30 Years of Biotherapeutics Development-What Have We Learned?

Since the birth of biotechnology, hundreds of biotherapeutics have been developed and approved by the US Food and Drug Administration (FDA) for human use. These novel medicines not only bring significant benefit to patients but also represent precision tools to interrogate human disease biology. Accordingly, much has been learned from the successes and failures of hundreds of high-quality clinical trials. In this review, we discuss general and broadly applicable themes that have emerged from this collective experience. We base our discussion on insights gained from exploring some of the most important target classes, including interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), IL-6, IL-12/23, IL-17, IL-4/13, IL-5, immunoglobulin E (IgE), integrins and B cells. We also describe current challenges and speculate about how emerging technological capabilities may enable the discovery and development of the next generation of biotherapeutics.

A Brief History of Psoriasis Management in Canada.

Psoriasis is a chronic, inflammatory disease with a varying degree of clinical presentations. Managing psoriasis has always been arduous due to its chronicity and its propensity to relapse. Prior to the development of targeted biologic therapies, there were few effective treatments for psoriasis. Ancient psoriasis therapies included pinetar, plant extracts, psychotherapy, arsenic, and ammoniated mercury. In the 19th century, chrysarobin was developed. Then, in the early half of the 20th century, anthralin and coal tar were in widespread use. In the latter half of the 20th century, treatments were limited to topical first-line therapies, systemic drugs, and phototherapy. However, as the treatment of psoriasis has undergone a revolutionary change with the development of novel biologic therapies, patients with moderate to severe psoriasis have been able to avail therapies with high efficacy and durability along with an acceptable safety profile. This article is a brief historical review of the management of psoriasis prior to the inception of biologics and with the development of novel biologic therapies.

Development of Phage Lysins as Novel Therapeutics: A Historical Perspective.

Bacteriophage lysins and related bacteriolytic enzymes are now considered among the top antibiotic alternatives for solving the mounting resistance problem. Over the past 17 years, lysins have been widely developed against Gram-positive and recently Gram-negative pathogens, and successfully tested in a variety of animal models to demonstrate their efficacy. A lysin (CF-301) directed to methicillin resistant Staphylococcus aureus (MRSA) has effectively completed phase 1 human clinical trials, showing safety in this novel therapeutic class. To validate efficacy, CF-301 is currently the first lysin to enter phase 2 human trials to treat hospitalized patients with MRSA bacteremia or endocarditis. If successful, it could be the defining moment leading to the acceptance of lysins as an alternative to small molecule antibiotics. This article is a detailed account of events leading to the first therapeutic use and ultimate development of phage-encoded lysins as novel anti-infectives.

Access to bacteriophage therapy: discouraging experiences from the human cell and tissue legal framework.

Cultures of human epithelial cells (keratinocytes) are used as an additional surgical tool to treat critically burnt patients. Initially, the production environment of keratinocyte grafts was regulated exclusively by national regulations. In 2004, the European Tissues and Cells Directive 2004/23/EC (transposed into Belgian Law) imposed requirements that resulted in increased production costs and no significant increase in quality and/or safety. In 2007, Europe published Regulation (EC) No. 1394/2007 on Advanced Therapy Medicinal Products. Overnight, cultured keratinocytes became (arguably) 'Advanced' Therapy Medicinal Products to be produced as human medicinal products. The practical impact of these amendments was (and still is) considerable. A similar development appears imminent in bacteriophage therapy. Bacteriophages are bacterial viruses that can be used for tackling the problem of bacterial resistance development to antibiotics. Therapeutic natural bacteriophages have been in clinical use for almost 100 years. Regulators today are framing the (re-)introduction of (natural) bacteriophage therapy into 'modern western' medicine as biological medicinal products, also subject to stringent regulatory medicinal products requirements. In this paper, we look back on a century of bacteriophage therapy to make the case that therapeutic natural bacteriophages should not be classified under the medicinal product regulatory frames as they exist today. It is our call to authorities to not repeat the mistake of the past.

A century of the phage: past, present and future.

Viruses that infect bacteria (bacteriophages; also known as phages) were discovered 100 years ago. Since then, phage research has transformed fundamental and translational biosciences. For example, phages were crucial in establishing the central dogma of molecular biology - information is sequentially passed from DNA to RNA to proteins - and they have been shown to have major roles in ecosystems, and help drive bacterial evolution and virulence. Furthermore, phage research has provided many techniques and reagents that underpin modern biology - from sequencing and genome engineering to the recent discovery and exploitation of CRISPR-Cas phage resistance systems. In this Timeline, we discuss a century of phage research and its impact on basic and applied biology.

Bacteriophage therapy against Enterobacteriaceae.

The Enterobacteriaceae are a class of gram-negative facultative anaerobic rods, which can cause a variety of diseases, such as bacteremia, septic arthritis, endocarditis, osteomyelitis, lower respiratory tract infections, skin and soft-tissue infections, urinary tract infections, intra-abdominal infections and ophthalmic infections, in humans, poultry, animals and fish. Disease caused by Enterobacteriaceae cause the deaths of millions of people every year, resulting in enormous economic loss. Drug treatment is a useful and efficient way to control Enterobacteriaceae infections. However, with the abuse of antibiotics, drug resistance has been found in growing number of Enterobacteriaceae infections and, as such, there is an urgent need to find new methods of control. Bacteriophage therapy is an efficient alternative to antibiotics as it employs a different antibacterial mechanism. This paper summarizes the history of bacteriophage therapy, its bacterial lytic mechanisms, and the studies that have focused on Enterobacteriaceae and bacteriophage therapy.

Phage therapy--history from Twort and d'Herelle through Soviet experience to current approaches.

Felix d'Herelle proposed the use of bacteriophages for the therapy of human and animal bacterial infections at the beginning of the 20th century. This approach, however, was not widely accepted in the West. After the emergence of antibiotics in 1940s, phage research was diverted to a more fundamental level. At the same time, phage therapy was widely practiced in the Soviet Union due to collaboration of Felix d'Herelle with his Georgian colleagues. The majority of the articles dedicated to this subject are from the 1930s and 1940s. The old Soviet literature indicates that phage therapy was used extensively to treat a wide range of bacterial infections in the areas of dermatology (Beridze, 1938), ophthalmology (Rodigina, 1938), urology (Tsulukidze, 1938), stomatology (Ruchko and Tretyak, 1936), pediatrics (Alexandrova et al., 1935; Lurie, 1938), otolaryngology (Ermolieva, 1939), and surgery (Tsulukidze, 1940, 1941). These articles were published in Russian and thus were not readily available to Western scientists. The Western skepticism toward phage therapy itself was again followed by renewed interest and reappraisal, mainly due to the emergence of drug-resistant bacteria. Often the experiments described in the old Soviet articles were not designed properly: the use of placebos and the coding of preparations were absent from most of the studies, number of patients in the experimental and control groups was unequal or missing, sometimes no control groups were used at all, or patients treated previously unsuccessfully with antibiotics were employed as an experimental group and as control. The results obtained and the efficiency of phage prophylaxis were estimated by comparing with results obtained in previous years. In most publications, phage titers and descriptions of methods used for evaluation of the results are not specified. Nevertheless, past experience indicates some effectiveness of phage therapy and prophylaxis. Therefore, these clinical results should not be neglected when designing any future studies.

Las terapias biológicas psiquiátricas en Chile / Psychiatric biological therapies in Chile

Hasta fines del siglo XIX las posibilidades de mejoría de las enfermedades mentales eran limitadas y poco alentadoras. El nihilismo terapéutico infiltraba tanto a los profesionales como a la población. La aparición de las terapias biológicas en la primera mitad del siglo XX junto con modificar las condiciones intrahospitalarias de los enfermos y personal transforma el pronóstico de algunas patología y la calidad de vida de los enfermos que pueden egresar del Manicomio. Mientras la Malarioterapia y la Penicilina terminan con la Neurolúes, el Coma Insulínico y el Electroschock, modifican dramáticamente el cuadro de estado de muchos pacientes esquizofrénicos y maníacos depresivos,si bien el pronóstico no varía. Por fin viene a añadir nuevas realizaciones la introducción de los psicofármacos en la segunda mitad del siglo XX.

Until the end of the 19th Century the possibilities of betterment/melioration with mental diseases were limited and not encouraging. Therapeutic nihilism infiltrated professionals and population. Development of biological therapies in the first half of the 20th Century apart from modifying the hospitaler conditions of patients and attending personnel caused major changes in the prognosis/prediction of some pathologies and the life quality of patients, who could leave the Madhouse. While Malariotherapy and Penicilin ended with Neurolues, the insulinic coma and the electroshock drastically modified the state picture of many schizophrenic and maniatic-depressive patients, although the prognosis/prediction did not vary. Finally, introduction of phychotropic drugs in the second half of the 20th Century allowed amelioration of. Performances.

Los tratamientos biológicos en el manicomio nacional chileno: 1894-1959 / Biological treatment in the Chilean National Asylum: 1894-1959

Hasta finales del siglo XIX, no obstante el espíritu de los alienistas las posiblidades de mejoría eran limitadas y poco alentadoras. El nihilismo terapéutico infiltraba tanto a los medios profesionales como a la población. La aparición de las terapias biológicas en la primera mitad del siglo XX junto con modificar las condiciones intrahospitalarias de los enfermos y personal transforma rotundamente el pronóstico de algunas patologías y la calidad de vida de los enfermos que pueden egresar del manicomio. Mientras la malarioterapia y la penicilina terminan con la neurolúes, el coma insulínico y el electroschock modifican dramáticamente el cuadro de estado de los pacientes con psicosis esquizofrénicas y maníaco-depresivas, si bien el pronóstico no varía. Por fin viene a añadir nuevas ilusiones la introducción de los psicofármacos que se concretaran en la segunda mitad del mismo siglo. (AU)

Um tratamento de choque: a aplicação da malarioterapia no Hospital Juquery (1925-1940) / A shock treatment: the application of malarioterapia in Juquery's Hospital (1925-1940)

O presente trabalho analisa o processo de consolidação da Malarioterapia como uma terapêutica específica e legitimada, conferindo maior credibilidade à Psiquiatria que, no período em questão, buscava a sua consolidação entre práticas médicas. Para tanto, busca traçar um quadro geral sobre a Psiquiatria paulista e sobre as intervenções terapêuticas que eram aplicadas nos pacientes do Hospital Juquery, para, desta forma, elucidar as razões que levaram os psiquiatras, sobretudo o diretor daquele estabelecimento, Dr. A.C. Pacheco e Silva, a optar pelo uso deste método, incipiente até então. Assim, demonstra que o modelo de intervenção inaugurado pela Malarioterapia, ou seja, a do 'choque humoral', se tornou a base para as terapias desenvolvidas posteriormente, conhecidas como 'terapias biológicas', como a convulsoterapia e os comas induzidos, por exemplo. (AU)

Considerations for determining if a natural product is an effective wound-healing agent.

Many research groups are examining natural products for their vulnerary activity. On the basis of the countless years of folklore and clinical observations, these preparations are being fractionated and applied to wounds in a variety of animal species. Despite this work, the number of agents that have documented ability to enhance wound healing is minimal. This article provides a brief review of some of the major historical milestones in wound care and provides a framework for studying plant products so as to achieve statistically significant results in biologically important models of healing. Only with the use of reference standards, data from appropriate animal models, and human trials can we begin to mine the great potential of these natural products.

Biotherapies of chronic diseases in the inter-war period: from Witte's peptone to Penicillium extract.

In the inter-war period physicians elaborated numerous 'biotherapies' grounded in the complex interactions between physiology, bacteriology and immunology. The elaboration of these non-specific biological treatments was stimulated by the theory of generalized anaphylaxis that linked the violent reaction to a foreign protein to a broad array of chronic diseases, from asthma and urticaria to rheumatism or chronic colitis. Such diseases were perceived as the result of an 'abnormal reactivity' to a sensitisation of tissues and organs by bacteria and by foreign proteins, a view that provided an effective bridge between new concepts derived from bacteriology and immunology and the long-standing pathological tradition. Accordingly, physicians attempted to treat these conditions through specific desensitisation and non-specific biological therapies: peptone treatment, protein therapy, haemotherapy, 'antivirus' or 'opotherapy'. Therapies that attempted to neutralise the harmful effects of chronic infections through 'desensitisation' were not seen as marginal medical practices, but were promoted by leading advocates of the 'Pasteurian sciences', such as Richet, Widal, Vallery-Radot, Wright and Fleming. They also led to development of new products by the pharmaceutical industry.

The 'experimental stable' of the BCG vaccine: safety, efficacy, proof, and standards, 1921-1933.

The anti-tuberculosis BCG (Bacille Calmette-Guérin) vaccine was conceived and developed between 1905 and 1921 at Pasteur Institutes in France. Between 1921 and A. Calmette's death in 1933, the vaccine went through a first period of national and international production and distribution for its use in humans. In France these activities were exclusively carried out by Calmette and his collaborators at the Pasteur Institute in Paris. Initially improvised production in a small room in the cellar gave way in 1931 to the construction of the spacious and magnificent 'New laboratories for research on tuberculosis and the preparation of the BCG' within the premises of the Pasteur Institute. Presentation and image-building of the vaccine in France insisted on the fact that the BCG was not a commercial specialty but distributed free of charge. The technical monopoly of its production nevertheless lay with the Paris Pasteur Institute and standardization of scientific proof of safety, efficacy and stability was dominated by that Institute in France. In contrast, the international production and distribution of the vaccine was entrusted and transferred, free of charge, to trustworthy laboratories outside France. Multiplication of producers and users led to an increased need for standardization. For this process the analysis distinguishes between the standardization of scientific proof concerning safety, efficacy and stability of the vaccine and standardization of its medical uses. Whereas standardization was rather successful in the inter-war period in France, the international efforts remained rather unsuccessful. Only after world war II under Scandinavian leadership and in the context of mass vaccination programs supported by the WHO and UNICEF was the international standardization effectively implemented and succeeded at least to some extend.

Appropriation and commercialization of the Pasteur anthrax vaccine.

Whereas Pasteur patented the biotechnological processes that he invented between 1857 and 1873 in the agro-food domain, he did not file any patents on the artificial vaccine preparation processes that he subsequently developed. This absence of patents can probably be explained by the 1844 patent law in France that established the non-patentable status of pharmaceutical preparations and remedies, including those for use in veterinary medicine. Despite the absence of patents, the commercial exploitation of the anthrax vaccine in the 1880s and 1890s led to a technical and commercial monopoly by Pasteur's laboratory as well as the founding of a commercial company to diffuse the vaccine abroad. Pasteur repeatedly refused to transfer his know-how and anthrax vaccine production methods to foreign laboratories, on the grounds that he wished to control the quality of the vaccines produced. Indeed, it was relatively difficult to transfer a method that was not yet perfectly stabilized in the early 1880s. Pasteur also wanted to maintain the monopoly of his commercial company and to increase the profits from vaccine sales so that the Institut Pasteur could be financially independent. The 'Pasteur anthrax vaccine' operating licences are described and analysed in detail in this article.