HAMBURG, Germany - Founded by molecular biologist Burghardt Wittig, the German start-up company Mologen AG holds key patents in developing DNA vaccines.

Its vision is to provide cheaper, faster and safer vaccines against infectious as well as tumor diseases. In May, Mologen, of Berlin, went public as Germany's second biotechnology company.

As a spin-off from the field of gene therapy, DNA-based immunization has attracted much attention from scientists and biotechnology companies.

Purified plasmid DNA, containing protein coding sequences and the necessary regulatory elements to express them, can be introduced into tissues of an organism by means of an injection or by particle bombardment. The number of cells transfected and the amount of protein produced are sufficient to produce a strong immune response to a wide variety of foreign proteins.

The absence of an exogenous infectious agent or immunogen results in the sudden appearance of a foreign protein within the normal cells of an immunologically mature and healthy individual. At least in laboratory animals, this form of antigen presentation provokes an energetic and efficient immune response.

With one exception, the technology has not reached the stage of clinical trials, but experts are confident this approach will revolutionize vaccination. Mologen, founded the same month it went public, aims to become a major player in this field.

Via its subsidiaries, Mologen GmbH and Soft Gene GmbH, the Berlin-based holding owns a set of proprietary methods for the safe and large-scale production of DNA vaccines developed in the laboratory of Wittig at the Freie Universitãt Berlin (FUB).

Returning from a Heisenberg-fellowship at the Massachusetts Institute of Technology, in Cambridge, in 1989, Wittig founded a molecular biology and bioinformatics chair at FUB and helped to launch the first clinical studies of gene therapy in Germany.

Gene Therapies Cause Adverse Immune Reactions

“Studying gene therapy strategies against tumors then,“ he told BioWorld International, “we realized that conventional vectors and gene transfer methods would not be suitable for broad therapeutic applications and even less for prophylactic means.“

The composition of the vectors causes several problems. Apart from the gene proper, viruses or plasmids consist of at least one, though in most cases two to five additional genes, which are necessary for the propagation or selection procedures. These gene constructions tend to be leaky, so that a small amount, or fragments, of the additional genes are expressed too.

“These byproducts are strong antigens,“ Wittig said, “sometimes even stronger than those you want to generate originally, so that you run into immunological problems.“

For safety reasons neither modified viruses nor plasmids should be spread via vaccination in the general population, he added.

So Wittig and his team explored the prospects of vaccination using naked DNA. They invented techniques to design and to transfer genetic structures that consist of the complementary DNA (cDNA) sequence and the necessary flanking regulatory sequences only. “We call that a minimalistic DNA construction“, Wittig said.

“Meanwhile, we have not only proven that our vectors are very stable and efficient, but that we can produce them relatively cheap in bulk quantity and under GMP conditions too.“ GMP stands for good manufacturing practices required by regulatory authorities.

Mologen, founded with capital of an unnamed private investor and aided by a DM2.5 million initial public offering in May, will start selling its technology to the research market soon. Production of cytokines will be one of the initial applications.

“Currently, we are negotiating with several large suppliers of plasmids and viral vectors,“ Wittig said. “And we are very confident [that we will] come to a licensing agreement soon. Our vectors are more than 100-fold more efficient in expression than existing products and they cannot be copied because they lack any propagating elements. So we have an in-built copy-protection, and we think this is a very interesting feature.“

Animal Applications May Provide Quick Revenues

In a second step, Mologen is targeting the pet market. “Domestic animal medicine is a big market for vaccines and approvals are easy to get as these animals do not enter the food chain,“ Wittig explained. The company is developing a DNA vaccine against an infectious peritonitis in cats.

Then farm animals will follow. Certain infections of the respiratory tracts cause a yearly death toll of 10 to 15percent of the cattle population; farmers try to cope with the infections by adding lots of antibiotics to the fodder, a measure worrying consumers and medical experts. A vaccination could be a cheap and healthy solution. The company already has hired an expert in regulatory and approval matters.

“These are really big markets,“ Wittig said. “If we are able to cover only 3 to 5 percent of it, we have exceeded the figures of our business plan by far.“

The big aim, however, will be the development of vaccines against human disease.

“We are not planning for the dramatic infections“, Wittig added. “We want to develop a vaccine against influenza and rhinoviruses.“

Both viruses have a high mutation rate. Today, designing an influenza virus vaccine is a tedious race against time, and hence up to 30 percent of the virus population usually escapes vaccination. For the same reason, there is no vaccine against rhinoviruses causing the common cold at all.

To overcome this problem, Mologen will rely on the experience of Soft Gene GmbH, of Berlin, a biological software company founded by Wittig in 1989 and now a subsidiary of the holding company.

Soft Gene is well known for its MacMolly program, which reaches a 15 percent share of the world market in DNA and protein sequence analysis software. Now a new software, BioConstructor, will help design plasmids and genetic vaccines.

“Influenza and rhinoviruses tend to mutate in specific regions and follow a certain pattern,“ Wittig explained. “Our new software is able to analyze known variations and to calculate possible alterations. So we are able to anticipate mutations which will occur most probably. And as our vaccination method allows the shooting of a nearly unlimited amount of different gene constructions and is able to transfer more than 10,000 molecules per cell, we could transfer as many variations as necessary.“

The vaccine will be shot in the arm by means of a gene gun.

Mologen expects to reach break even point by the year 2000. The company employs a staff of 10 and just took over for a term of three years Wittig's university department, consisting of several laboratories, equipment and a staff of 30.

Currently, Mologen is negotiating cross licensing with PowderJect Pharmaceuticals plc, of Oxford, U.K., which holds the key patent for all needle-less injection of drugs by the acceleration of fine particles, including gene guns. *

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