Experience related to the research and development of antibody-based therapeutics is unusually broad for a management consultancy group in that it started well before the discovery of monoclonal antibodies (MAbs) by César Milstein of the UK Medical Research Council in 1975. It includes not only the MAbs and their optimisation for human use but also the mammalian cell production technologies that the innovator companies have used to produce the products. We also keep up to date with the field, through ownership and control of a MABs platform discovery company, namely MSM Protein Technologies.
The earliest UAG experience comes from partner Dr. Raphael Levey, who, in the 1970s, helped discover and develop the by today’s standards relatively non-specific antiserum against lymphocytes. It is used to suppress rejection of grafts or organ transplants and the globulin fraction of the heterologous serum is usually used in conjunction with other immunosuppressive agents (drugs or chemicals). Thymoglobulin® (Anti-thymocyte Globulin; the current product, is manufactured by Genzyme in Boston, MA) is a purified, pasteurized, gamma immune globulin, obtained by immunization of rabbits with human thymocytes. This immunosuppressive product contains cytotoxic antibodies directed against antigens expressed on human T-lymphocytes. Muromonab-CD3 (trade name Orthoclone OKT3, marketed by Janssen-Cilag) is modern more specific monoclonal derivative from this era of research. It is of some historical importance as the first ever monoclonal antibody to be approved for clinical use in humans.
The next field of experience for UAG comes from the start of the commercial recombinant DNA era, the1980s, within the UK biotech company Celltech. UAG partner Dr. Chris Hentschel was head of its molecular genetics department. The first recombinant DNA proteins were manufactured using microbial, usually E. coli, fermentation. Recombinant proteins usually congeal in these systems as ‘inclusion bodies,’ essentially packages of highly denatured and unmodified peptide chains. This approach worked well for small proteins/peptides like insulin but much less well for complex multi-chain proteins like monoclonal antibodies. Under Chris’ leadership, Celltech developed mammalian expression systems based on highly inducible gene promoters and bovine papilloma virus vectors. The latter were patented, widely licenced, refined and extensively used by the biotech industry in the following decades, particularly for the manufacture of therapeutic antibody products. The most used embodiment is known as the GS expression system and is marketed in conjunction with optimized fermentation and cell line development by Lonza. Note that UAG partners do not represent themselves as experts on the related engineering or fermenter side of this complex technology but do have experts amongst their affiliates.
Dr. Hentschel moved to lead the UK’s Medical Research Council Collaborative Centre in 1987, a job that he did for a decade. The role of this organisation is described in some detail in the UAG web site. Essentially, it was pioneering public-private partnership in life sciences innovation. Although its remit was very wide ranging, one of its main focus areas under Chris’ leadership was monoclonal antibodies and specifically the discovery of ones that not only acted on qualified target antigens (therapeutic targets) but did so with optimal efficacy and safety. This work was done with private sector partner companies with MRC licencing out products and/or enabling technologies. Antibody humanization, also known as CDR-grafting, was one such technology and was first invented at the Medical Research Council (MRC) Laboratory of Molecular Biology in the UK by Dr. Greg Winter and patented by the MRC in the late 1980s. Today many of the inventors of marketed blockbusters mAbs stemming from this period worked for Chris and are today UAG affiliates (example products include Tysabri®, Actemra® and Entyvio®). More recent therapeutic mAbs use so called phage libraries as sources. This powerful approach was also invented by the MRC in the 1980s. Variants of the latter technology comprise the unique MSM platform. Note again that while UAG partners do not represent themselves as experts on every detail of this complex technology, such experts are well represented amongst our affiliates. In addition, we have such experts reporting to us from MSM.
In 1995, Davis Farmer, Jerry Balter and Dr. Hentschel formed Obesys Ltd., a company that was focused on antibodies to treat obesity. The concept proved ahead of its time for human use but has potential uses in animal husbandry.
The Ulysses Group (predecessor company to UAG) was an advisor to Cambridge Antibody Technologies (“CAT”), the MRC Collaborative Centre, Imclone Pharmaceuticals and others. It was focused on helping these groups in-license and/or out-license various anti-body products and technologies. In the case of CAT, many of its most important collaborations were the product of work undertaken by Ulysses.
Jerry Balter was an investment banking advisor to NeoRX, one of the first publicly traded antibody companies, from 1987-1990.
Dr. Hentschel moved to lead the R&D of the US biotechnology company Centocor in 1987, a job that he did until it was purchased in 1999 by J&J (it is now Janssen Biologics is headquartered in Leiden, the Netherlands.) Its innovative products mainly focused on mAbs targeting cardiovascular and immunological disorders and it already had four marketed products by 1999. The main reason Centocor was purchased for $5 billion, however, was not its product sales (just shy of $1 billion in 1999) but because of the value of its R&D pipeline, which included phase II data for its anti-TNF antibody REMICADE® (infliximab). Remicade is a blockbuster considered one of the most lucrative potential targets for the emerging biosimilars industry - see below .