~ 81

Author(s):

Deborah K. Armstrong ◽

Allen J. White ◽

Susan C. Weil ◽

Martin Phillips ◽

Robert L. Coleman

Keyword(s):

Ovarian Cancer ◽

Monoclonal Antibody ◽

Folate Receptor ◽

Folate Receptor Alpha ◽

Receptor Alpha ◽

Platinum Sensitive

Download Full-text

Farletuzumab, a monoclonal antibody directed against folate receptor alpha, shows no evidence of teratogenicity in cynomolgus monkeys

Reproductive Toxicology ◽

10.1016/j.reprotox.2018.06.007 ◽

2018 ◽

Vol 79 ◽

pp. 89-95

Author(s):

Tomoyuki Moriyama ◽

Dai Kakiuchi ◽

Luigi Grasso ◽

David L. Hutto ◽

Danielle Fernando ◽

...

Keyword(s):

Monoclonal Antibody ◽

Folate Receptor ◽

Folate Receptor Alpha ◽

Cynomolgus Monkeys ◽

Receptor Alpha

Download Full-text

Abstract 4411: Farletuzumab (mAb003), a neutralizing monoclonal antibody to folate receptor alpha, enhances paclitaxel efficacy in an ovarian cancer model

10.1158/1538-7445.am2012-4411 ◽

2012 ◽

Author(s):

Christopher Maddage ◽

Katherine Rybinski ◽

Yuhong Zhou ◽

Luigi Grasso ◽

Nicholas C. Nicolaides ◽

...

Keyword(s):

Ovarian Cancer ◽

Monoclonal Antibody ◽

Folate Receptor ◽

Cancer Model ◽

Folate Receptor Alpha ◽

Receptor Alpha ◽

Neutralizing Monoclonal Antibody

Download Full-text

A phase I study of MORAb-003, a fully humanized monoclonal antibody against folate receptor alpha, in advanced epithelial ovarian cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.5553 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 5553-5553

Author(s):

K. M. Bell-McGuinn ◽

J. Konner ◽

N. Pandit-Taskar ◽

S. Gerst ◽

N. Nicolaides ◽

...

Keyword(s):

Monoclonal Antibody ◽

Folate Receptor ◽

Human Antibody ◽

Planar Imaging ◽

Open Label ◽

Folate Receptor Alpha ◽

Receptor Alpha ◽

Platinum Resistant ◽

Human Dose ◽

Humanized Monoclonal Antibody

5553 Background: Folate receptor alpha (FRA) is over-expressed in the majority of epithelial ovarian cancers (EOC) but is largely absent from normal tissue. MORAb-003 is a humanized monoclonal antibody (MAb) to FRA. Binding of MORAb-003 to FRA can prevent phosphorylation of substrates specific for Lyn kinase, suppress proliferation of cells over-expressing FRA, mediate FRA-positive tumor cell killing via antibody-dependent cellular and complement-dependent mechanisms, and suppress tumor growth in vivo of FRA-expressing tumors in rodent xenograft models. Toxicology studies in non-human primates found no evidence of toxicity with MORAb-003 at supra- pharmacological doses. This open-label, multiple-infusion, first-in-human, dose-escalation trial evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of MORAb-003 in patients with platinum-resistant EOC. Methods: Sequential cohorts of patients received four weekly infusions at escalating dose levels of MORAb-003 from 12.5 mg/m2 to 400 mg/m2. Eligible patients had platinum-resistant EOC, acceptable organ function, KPS = 70%, and measurable disease by GOG-RECIST criteria. A subset of subjects received a tracer dose of 111In-labelled MORAb-003 and SPECT-CT and planar imaging. Human anti-human antibody (HAHA) and PK analyses were performed. Results: To date, 18 subjects have been dosed with up to 200 mg/m2. No dose limiting toxicity or significant related adverse events have been observed. Four subjects had rigors (2 grade 1) or fevers (3 grade 1, 1 grade 2) following the first infusion. Nine subjects have had radiologically stable disease, and 7 subjects have had stable or declining CA125. Two subjects have received extended therapy for an apparent clinical benefit. Radiolabelled tracer studies have demonstrated significant tumor uptake of labeled MORAb-003. The 400 mg/m2 dose cohort is currently enrolling. Conclusions: The FRA-specific MAb MORAb-003 appears to be well tolerated in patients with EOC and may have activity in platinum-resistant patients. These results support further evaluation of the efficacy of MORAb-003 in a phase 2 study which is ongoing. [Table: see text]

Download Full-text