History of Aptamers and Antibodies

Antibodies and Aptamers: From Discovery to Therapeutics

Ab vs aptamer sizeAntibodies and aptamers are selective affinity reagents that can be used in a wide range of research, diagnostic, and therapeutic applications. While antibodies and nucleic acids were both discovered in the late 19th century and early discoveries in isolation and production of antibodies and DNA, and RNA took place in the late 1950s, successful antibody therapeutics are a more recent phenomenon and the field of aptamer-based therapeutics is still developing.2,7,9,10 Methods for producing monoclonal antibodies and selecting DNA/RNA aptamers took many years to develop. Eleven years after the discovery of the hybridoma, the first antibody drug was approved by the FDA. It was eleven more years before approval of the first humanized antibody in 1997. This was the first highly successful antibody drug. It was then another 15 years for FDA approval of the first antibody-drug conjugate. With the discovery of aptamers and SELEX in 1990 and the approval of the first therapeutic aptamer in 2004, many are looking for the next major milestone in aptamer-based therapeutics.1 Learn more about aptamers and SELEX.

Challenges in the Development of Therapeutic Antibodies

Many of the early challenges related to antibody usage in therapeutics stemmed from the use of animal-derived antibodies. A concerning percentage of patients had a strong immune response to the antibody drugs. The antibodies were often rapidly cleared by the body’s immune system, requiring repeated administration, and showed poor recognition of human cell surface receptors. In addition to antibody design hurdles, antibody production required investment in new manufacturing facilities and the development of new manufacturing and testing procedures. The failure of the drug Centoxin to get FDA approval for sepsis treatment in the early 1990s nearly put Centocor out of business. It also highlighted the need for advancements in the design and analysis of clinical trials and the advantage of developing drugs for more well-defined diseases. Thankfully, the successful launch of Centocor’s cardiovascular drug abciximab in 1994 got both Centocor (now Janssen Biotech) and the industry back on a path toward success.11 In subsequent years, advances have been made in antibody design, manufacturing equipment and procedures, and clinical trials. Though potential toxicity, drug metabolism and clearance, and drug efficacy are evaluated as early as possible in the drug development process to limit investment in failed candidates, the high cost of antibody drug development and the high price to consumers for antibody drugs remain an ongoing challenge.

Challenges in the Development of Therapeutic Aptamers

Historically, DNA has been studied for its role in the storage and transfer of genetic information. It wasn’t until the discovery of aptamers and SELEX in 1990 that the greater research community began to consider the selective binding potential of DNA and RNA and the advantages of oligonucleotides as affinity agents.8 Unlike hybridoma development, however, the process of selecting aptamers was heavily protected by patents, limiting commercial investment in aptamer development until about 2012.15 The development of the aptamer field from 2000 to today has also coincided with the growth phase of antibody-based therapeutics. Despite the advantages of small, non-immunogenic aptamers that can be easily complexed and chemically synthesized, significant infrastructure for the discovery and production of antibody-based therapeutics was already in place and several antibody-based drugs were seeing great success, limiting aptamer-based therapeutic research.11 As the field of therapeutic antibodies begins to mature, key areas and opportunities for the development of aptamer-based therapeutics are emerging. Learning from the early challenges in the development of therapeutic antibodies, researchers are highlighting the low immunogenicity, in vivo stability/clearance, selectivity, and efficacy of aptamer-based therapeutics in pre-clinical studies.

What Next?

While antibody drugs have made great strides in cancer therapies, crossing the blood-brain barrier (BBB) and ensuring proper clearance from the brain have hindered the use of antibody drugs for the treatment of neurological diseases. The use of bispecific antibodies to both drug targets and transport receptors is one approach being explored, but antibody size and the associated issues with accessibility, immunogenicity and clearance are an ongoing challenge.12 Aptamers are approximately one tenth the size of an antibody. They are intrinsically non-immunogenic and are better able to access tissues and cells.16,17 In several animal studies, aptamers and aptamer-drug complexes have successfully crossed the blood-brain barrier to deliver effective treatment. Read about recent aptamer successes in neurological disease.

An estimated 50 million people worldwide are living with Alzheimer’s disease.4 Brain tumors and tumors of the central nervous system are the most common form of cancer in children under 19 and the leading cause of cancer-related deaths in children under 14 in the United States.5 Aptamers can potentially meet a critical unmet need for therapeutics addressing neurological diseases. Could approval of an aptamer drug or aptamer-drug conjugate for the treatment of a neurological disease be the next major milestone? Though there is risk associated with the pursuit of novel drug therapies, there is huge potential for pharmaceutical sales, increased survival rates, reduced health care costs, and enhanced quality of life. The development of aptamer-based therapeutics in areas that have been most challenging for antibody-based therapies may indeed open the door for the wider application of aptamers in therapeutics, offering rapid in vitro discovery, simple chemical synthesis, excellent batch-to-batch consistency, and unlimited supply of critical therapeutics.16,17

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History of Antibodies

History of Aptamers

 

1869

Friedrich Mieschner isolates DNA for the first time, calling it “nuclein”. 

1891

Emil von Behring successfully utilizes a serum treatment to cure a child with diptheria. In the years following, he works with Shibasaburo Kitasato, Paul Ehrlich and the Hoechst chemical and pharmaceutical company to manufacture diptheria “antitoxin”. Behring is awarded the first Nobel Prize in 1901.

1908

Paul Ehrlich shares the Nobel Prize for his chemical theory on the role of antibodies in the immune system.

1953

James Watson and Francis Crick propose a model of the helical structure of DNA in Nature based on X-ray crystallography images from Rosalind Franklin. Watson, Crick, and Maurice Wilkins receive the nobel prize in 1962 for the determination of the structure of DNA.

1958

Gustav V. J. Nossal and Joshua Lederberg demonstrate clonal selection, a theory pioneered by Niels Kaj Jerne and further expanded by David Talmage and Frank Macfarlane Burnet.

1958

Arthur Kornberg publishes his discovery of DNA Polymerase I. In 1959, Arthur Kornberg and Severo Ochoa receive the nobel prize for the discovery of natural DNA and RNA synthesis.

1975

Georges J.F. Kohler and Cesar Milstein publish the first paper on antibody hybridoma production. No patents were filed by the inventors. Cesar Milstein, Georges J.F. Kohler, and Niels Kaj Jerne share the nobel prize in 1984.

1986

FDA approval of the first therapeutic antibody, muromonab, as a treatment for transplant rejection

1990

Craig Tuerk and Larry Gold publish a paper describing a new process called SELEX. Andy Ellington and Jack Szostak coin the term “aptamer” in a publication in Nature. Several patents were filed by the inventors.

1997

FDA approves the first humanized antibody drug, Rituximab (Rituxan), for the treatment of leukemia and lymphoma. This was the first “blockbuster” antibody drug. (Annual sales reached $7 billion in 2012)

1999

First publication describing the selection of aptamers using live cells by Matthias Homann and H. Ulrich Goringer, later coined cell-SELEX.

2004

FDA approval of the first aptamer drug, macugen, for the treatment of neovascular age-related macular degeneration.

2012

The first antibody-drug conjugate, brentuximab, is approved by the FDA. (Up to $307 million in annual sales in 2017)

2012

Expiration of several key aptamer patents.

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References

  1. ACTIP. http://www.actip.org/products/monoclonal-antibodies-approved-by-the-ema-and-fda-for-therapeutic-use/. Accessed Feb 5, 2019.
  2. Alkan, Sefik S., Monoclonal antibodies:the story of a discovery that revolutionized science and medicine. Nature Reviews Immunology. 2004. 4:153-156.
  3. Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/facts-figures. Accessed Feb 22, 2019.
  4. Alzheimer’s Disease International. https://www.alz.co.uk/research/statistics. Accessed Feb 22, 2019
  5. Brain Tumors By the Numbers. https://events.braintumor.org/wp-content/uploads/2016/03/BrainTumorsBytheNumbers_12.04.15.pdf. Accessed Feb 22, 2019.
  6. Brownlee, Jason. A review of the clonal selection theory of acquired immunity. CIS Technical Report 070223A. 2007. https://pdfs.semanticscholar.org/15a6/7411ba3bf71862d75587093412c7945d0b83.pdf
  7. Dahm, Ralf. Friedrich Miescher and the discovery of DNA. Developmental Biology. 2005. 28(2):274-288.
  8. Gold, L., et al. Aptamers and the RNA World, Past and Present. Cold Spring Harbor Perspectives in Biology. 2012. 4(3)a003582.
  9. Kohler, Georges J.F. and Cesar Milstein. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975. 256(5517):495-7.
  10. Kresge, N., et al. Arthur Kornberg’s Discovery of DNA Polymerase I. Journal of Biological Chemstry. http://www.jbc.org/content/280/49/e46. Accessed Feb 20, 2019.
  11. Marks, Lara, The birth pangs of monoclonal antibody therapeutics: The failure and legacy of Centoxin. mAbs. 2012. 4(3):403-412.
  12. Neves, V. et al. Antibody approaches to treat brain diseases. Rends in Biotechnology. 2016. 34(1):36-48.
  13. Science History Institute. https://www.sciencehistory.org/historical-profile/paul-ehrlich. Accessed Feb 19, 2019. The Nobel Prize. https://www.nobelprize.org/prizes/medicine/1901/behring/article/. Accessed Feb 19, 2019.
  14. Science History Institute. https://www.sciencehistory.org/historical-profile/james-watson-francis-crick-maurice-wilkins-and-rosalind-franklin. Accessed Feb 21, 2019.
  15. Wade. Nicholas. Inventor of hybridoma technology failed to file for patent. Science. 1980. 208(4445):693.
  16. Jayasena, S. D. Aptamers: An emerging class of molecules that rival antibodies in diagnostics. Clinical Chemistry. 1999. 45(9):1628-50.
  17. Sun, H. et al. Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy. Molecular Therapy – Nucleic Acids. 2014. 3, e182. Doi: 10.1038/mtna.2014.32.