Monoclonal Antibodies for Biodefense
Gigi Kwik Gronvall, PhD, February 8, 2013
Monoclonal antibodies (mAbs) have become a blockbuster drug platform with the biggest portion of sales growth in the pharmaceutical industry.1 Nearly all large pharmaceutical companies have at least one mAb-licensed product and more candidates in their pipelines. However, the concentration of effort in mAb development has been to address oncological indications and immunological diseases, such as rheumatoid arthritis (RA).2 For infectious diseases, there are just 2 licensed mAbs: one for prevention of respiratory syncytial virus (RSV) in premature babies and another recently approved to treat inhalational anthrax.
A Larger Role in Biodefense
Now the Center for Biosecurity has released a report in which the case is made for a larger role in biodefense for mAbs.3 For Department of Defense personnel, in particular, and other special populations, the possibility of using mAbs that target traditional bioweapons agents offers great promise. mAbs have several advantages that other medical countermeasures do not: they provide near-instant immunity regardless of prior immune status, immunity is not permanent, the rate of adverse reactions is relatively low, and the pathway to development may be faster as compared with vaccines or small-molecule drugs.
One of the challenges to using mAbs for medical countermeasures is that they are specific and require a specific disease diagnosis. A mAb that targets botulinum toxin, for example, cannot be used to treat a tetanus infection. In contrast, broad-spectrum antivirals and antibiotics do not require specific diagnoses. Further, the broad-spectrum therapeutics tend to be more effective than mAbs later in the course of disease.4 In spite of the current lack of commercial attention to mAbs for infectious disease, there are a number of reasons to believe they may be more desirable in the future.
Post-antibiotic Era Treatments
The increased prevalence and rising costs of treatment for methicillin-resistant S. Aureus (MRSA) and resistant nosocomial and community-based infections have prompted experts to declare that we are entering a “post-antibiotic era.”5,6 The commercial pipeline for new classes of antibiotics is not projected to offer a solution to this problem any time in the near future, which necessitates development of alternative approaches to treating infectious diseases.4
Treatment for Immunocompromised People
There are at least 10 million people in the United States (3.6% of the population) who are considered immunocompromised.7,8 This has implications for treatment of naturally occurring infections and for response to a biological attack, as this population may be more adversely affected and may not benefit from vaccination. Conceivably, a mAb could provide protection for this population without exposing immunocompromised people to the risks of live virus vaccines.
More Effective Prophylaxis
Many childhood diseases are not confined to children, and mAbs may be beneficial as treatment or post-exposure prophylaxis for exposed adults.9 For example, adults who have not been vaccinated against pertussis in many years may benefit from a mAb to boost their immune response if they are at risk for whooping cough.10 With mumps, there is diminished herd immunity, leaving college students particularly at risk.11 Influenza vaccine is less effective for the elderly, who are more likely to suffer the effects of the disease.12 For all of these diseases, a mAb may be more effective than vaccine as prophylaxis or to aid those who have become infected or are at risk of developing the disease.
Protecting the Microbiome
There is increased scientific understanding of the health maintenance role of the microbiome—the collection of microbes that live in or on the human body, including in the gastrointestinal tract, mouth, skin, nose, and urogenital tract.13 However, the microbiome is disrupted by broad-spectrum antibiotics, which kill many microbes, alter the body’s ecosystem, and affect health. There is evidence that alterations of the microbiome may contribute to disease and even to obesity.14 As these disease pathways become better understood, reluctance may grow to using broad-spectrum antibiotics as a first-step prophylaxis.4 A specific medical countermeasure, such as a mAb, may protect the microbiome while limiting an infection.
Increased Availability of Diagnostics
In contrast to broad-spectrum antibiotics, the specificity of mAbs requires a diagnosis of disease before treatment. This has been a clear barrier in the past, but recent government efforts to develop and promote diagnostic tests for infectious diseases may allow the more widespread use of mAbs for early treatment of disease.15 If diseases are diagnosed routinely and quickly, there may be more opportunities to use a specific medical countermeasure such as a mAb, and more commercial interest in providing specific therapeutics.
Improvements in Environmental Detection
Fielded environmental biological detection capabilities offer more rapid recognition of biological agent exposures than has been available in the past. These detection systems are increasing the range of agents that can be detected and are decreasing the time from collection to identification and confirmation. Faster identification of exposures could boost the effectiveness of a mAb therapy.
Regulatory Allowance of Cocktails
There is some evidence that mAbs are more effective against infectious diseases when administered as a cocktail—a mix of 2 or more mAbs administered at once.4 However, if each mAb in a cocktail had to attain FDA licensure individually, the burden and cost of clinical testing would be prohibitive. The FDA has allowed one combination product, a cocktail of mAbs against rabies (developed by Crucell/Sanofi and currently in phase II clinical trials) to be tested and regulated as one product.16 This approach will be advantageous for licensing mAbs for other infectious disease that require multi-mAb treatment.4
The Center for Biosecurity of UPMC conducted this study to provide leaders in the US Department of Defense with an expert assessment of the technical feasibility and strategic implications of next-generation monoclonal antibodies as medical countermeasures for DoD personnel. The full report includes recommendations for potentially appropriate DoD investments in mAb technologies.
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Jennifer B. Nuzzo, Kunal J. Rambhia, Samuel B. Wollner, et al. Diagnostics for Global Biosurveillance: Turning Promising Science into the Tools Needed in the Field. Center for Biosecurity of UPMC; September 2011.
Crucell. Developing a Rabies Antibody Combination. 2012. Available at http://www.crucell.com/R_and_D-Clinical_Development-Rabies_Antibody_Product. Accessed August 21, 2012.