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Bavituximab (PGN401) is a chimeric monoclonal antibody designed for the treatment of cancers and viral infections. It was developed by UT Southwestern Medical Center and Philip E. Thorpe and is currently owned by Peregrine Pharmaceuticals, Inc.
- 1 Mechanism of action
- 2 Clinical trials
- 3 Second-line non-squamous non-small cell lung cancer (NSCLC)
- 4 First-line non-squamous non-small cell lung cancer (NSCLC)
- 5 Advanced melanoma
- 6 Breast cancer
- 7 Advanced liver cancer
- 8 Advanced pancreatic cancer
- 9 Other monoclonal antibodies targeting phospholipids
- 10 References
- 11 Further reading
Mechanism of action
Bavituximab binds to phosphatidylserine which is exposed on the surface of certain atypical animal cells, including tumour cells and cells infected with any of six different families of virus. These viral families contain the viruses hepatitis C, influenza A and B, HIV 1 and 2, measles, respiratory syncytial virus, pichinde virus, which is a model for the Lassa virus, and Ebola virus Other cells are not affected since phosphatidylserine normally is only intracellular.
These target aminophospholipids, usually residing only on the inner leaflet of the plasma membrane of cells, become exposed in virally infected, damaged or malignant cells, and more generally in most cells undergoing the process of apoptosis.
The antibody's binding to phospholipids alerts the body’s immune system to attack the tumor endothelial cells, thrombosing the tumor's vascular network and/or attacking free floating virally infected and metastatic cells while potentially minimizing side effects in healthy tissues.
Data detailing the immune-stimulatory mechanism of action of PS-targeting antibodies, such as bavituximab, are the subject of a manuscript published in the October 2013 issue of the American Association for Cancer Research (AACR) journal, Cancer Immunology Research. Bavituximab is currently being evaluated in several solid tumor indications.
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Second-line non-squamous non-small cell lung cancer (NSCLC)
A phase III SUNRISE trial evaluating bavituximab plus docetaxel versus docetaxel plus placebo in approximately 600 patients at clinical sites worldwide, started in December 2013 and is expected to end in December 2016.
Final data from the 121-patient Phase II trial in 2nd line lung cancer showed increase of overall survival (OS) of 11.7 months in the 3 mg/kg bavituximab plus docetaxel arm compared to 7.3 months in the combined control arm, with a persistent separation in the Kaplan Meier survival curves (HR=0.662) Overall response rate (ORR) was 17.1% in the 3 mg/kg bavituximab plus docetaxel arm versus 11.3% in the combined control arm. Progression free survival was 4.2 months in the 3 mg/kg bavituximab plus docetaxel arm, versus 3.9 months in the combined control arm. Post study unblinding, vial coding discrepancies were discovered in the placebo and 1 mg/kg vials. As a result, data from these two arms were combined for data analysis.
First-line non-squamous non-small cell lung cancer (NSCLC)
Interim data from the Phase Ib investigator-sponsored trial (IST) of immunotherapy bavituximab in combination with the chemotherapies pemetrexed and carboplatin in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Data from this single-arm, open-label, multi-center trial show an overall tumor response (ORR) of 35%, a median progression-free-survival (PFS) of 4.8 months, and a median overall survival (OS) of 12.2 months.
Phase I open label, two-arm, randomized, single-center Phase Ib trial of bavituximab plus ipilimumab (an anti-CTLA-4 antibody), in 24 patients with advanced melanoma. The study started in April 2014 and is expected to end in March 2016. Previously, preclinical studies showed that PS targeting antibodies (such as bavituximab) enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies. Tumor growth inhibition correlates with infiltration of immune cells in tumors and induction of adaptive immunity. The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.
Interim data from a Phase I trial evaluating bavituximab plus paclitaxel therapy in patients with HER2-negative metastatic breast cancer (MBC) showed that 85% of patients achieved an objective tumor response, including 15% of patients achieving a complete response (CR) measured in accordance with RECIST criteria.
A phase II trial of bavituximab used with docetaxel against advanced breast cancer has yielded median progression-free survival (PFS) data of 7.4 months, a best overall response rate of 61% (28 of 46 patients) with 11% (5 of 46) of the patients achieving a clinical complete response. (This compares favorably to a separately published study of a similar patient population receiving docetaxel alone, which showed an objective response rate of only 41% with no complete responses.) 
A phase II trial of bavituximab used with paclitaxel and carboplatin chemotherapy against locally advanced or metastatic breast cancer has yielded 23.2 month median overall survival (OS) in patients with locally advanced or metastatic breast cancer. In a separate published study using a similar chemotherapy regimen of carboplatin and paclitaxel(1), median OS was 16.0 months in a similar patient population.
Advanced liver cancer
Data from the Phase I portion of the Phase I/II trial evaluating bavituximab plus sorafenib in patients with advanced hepatocellular carcinoma (HCC) in 48 patients showed no dose limiting toxicity (DLT), no grade 3 or 4 adverse events, and common toxicities limited to sorafenib. 
As of January 2015, data from the Phase II portion of this trial (38 patients) demonstrated median Time To Progression (TTP) of 6.7 months, Disease Specific Survival (DSS) of 8.7 months, Overall Survival (OS) of 6.2 months, four month PFS of 62%, Disease Control Rate (DCR) of 58% and 2 partial responses measured according to RECIST criteria. HCV prevalence was 79%, macrovascular invasion 84%, metastatic disease 24%, ECOG 1 or higher 66%, previous treatment 40%. 2 of 6 patients' tissue analysis showed tumor infiltration of CD4+, CD8+ and macrophages with a corresponding increase in Tregs. 
Advanced pancreatic cancer
Results from a randomized Phase II trial of bavituximab plus gemcitabine in patients with non-resectable Stage IV pancreatic cancer demonstrated 28% overall response rate (ORR) versus 13% in the control arm, and 5.6 months overall survival (OS) versus 5.2 months in the control arm (HR=0.75), including a delayed separation in the Kaplan-Meier survival curve that is commonly seen in clinical studies of promising cancer immunotherapies.
Other monoclonal antibodies targeting phospholipids
- Bavituximab (USAN/INN)
- Nature Medicine 14, 1357 - 1362 (2008)
- He, J.; Yin, Y.; Luster, T. A.; Watkins, L.; Thorpe, P. E. (2009). "Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma". Clinical Cancer Research 15 (22): 6871–6880. PMID 19887482. doi:10.1158/1078-0432.CCR-09-1499.
- http://clinicaltrials.gov/ct2/show/NCT01999673 Phase 3 Study of Bavituximab Plus Docetaxel Versus Docetaxel Alone in Patients With Late-stage Non-squamous Non-small-cell Lung Cancer (SUNRISE)
- http://clinicaltrials.gov/ct2/show/NCT01138163 Study of Bavituximab Plus Docetaxel in Patients With Locally Advanced or Metastatic Non-Squamous Non Small-Cell Lung Cancer
- http://clinicaltrials.gov/ct2/show/NCT01323062 Bavituximab Plus Carbo and Pemetrexed in Chemo-Naive Stage IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Subjects
- http://clinicaltrials.gov/ct2/show/NCT01984255 A Two-arm, Single Center Phase 1b Trial of Bavituximab Plus Ipilimumab in Advanced Melanoma Patients
- http://clinicaltrials.gov/ct2/show/NCT01288261 Paclitaxel and Bavituximab in Treating Patients With HER2-Negative Metastatic Breast Cancer
- New Progression-Free Survival Data From Peregrine's Bavituximab in Phase II Refractory Breast Cancer
- http://clinicaltrials.gov/ct2/show/NCT00669591 A Safety and Efficacy Study of Bavituximab Plus Docetaxel in Patients With Advanced Breast Cancer
- http://clinicaltrials.gov/ct2/show/NCT00669565 Safety and Efficacy Study of Bavituximab Plus Paclitaxel and Carboplatin to Treat Breast Cancer
- http://clinicaltrials.gov/ct2/show/NCT01264705 Study of Bavituximab and Sorafenib In Patients With Advanced Liver Cancer
- http://clinicaltrials.gov/ct2/show/NCT01272791 Trial of Gemcitabine With or Without Bavituximab in Patients With Previously Untreated Stage IV Pancreatic Cancer
- Pharma company completes humanization of 3G4 antibody
- He, J.; Luster, T. A.; Thorpe, P. E. (2007). "Radiation-Enhanced Vascular Targeting of Human Lung Cancers in Mice with a Monoclonal Antibody That Binds Anionic Phospholipids". Clinical Cancer Research 13 (17): 5211–5218. PMID 17785577. doi:10.1158/1078-0432.CCR-07-0793.
- Ran; Downes, A.; Thorpe, P. E. (2002). "Increased exposure of anionic phospholipids on the surface of tumor blood vessels". Cancer Research 62 (21): 6132–6140. PMID 12414638.
- Soares M, Syed S, Barbero G, Thorpe PE (April 2007). "Antibody-mediated targeting of "inside-out" anionic phospholipids in viral disease". J Immunol 178 (Meeting Abstracts): 47.21.
- Nature Medicine, V14, p1357.