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Antimicrob Agents Chemother. 2010 June; 54(6): 2431–2436.
Published online 2010 March 29. doi:  10.1128/AAC.01178-09
PMCID: PMC2876374

Safety and Pharmacokinetics of Single Intravenous Dose of MGAWN1, a Novel Monoclonal Antibody to West Nile Virus[down-pointing small open triangle]

Abstract

West Nile Virus (WNV) is a neurotropic flavivirus that can cause debilitating diseases, such as encephalitis, meningitis, or flaccid paralysis. We report the safety, pharmacokinetics, and immunogenicity of a recombinant humanized monoclonal antibody (MGAWN1) targeting the E protein of WNV in a phase 1 study, the first to be performed on humans. A single intravenous infusion of saline or of MGAWN1 at escalating doses (0.3, 1, 3, 10, or 30 mg/kg of body weight) was administered to 40 healthy volunteers (30 receiving MGAWN1; 10 receiving placebo). Subjects were evaluated on days 0, 1, 3, 7, 14, 21, 28, 42, 56, 91, 120, and 180 by clinical assessments, clinical laboratory studies, electrocardiograms (ECGs), and pharmacokinetic and immunogenicity assays. All 40 subjects tolerated the infusion of the study drug, and 39 subjects completed the study. One serious adverse event of schizophrenia occurred in the 0.3-mg/kg cohort. One grade 3 neutropenia occurred in the 3-mg/kg cohort. Six MGAWN1-treated subjects experienced 11 drug-related adverse events, including diarrhea (1 subject), chest discomfort (1), oral herpes (1), rhinitis (1), neutropenia (2), leukopenia (1), dizziness (1), headache (2), and somnolence (1). In the 30-mg/kg cohort, MGAWN1 had a half-life of 26.7 days and a maximum concentration in serum (Cmax) of 953 μg/ml. This study suggests that single infusions of MGAWN1 up to 30 mg/kg appear to be safe and well tolerated in healthy subjects. The Cmax of 953 μg/ml exceeds the target level in serum estimated from hamster studies by 28-fold and should provide excess WNV neutralizing activity and penetration into the brain and cerebrospinal fluid (CSF). Further evaluation of MGAWN1 for the treatment of West Nile virus infections is warranted.

West Nile Virus (WNV) is a neurotropic enveloped flavivirus. Since 1999, there have been more than 29,000 cases of confirmed symptomatic WNV infection in the United States, which include more than 12,000 cases of West Nile neuroinvasive disease (WNND) and more than 1,100 deaths. WNND is estimated to occur in approximately 1 of 150 infections, and it is likely that as many as 2 million people have been infected by the virus (4, 11, 13, 16, 20). WNV is now the most common cause of epidemic viral encephalitis in the United States, and it will likely remain an important cause of neurological disease for the foreseeable future (5). No effective therapy or vaccine is available for humans.

Anecdotal case reports of WNV encephalitis patients who were treated with intravenous immunoglobulin (IVIG) from convalescent WNV-infected persons provide some support for the efficacy of neutralizing antibodies against WNV (2). A placebo-controlled, randomized, double-blind human clinical trial with an IVIG product (Omr-IgG-am), which was sponsored by the Collaborative Antiviral Study Group (CASG), was terminated in December 2006. As of April 2010, no analysis of the data had been published.

MGAWN1 is a high-affinity, humanized monoclonal antibody (MAb) that specifically recognizes the E (envelope) protein of WNV (12). MGAWN1 exhibits neutralizing and fusion-inhibitory activity against WNV but exhibits no reactivity or neutralization of closely or distantly related flaviviruses (14). The mechanism of virus neutralization and clearance likely involves the binding of MGAWN1 to cell surface-attached virus particles (12) and the prevention of E protein conformational changes required to release virus core particles from the endosomes into the cytoplasm (22).

Pharmacology studies have demonstrated that MGAWN1 is effective both prophylactically and therapeutically in WNV-infected mice and hamsters (8-10, 14). A single dose of MGAWN1 significantly improves survival when administered as late as 5 days postinfection, a time after the establishment of neurological infection. Toxicology studies performed on uninfected rats have revealed no toxicities at single intravenous doses as high as 100 mg/kg of body weight. At 300 mg/kg, minimal to moderate hypertrophy of cells lining the hepatic sinusoids and increased mitotic hepatocytes were noted in female animals at 14 days postinfusion, although no changes in serum chemistry, including liver function test results, were detected. Based on these data, the NOAEL (no-observed-adverse-effect level) was determined to be 100 mg/kg.

This phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of single escalating doses of MGAWN1 in healthy subjects.

MATERIALS AND METHODS

MGAWN1.

MGAWN1 is a recombinant humanized monoclonal antibody [IgG1(κ)] against the E (envelope) protein of WNV, produced by a mammalian (Chinese hamster ovary [CHO]) cell suspension culture grown in chemically defined medium and purified by a series of chromatographic and filtration steps. MGAWN1 is manufactured by MacroGenics as a sterile, preservative-free liquid concentrate that is supplied at a concentration of 25 mg/ml in 4-ml (100-mg) single-use vials.

Study design and subjects.

This was a single ascending dose randomized, double-blind, placebo-controlled study. Healthy adult male or female subjects aged 18 to 65 years, with a body mass index (BMI) of 18 to 32 kg/m2, were eligible for this study. Based on the NOAEL of 100 mg/kg, escalating doses were selected with a starting dose of 0.3 mg/kg, which is 333-fold less than the NOAEL value. The highest dose was 30 mg/kg. It is anticipated that high doses are likely to be necessary for neutralizing levels of the antibody to penetrate into the central nervous system. All subjects were required to have normal laboratory parameters at enrollment, were nonsmokers, and did not use any concomitant medications. Females of child-bearing potential were enrolled as long as they had a negative pregnancy test at enrollment and used appropriate birth control methods. Written informed consent was obtained from potential subjects prior to screening. The study was conducted in accordance with an Institutional Review Board-approved protocol.

Study procedures.

Subjects were sequentially enrolled into 1 of 5 dose cohorts, with 8 subjects per cohort. Each subject in a given dose cohort was randomized to receive a single intravenous (i.v.) infusion of MGAWN1 or saline control at a 6:2 ratio. Cohort 1 was administered the lowest dose of MGAWN1 (0.3 mg/kg); the remaining cohorts (cohorts 2 through 5) corresponded to escalating doses of MGAWN1 (1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg, respectively).

Subjects were screened within 21 days before study entry. Those subjects who met the inclusion/exclusion criteria were admitted to the study unit. Subjects were admitted at least 12 h before administration of the study drug and were discharged after the completion of all procedures on study day 2. On study day 0, the pharmacist prepared individual treatments by adding the calculated volume of MGAWN1 to 0.9% sodium chloride injection USP to make a total of 250 ml. The study drug was administered intravenously over at least 60 min. Thereafter, subjects were evaluated on study days 3, 7, 14, 21, 28, 42, 56, 91, 120, and 180. All adverse events were graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Pharmacokinetic analysis.

Serum from each subject was collected on day −1 (also called predose) and at the following time points after the infusion: 15 min, 30 min, 1 h, 2 h, 3 h, 6 h, 12 h, day 1, day 3, day 7, day 14, day 21, day 28, day 42, day 56, day 91, day 120, and day 180. Serum MGAWN1 concentrations were measured by a quantitative sandwich enzyme-linked immunosorbent assay (ELISA). Briefly, a 96-well microplate was coated with an affinity-purified polyclonal goat anti-E16 Fv (idiotype) antibody. Samples and standards were pipetted into the coated wells and incubated, and then the plate was washed to remove unbound MGAWN1. Subsequently, biotinylated 9B6.3 (an anti-MGAWN1 idiotype monoclonal antibody) was added to the wells. After any unbound substances had been washed away, alkaline phosphatase-conjugated streptavidin was added, followed by 4-methyumbelliferyl phosphate (4-MUP). The resulting fluorescent signal was then measured. The serum MGAWN1 concentration in each sample was determined from an MGAWN1 standard curve. Pharmacokinetic parameters were calculated by noncompartmental techniques using WinNonLin (version 5.2.1; Pharsight Corporation, Mountain View, CA).

Immunogenicity analysis.

The presence of anti-drug antibodies (ADA) against MGAWN1 in serum samples was determined using a bridging ELISA format (7). In this format, the anti-MGAWN1 antibody present in the sample creates a bridge between the immobilized MGAWN1 and biotinylated MGAWN1. Serum samples or the positive control (goat anti-E16 Fv) was subjected to acid dissociation and mixed with biotinylated MGAWN1. The mixture was then transferred to MGAWN1-coated wells, neutralized by Tris base, and incubated at room temperature. After any unbound substances were washed away, alkaline phosphatase-conjugated streptavidin and the 4-MUP substrate were utilized, and the resulting fluorescent signal was measured. Samples with values greater than a predetermined cutoff point (determined using a one-sided 95% reference interval of results from negative normal donor sera) were retested in the presence of excess MGAWN1. Any samples with responses above the cutoff point and with confirmed specificity were reported as positive for MGAWN1 ADA.

Statistical analysis.

Continuous data were described using descriptive statistics: number of observations, mean (arithmetic), median, standard deviation (SD), minimum, and maximum. Frequencies and percentages were used for summarizing discrete (categorical) data. Missing data were not imputed. Data are summarized by treatment group (the pooled placebo data from the different cohorts constitute one treatment group, and the other treatment groups are defined by the level of the MGAWN1 dose [0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, or 30 mg/kg]).

RESULTS

Forty subjects were enrolled between August 2007 and December 2008. All subjects received a single i.v. infusion of MGAWN1 (at 1 of the following 5 doses: 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, or 30 mg/kg [6 subjects each]) or saline control (placebo) (10 subjects). One subject (enrolled in cohort 2 and randomized to receive placebo) was lost to follow-up after the day 42 visit.

Baseline demographic characteristics were comparable among all dose groups, including the subjects receiving the placebo (Table (Table1).1). Most of the MGAWN1-treated subjects were either African-American (18/30 subjects [60%]) or Caucasian (10/30 subjects [33%]). Slightly more than half of the MGAWN1-treated subjects were female (16/30 subjects [53%]).

TABLE 1.
Baseline demographics

Safety.

All of the subjects in each treatment group experienced at least 1 adverse event (AE) during the study (a total of 262 AEs, of which 261 were not serious and 1 was serious). Of these, 6 subjects (all treated with MGAWN1) experienced at least 1 AE attributed by the investigator to the study drug. Most of the AEs were grade 1 (mild) in severity. One subject experienced a grade 3 AE (neutrophil count decreased; 3 mg/kg MGAWN1). None of the subjects experienced a grade 4 (life-threatening) or grade 5 (fatal) AE. One serious AE (SAE), hospitalization for schizophrenia (grade 2, moderate) on study day 50, was reported for a subject who received 0.3 mg/kg MGAWN1; the event was not attributed to the study drug. No subject discontinued the study due to an AE.

AEs that occurred in ≥10% of all MGAWN1-treated subjects (n = 30), compared to results for the placebo group, are presented in Table Table2.2. A drug-related AE was defined as any AE with an investigator causality assessment of possible, probable, or definite. Six (20%) of the 30 MGAWN1-treated subjects experienced a total of 11 AEs that were considered drug related. All drug-related AEs that occurred during the study are presented in Table Table3.3. Drug-related AEs that occurred in >1 MGAWN1-treated subject were decreased neutrophil count and headache (2 subjects each [7%]). No drug-related AEs were reported for placebo-treated subjects.

TABLE 2.
Adverse events occurring in ≥10% of all MGAWN1-treated subjects by preferred term and cohort
TABLE 3.
Number and percentage of subjects with an investigator-assessed drug-related adverse event by system organ class, preferred term, severity, and cohort

Changes from baseline or vital signs were generally small and were comparable among treatment groups at each evaluation. No clinically relevant changes in vital signs were observed. Three subjects (2 receiving MGAWN1, 1 receiving placebo) had a blood pressure increase reported as an AE, and each event was mild in severity.

Electrocardiogram (ECG)-related AEs that occurred in >1 MGAWN1-treated subject included sinus arrhythmia (5/30 MGAWN1-treated subjects [17%]; 3/10 subjects receiving placebo [30%]), sinus bradycardia (5/30 MGAWN1-treated subjects [17%]; 3/10 subjects receiving placebo [30%]), electrocardiogram repolarization abnormality (2/30 MGAWN1-treated subjects [7%]; 0% of subjects receiving placebo), and electrocardiogram T wave abnormality (2/30 MGAWN1-treated subjects [7%]; 0% of subjects receiving placebo). All of the ECG-related AEs were grade 1 in severity, and none were attributed to the use of the study drug. Overall, AEs showed no relationship to the level of the MGAWN1 dose.

Pharmacokinetics.

The pharmacokinetic parameters are presented in Table Table4.4. The log-linear plots of serum MGAWN1 concentrations over time are indicative of first-order elimination kinetics (Fig. (Fig.1A).1A). For the 10-mg/kg and 30-mg/kg dose cohorts, the maximum concentrations of MGAWN1 in serum (Cmax) were 349.2 μg/ml and 953.3 μg/ml, respectively; terminal half-life (t1/2) values were 32.7 days and 26.7 days, respectively; and the areas under the concentration-time curve from day 0 to day 180 (AUC0-4,320) were 139,249 and 358,265 μg·h/ml, respectively. The Cmax and AUC values were linearly proportional to the dose.

FIG. 1.
Log-linear serum MGAWN1 concentrations (μg/ml) over time. (A) The mean serum MGAWN1 concentrations for each cohort are plotted. (B) The individual serum MGAWN1 concentrations for subject 106 and the mean concentrations for the rest of cohort 1 ...
TABLE 4.
Pharmacokinetic parameters after a single dose of MGAWN1

Immunogenicity.

One MGAWN1-treated subject (receiving 0.3 mg/kg) tested positive for the formation of antibody to MGAWN1 on study days 91, 120, and 180 and exhibited more-rapid clearance of MGAWN1 than other subjects in the same cohort (Fig. (Fig.1B).1B). For this subject, the t1/2 was 9.7 days (compared to 24.3 days for the remainder of the cohort), and AUC0-4,320 was 2,592 μg·h/ml (compared to 3,425 μg·h/ml for the rest of the cohort). This finding indicates that an immunogenic reaction to MGAWN1 is possible. At the higher doses tested (1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg), none of the subjects tested positive for the formation of antibody to MGAWN1. Since MGAWN1 is given as a single infusion, the development of antibodies to MGAWN1 does not increase the risk associated with this drug but could potentially reduce the effectiveness of the drug in subjects who develop antibodies early after treatment.

DISCUSSION

MGAWN1 is an investigational humanized anti-WNV monoclonal antibody that is being developed for the treatment of West Nile virus infections. The results of this phase 1 study suggest that single infusions of MGAWN1 up to 30 mg/kg appear to be safe and well tolerated in healthy subjects.

Mean Cmax were linearly proportional to the dose, reaching levels as high as 953 μg/ml at the 30-mg/kg MGAWN1 dose. Terminal half-life values ranged from 21.7 days to 32.7 days. The volumes of distribution were slightly larger than the plasma volume (~40 ml/kg), indicating distribution of some of the antibody out of the vascular compartment into the extracellular space. The PK parameters observed with MGAWN1 are consistent with those for other humanized IgG1 MAbs with specificities against nonendogenous targets (viruses or bacterial agents) (1, 3, 18, 21).

Estimates of serum MGAWN1 concentrations associated with therapeutic activity were obtained from studies utilizing hamsters, which are highly susceptible to WNV infection and which model many aspects of the neuroinvasive disease observed in humans (8-10). Following subcutaneous (s.c.) inoculation (which mimics the natural route of WNV infection), hamsters develop viremia, transient infection of the spleen, and, subsequently neuroinvasive infection of the brain and spinal cord, where virus levels and neuronal degeneration increase daily until death. Neurological impairment is associated with the appearance of initial disease signs (weight loss, lethargy, nosebleed, lacrimation) that progress to tremors, paralysis, and moribundity. Unlike those for human infections, the percentage of mortality is high (70 to 100%) and the median time to death is short (12 to 14 days). In this model, animals may be effectively treated with MGAWN1 up to 5 days postinfection, a time subsequent to the establishment of neurological infection (9). For MGAWN1 administered intraperitoneally (i.p.) to WNV-infected hamsters at 5 days postinfection, the half-maximally effective dose (ED50) for survival is approximately 0.1 mg/kg (9). Mean Cmax vary linearly with the dose level, and the mean 50% and 99% effective concentrations (EC50 and EC99) in serum for survival are estimated at 0.34 μg/ml and 34 μg/ml, respectively.

In human subjects, a single infusion of 30 mg/kg MGAWN1 resulted in a mean Cmax of 953 μg/ml, which exceeds the serum EC99 target level estimated from hamster studies by 28-fold. The optimal dose for the treatment of humans infected with WNV is not known. MGAWN1 at 32 mg/kg administered by i.p. injection to WNV-infected hamsters resulted in mean MGAWN1 concentrations in cerebrospinal fluid (CSF) after 24 h that were approximately 0.25% of those in serum (i.e., the serum/CSF ratio was approximately 400), and in the cerebral cortex, brain stem, and thoracic/lumbar spinal cord, the MGAWN1 concentrations ranged from 0.2 to 0.5 μg/g of tissue (9). Based on the correlation of MGAWN1 levels in serum and CSF, the serum/CSF concentration ratio of approximately 400:1, and the mean EC99 in serum of ~34 μg/ml, the mean EC99 in CSF for survival is estimated to be approximately 0.085 μg/ml. Other monoclonal antibodies demonstrate a serum/CSF ratio of approximately 1,000 in humans (6, 15, 17, 19). Using this ratio, the maximal CSF MGAWN1 concentration in human subjects following a 30-mg/kg dose is projected to be ~0.95 μg/ml, which exceeds the CSF EC99 target level by more than 10-fold. Hence, as long as the neuroinvasive disease has not progressed too far, treatment of subjects with 30 mg/kg MGAWN1 should provide an excess of WNV neutralizing activity, and the terminal half-life of 26.7 days suggests that a single dose should be sufficient.

One MGAWN1-treated subject (receiving 0.3 mg/kg) tested positive for antibody to MGAWN1 on study day 91. The development of antibodies to MGAWN1 explains the altered terminal pharmacokinetics for this subject (occurring after study day 42). This finding indicates that an immunogenic reaction to MGAWN1 is possible. At the higher doses tested (1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg), none of the subjects tested positive for the formation of antibody to MGAWN1. Since MGAWN1 is given as a single infusion, the development of antibodies to MGAWN1 does not appear to increase the risk associated with this drug but could possibly reduce the effectiveness of the drug for subjects who develop antibodies.

The safety assessment revealed that the majority of AEs that were considered to be related to MGAWN1 were mild. In addition, the AEs showed no apparent relationship to the dose level or to serum MGAWN1 concentrations. This is not unexpected, since MGAWN1 has no target in the human body but is directed against WNV. Based on the PK, safety, and tolerability data obtained in this study, further clinical evaluation of MGAWN1 for the treatment of West Nile virus infections is warranted.

Acknowledgments

This research was supported by the Division of Microbiology and Infectious Diseases, NIAID, NIH (DPHS contract HHSN266200600013C).

We are grateful to the volunteers for their generous contributions to this study and to the Safety Monitoring Committee (Richard Johnson, John Gnann, and Wellington Sun) for their time and the oversight of the study.

D.R.G. has no conflicts of interest. J.H.B., J.L.N., S.R.P., C.R., H.L., P.C.H., S.J., K.S., and S.K. are employees of MacroGenics Inc.

Footnotes

[down-pointing small open triangle]Published ahead of print on 29 March 2010.

Clinical Trials.gov identifier NCT00515385.

REFERENCES

1. Abarca, K., E. Jung, P. Fernandez, L. Zhao, B. Harris, E. M. Connor, and G. A. Losonsky. 2009. Safety, tolerability, pharmacokinetics, and immunogenicity of motavizumab, a humanized, enhanced-potency monoclonal antibody for the prevention of respiratory syncytial virus infection in at-risk children. Pediatr. Infect. Dis. J. 28:267-272. [PubMed]
2. Agrawal, A. G., and L. R. Petersen. 2003. Human immunoglobulin as a treatment for West Nile virus infection. J. Infect. Dis. 188:1-4. [PubMed]
3. Boeckh, M., M. M. Berrey, R. A. Bowden, S. W. Crawford, J. Balsley, and L. Corey. 2001. Phase 1 evaluation of the respiratory syncytial virus-specific monoclonal antibody palivizumab in recipients of hematopoietic stem cell transplants. J. Infect. Dis. 184:350-354. [PubMed]
4. CDC. 2 June 2009, revision date. West Nile virus: statistics, surveillance, and control. CDC, Atlanta, GA. http://www.cdc.gov/ncidod/dvbid/westnile/surv&control.htm.
5. Davis, L. E., R. DeBiasi, D. E. Goade, K. Y. Haaland, J. A. Harrington, J. B. Harnar, S. A. Pergam, M. K. King, B. K. DeMasters, and K. L. Tyler. 2006. West Nile virus neuroinvasive disease. Ann. Neurol. 60:286-300. [PubMed]
6. Harjunpää, A., T. Wiklund, J. Collan, R. Janes, J. Rosenberg, D. Lee, A. Grillo-Lopez, and S. Meri. 2001. Complement activation in circulation and central nervous system after rituximab (anti-CD20) treatment of B-cell lymphoma. Leuk. Lymphoma 42:731-738. [PubMed]
7. Koren, E., H. W. Smith, E. Shores, G. Shankar, D. Finco-Kent, B. Rup, Y. C. Barrett, V. Devanarayan, B. Gorovits, S. Gupta, T. Parish, V. Quarmby, M. Moxness, S. J. Swanson, G. Taniguchi, L. A. Zuckerman, C. C. Stebbins, and A. Mire-Sluis. 2008. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. J. Immunol. Methods 333:1-9. [PubMed]
8. Morrey, J. D., V. Siddharthan, A. L. Olsen, G. Y. Roper, H. Wang, T. J. Baldwin, S. Koenig, S. Johnson, J. L. Nordstrom, and M. S. Diamond. 2006. Humanized monoclonal antibody against West Nile virus envelope protein administered after neuronal infection protects against lethal encephalitis in hamsters. J. Infect. Dis. 194:1300-1308. [PubMed]
9. Morrey, J. D., V. Siddharthan, A. L. Olsen, H. Wang, J. G. Julander, J. O. Hall, H. Li, J. L. Nordstrom, S. Koenig, S. Johnson, and M. S. Diamond. 2007. Defining limits of treatment with humanized neutralizing monoclonal antibody for West Nile virus neurological infection in a hamster model. Antimicrob. Agents Chemother. 51:2396-2402. [PMC free article] [PubMed]
10. Morrey, J. D., V. Siddharthan, H. Wang, J. O. Hall, R. T. Skirpstunas, A. L. Olsen, J. L. Nordstrom, S. Koenig, S. Johnson, and M. S. Diamond. 2008. West Nile virus-induced acute flaccid paralysis is prevented by monoclonal antibody treatment when administered after infection of spinal cord neurons. J. Neurovirol. 14:152-163. [PMC free article] [PubMed]
11. Mostashari, F., M. L. Bunning, P. T. Kitsutani, D. A. Singer, D. Nash, M. J. Cooper, N. Katz, K. A. Liljebjelke, B. J. Biggerstaff, A. D. Fine, M. C. Layton, S. M. Mullin, A. J. Johnson, D. A. Martin, E. B. Hayes, and G. L. Campbell. 2001. Epidemic West Nile encephalitis, New York, 1999: results of a household-based seroepidemiological survey. Lancet 358:261-264. [PubMed]
12. Nybakken, G. E., T. Oliphant, S. Johnson, S. Burke, M. S. Diamond, and D. H. Fremont. 2005. Structural basis of West Nile virus neutralization by a therapeutic antibody. Nature 437:764-769. [PubMed]
13. O'Leary, D. R., A. A. Marfin, S. P. Montgomery, A. M. Kipp, J. A. Lehman, B. J. Biggerstaff, V. L. Elko, P. D. Collins, J. E. Jones, and G. L. Campbell. 2004. The epidemic of West Nile virus in the United States, 2002. Vector Borne Zoonotic Dis. 4:61-70. [PubMed]
14. Oliphant, T., M. Engle, G. E. Nybakken, C. Doane, S. Johnson, L. Huang, S. Gorlatov, E. Mehlhop, A. Marri, K. M. Chung, G. D. Ebel, L. D. Kramer, D. H. Fremont, and M. S. Diamond. 2005. Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat. Med. 11:522-530. [PMC free article] [PubMed]
15. Pestalozzi, B. C., and S. Brignoli. 2000. Trastuzumab in CSF. J. Clin. Oncol. 18:2349-2351. [PubMed]
16. Petersen, L. R., and A. A. Marfin. 2002. West Nile virus: a primer for the clinician. Ann. Intern. Med. 137:173-179. [PubMed]
17. Rubenstein, J. L., D. Combs, J. Rosenberg, A. Levy, M. McDermott, L. Damon, R. Ignoffo, K. Aldape, A. Shen, D. Lee, A. Grillo-Lopez, and M. A. Shuman. 2003. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood 101:466-468. [PubMed]
18. Sáez-Llorens, X., M. T. Moreno, O. Ramilo, P. J. Sanchez, F. H. Top, Jr., and E. M. Connor. 2004. Safety and pharmacokinetics of palivizumab therapy in children hospitalized with respiratory syncytial virus infection. Pediatr. Infect. Dis. J. 23:707-712. [PubMed]
19. Schulz, H., H. Pels, I. Schmidt-Wolf, U. Zeelen, U. Germing, and A. Engert. 2004. Intraventricular treatment of relapsed central nervous system lymphoma with the anti-CD20 antibody rituximab. Haematologica 89:753-754. [PubMed]
20. Sejvar, J. J., and A. A. Marfin. 2006. Manifestations of West Nile neuroinvasive disease. Rev. Med. Virol. 16:209-224. [PubMed]
21. Subramanian, G. M., P. W. Cronin, G. Poley, A. Weinstein, S. M. Stoughton, J. Zhong, Y. Ou, J. F. Zmuda, B. L. Osborn, and W. W. Freimuth. 2005. A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers. Clin. Infect. Dis. 41:12-20. [PubMed]
22. Thompson, B. S., B. Moesker, J. M. Smit, J. Wilschut, M. S. Diamond, and D. H. Fremont. 2009. A therapeutic antibody against West Nile virus neutralizes infection by blocking fusion within endosomes. PLoS Pathog. 5:e1000453. [PMC free article] [PubMed]

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