by Diane Seimetz
When I started working in the biopharmaceutical industry 20 years ago, only a handful of biopharmaceuticals were on the market and critical voices challenged their value. They have been proved wrong. Today almost 50% of approved products are indeed biopharmaceuticals and this proportion will only further increase.
So how did it all start? The story goes back to the 18th century where smallpox infections eradicated between 10 and 20% of the European population. This stopped when Edward Jenner (1749 – 1823), a smart English physician, observed that milk maids where not as severely infected as the general population. His observation lead to the development of the first smallpox vaccine, produced in a living organism, a cow. Jenner’s work is said to have saved more lives than the work of any other human Today more than 100 different vaccines are available for a multitude of infectious diseases. The experience with vaccines against these, e.g. the first wave of biopharmaceuticals (see Figure 1), clearly tells us that preventing a disease is better than any treatment.
However, there are instances where a disease cannot be prevented, and treatment is needed. Recombinant proteins offer a valuable solution here: Insulin, originally derived from animal pancreas, has been available by recombinant DNA technology since 1978, followed by the first rDNA technology derived rapid and intermediate-acting insulin marketed in 1982. Another major class of recombinant proteins are antibodies. Important forerunners of therapeutic monoclonal antibodies were polyclonal antibodies, produced by immunization of animals. Polyclonal antibodies were used to treat, for example, severe infections. Today polyclonal antibodies are still used in organ transplantation to prevent organ rejection and as part of the conditioning regimen in stem cell transplantation. In 1975 Köhler and Milstein made a ground-breaking discovery, the hybridoma technology to produce monoclonal antibodies. The hybridoma technology paved the way for further optimization of biopharmaceutical products and generated a series of monoclonal antibodies for various indications. Thereby the second wave of biopharmaceuticals was introduced. The first antibody approved via the EU’s centralized procedure in 1998 was rituximab, an anti-CD20 antibody for use in oncology and rheumatology. One year later, infliximab, the first anti-TNF-alpha antibody was approved. The approval of TNF-alpha directed biologicals revolutionized the treatment of severe inflammatory skin diseases such as psoriasis. Ten years later the first bispecific antibody catumaxomab (anti-CD3 x anti-EpCAM) was approved , creating the path for many T-cell engaging therapies that are on the market today. In 2011, ipilimumab was approved as the first check point inhibitor, engaging the body’s own immunological mechanisms to fight against cancer. Multiple other check point inhibitors targeting different immune check points followed in the years thereafter.
However, the challenge associated with antibodies and recombinant proteins as therapies is the remarkable price tag and thus creating affordability issues with the health care systems. As a response to this challenge, the concept of biosimilars was developed. The first biosimilar, somatropin was approved in 2006 in the EU. By the end of 2018, a total of 58 biosimilars were approved in the EU, comprising 16 different active substances. In the US and in Japan, 17 biosimilars are authorized, comprising 9 and 10 different active substances, respectively.
The successes seen with antibodies and the power of engaging the body’s immune system to fight against diseases triggered the third wave of biopharmaceuticals, cell and gene therapies. This wave was initiated with the approval of Glybera, the first gene therapy in the EU. More products followed including the oncolytic virus Imlygic. Important milestones were the approval of the first CAR-T cell products Kymriah and Yescarta in 2017 in the US. In the meantime, more cell and gene therapies are approved in different territories and it appears that we have solved many of the initial hurdles seen with the development of cell and gene therapies, also referred to as Advanced Therapy Medicinal Products (ATMPs) .
An important landmark was the discovery of the Crispr/Cas9 system in 2013 by Emmanuelle Charpentier and Jennifer Doudna. Crispr/Cas9 is a disruptive technology to edit the genome and thought to shape the future of gene therapy. The first commercial clinical trial investigating Crispr/Cas9 edited cells was initiated this year by Crispr Therapeutics .
The 4th wave of biologicals may combine novel genome editing technologies with the intention to prevent diseases rather than treating them. However, this will need careful consideration, not only in terms of technically feasibility but also in terms of ethical acceptability. The future of biologicals has started and will change faster than ever. Deep learning algorithms, an advanced artificial intelligence approach, are believed to catalyze this development.
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 Seimetz D, Lindhofer H, Bokemeyer C. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev. 2010;36(6):458–67. DOI: 10.1016/j.ctrv.2010.03.001.
 Seimetz D, Heller K, Richter J. Approval of First CAR-Ts: Have we Solved all Hurdles for ATMPs?. Cell Med. 2019;11. Published 2019 Jan 22. DOI:10.1177/2155179018822781
 http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-and-vertex-announce-progress-clinical [accessed on 25 June 2019]