Friday, December 4, 2015

Antibodies as Drugs: A Lesson from Before the Antibiotic Era

This post was contributed by Twist Bioscience


'His penicillin will save more lives than war can spend’ was the tagline accompanying a serious-looking Alexander Fleming on the cover of the May 15th, 1944 issue of TIME Magazine. With his discovery of penicillin came the antibiotic era of medicine. However, when one giant rises, another must fall. Serum therapy was, almost overnight, systematically dethroned as the accepted treatment for infectious diseases.

The cover of the May 15th 1944 issue of TIME magazine, which features Alexander Fleming shortly after his discovery of Penicillin. Source.

Serum therapy, the treatment of an infectious disease by injection of an immunized animal’s blood serum, was first used to cure disease in the 1890s. In the 40 years it took for penicillin to be discovered, serum therapy treated a swath of diseases including tetanus, diphtheria, measles and chicken pox.

By inoculating an animal with a dead pathogen, the animal’s antibody-rich immune sera could be extracted. Injecting the immunized animal sera into patients lead to prophylactic, bactericidal, antitoxic and protective benefits. However, it would take around six months to develop a serum, and even then only around 40% of patients would show improvement, making antibiotics were a better solution1.

Today, with the threat of antibiotic resistance looming, antibody treatment is reinstating itself into the next era of medicine. Significant developments that enable us to mass-engineer an antibody’s binding domains have occurred in recent years. Our ability to screen candidates for highly efficient binding, and grow them into concentrated sera of monoclonal antibodies has also drastically improved.

With this, antibody therapy has become accepted into routine clinical practice. Antibody research is now at fever pitch, with thousands of published clinical trials on PubMed today.

Monoclonal antibodies have incredible potential in disease and disorder treatment, due to their ability to explicitly bind specific molecules. The immunosuppressant Muromonab-CD3, given to organ transplant patients, was the very first to be approved by the FDA for human use in 1985. Since its approval, many monoclonal antibodies have now been cleared for use, or are advancing through clinical testing. Disease targets include Crohn’s disease, cancer, asthma, psoriasis, diabetes, HIV, influenza and Alzheimer’s disease.

Importantly, antibody-based therapies are moving toward completely humanized monoclonals (as opposed to those sourced from mice). Research focuses on engineering low toxicity, high target specificity and improved manufacturability – all characteristics bolstered by the advent of synthetic biology, especially massively multiplex DNA libraries.

These vast libraries contain around 1010 different antibody sequences, representing every possible combination of mutations at particular points within an antibody’s variable regions. The single set of mutations that confers perfect, high-specificity binding to an antigen of interest can then be fished out with a number of high throughput screening technologies. Such advancement has been pivotal to antibody therapy research, pushing engineering costs down, reinforcing efforts to treat complex diseases with global reach, such as cancer.

The many ways an antibody can be engineered to destroy a tumor cell. Source: (Chao et al., 2012)

In addition to DNA libraries, advances in next-generation sequencing-based diagnostics have opened new avenues for targeted, personalized, antibody-based therapies. By sequencing a tumor biopsy, it is possible to identify specific cancer-related surface antigens that are overexpressed – known as the ‘oncotype’ of the patient’s tumor. The corresponding antibody treatment can then be administered.

One well-known example of a cancer-treating, FDA-approved monoclonal antibody is Herceptin – for treatment of HER2-positive (HER2+) breast cancer oncotypes. In a large fraction of aggressive breast cancers, HER2 is overexpressed causing accelerated cellular proliferation. Herceptin targets HER2 receptors, blocks their signaling pathway, and attenuates tumor growth and proliferation. In a 10-year study of 4,000 women with early-stage HER2+ breast cancer, treatment with Herceptin showed a 37% increase in overall survival and a 40% increase in disease-free survival compared to a cohort treated only with chemotherapy2.

A vial of the breast cancer fighting, monoclonal antibody - Herceptin. Source.

Herceptin binds specifically to its cancer-specific antigen, however, oftentimes antigens are shared between cancer and some of the body’s own cells, causing the destruction of healthy tissues.

Yvonne Chen of UCLA, who spoke at the recent 2015 Synthetic Biology Congress in London, discussed her research on integrating synthetic biology and antibody engineering to solve this problem. Her group engineered antibodies to contain additional binding domains – so one antibody will only have strong binding if two antigens are present. This ensures the antibodies exclusively bind to a specific cancer cell.

Synthetic biology tools are revolutionizing high-throughput antibody engineering. As the cost of writing DNA decreases with new methods of DNA synthesis, the speed of development will increase. Simply, pharmaceutical and biotechnology companies will be able to test more options to improve specificity and manufacturability. In turn, this will enable highly targeted and highly beneficial therapies for the hardest-to-treat diseases, which can be delivered to patients worldwide.



About Twist Bioscience
At Twist Bioscience, our expertise is synthetic DNA. We have developed a proprietary semiconductor-based synthetic DNA manufacturing process featuring a 10,000-well silicon platform capable of producing synthetic biology tools, such as oligonucleotides, genes, pathways, chassis and genomes. By synthesizing DNA on silicon instead of on traditional 96-well plastic plates, our platform overcomes the current inefficiencies of synthetic DNA production, and enables cost-effective, rapid, high-quality and high throughput synthetic gene production. The Twist Bioscience platform has the potential to greatly accelerate the development of personalized medicine, sustainable chemical production, improved agriculture production as well as new applications such as in vivo diagnostics, biodetection and data storage. For more information, please visit www.twistbioscience.com. Twist Bioscience is on Twitter. Sign up to follow our Twitter feed @TwistBioscience at https://twitter.com/TwistBioscience.






1. Glatman-Freedman, Casadeval. Serum Therapy for Tuburculosis Revisited: Reappraisal for the Role of Antibody-Mediated Immunity Against Mycobacterium Tuburculosis. Clin Microb Rev. 1998.

2. Perez et al. Trastuzumab Plus Adjuvant Chemotherapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Planned Joint Analysis of Overall Survival From NSABP B-31 and NCCTG N9831. J. Clin. Oncol. 2014.


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1 comment :

Creative Biolabs said...

The Antibiotic Era did make us suffer, but it is the challenge it brought that move forward the development of antibody drugs.

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