Biological therapy: chronicling 15 years of progress

Keywords:

• biological therapy
• biologics
• immunotherapy
• osteoporosis

Since its launch in 2001, Expert Opinion of Biological Therapy (EOBT) has covered many remarkable advances in the field of biological therapy. The occasion of its 15th year of publication is an opportune time to review progress in this area and consider the inevitable challenges. The historical origins of biological therapy can be traced to ancient China, Africa, and Turkey, perhaps as early as 1000 BC, when smallpox inoculation (‘variolation’) was used to provide immunity to that disease. This early method of preventing smallpox presumably followed the observation that individuals who survived smallpox seemed to be resistant to further infections. This knowledge was also applied in the selection of survivors to nurse those with active infections [1]. There was justifiable concern that variolation might have adverse effects, including transmission of disseminated smallpox or other bloodborne diseases, such as syphilis, but at least some individuals must have felt that the benefits outweighed the risks. Variolation was probably first introduced to Europeans by travelers from Istanbul in the early 1700s [2].

Edward Jenner applied scientific methods for investigation of smallpox prevention and is credited by some as being the ‘father’ of immunology. Knowing that dairymaids with cowpox infections were subsequently protected from smallpox, he conducted a small (n = 1) ‘proof of concept’ study in 1796 by inoculating an 8-year boy with material from cowpox lesions. When the boy was exposed to smallpox several months later, no disease developed. Although the Royal Society rejected his short communication describing the experiment, he persisted with additional experiments of what he called ‘vaccination.’ More cases were reported in 1798 in a privately published booklet. Within several years, the concept of vaccination with cowpox material achieved acceptance in the medical communities of Europe and America. The work of Jenner was later refined by others, including Louis Pasteur, who in 1885 developed the first rabies vaccine using artificially attenuated viruses [3]. The principles established by Pasteur were subsequently used to develop vaccines with killed or live-attenuated microorganisms for diseases such as plague and pertussis. Other vaccines followed, providing great public health benefits, particularly in the prevention of serious and sometimes fatal childhood diseases. It was a great accomplishment for the legacy of Edward Jenner when, in 1980, the World Health Organization declared the worldwide eradication of smallpox [4].

With improvements in understanding the genetic and molecular origins of a broad array of disease states, biological therapy (also known as biologic therapy, biologics, biologicals, and biopharmaceuticals) has become an area of vast scientific interest, providing a fertile milieu for establishing a journal such as EOBT, exclusively devoted to communicating advances and controversies in this area. Biological products have come to mean much more than vaccines, now including viruses, therapeutic serums, toxins, antitoxins, blood, blood components and derivatives, allergenic products, hormones, monoclonal antibodies, nanotherapies, cellular and gene therapies for the prevention or treatment of diseases and conditions in humans [5].

In my own small area of interest, osteoporosis, the modern age of treatment began in 1995 with the US FDA approval of the bisphosphonate medication alendronate, a synthetic analog of pyrophosphate, and intranasal salmon calcitonin, a synthetic polypeptide of 32 amino acids in the same linear sequence as calcitonin of salmon origin. It was recognized at that time that postmenopausal osteoporosis is caused by acceleration and imbalance of bone remodeling, with osteoclastic bone resorption overwhelming the ability of osteoblasts to form new bone. The eventual result is bone loss and weakening of bone, leading to increased risk of potentially devastating fractures. Alendronate, salmon calcitonin, and almost all medications that have subsequently been approved for treating osteoporosis (e.g., raloxifene, risedronate, ibandronate, zoledronic acid) modulate the bone remodeling process by primarily inhibiting the formation, activity, and/or survival of osteoclasts. These agents are typically classified as antiresorptives or anti-remodeling drugs. Osteoporosis treatment took a major leap forward in 2002, the year after the launch of this journal, when teriparatide, the first osteoanabolic agent for osteoporosis, was approved. This is a recombinant human (rh) molecule with an amino acid sequence identical to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone (PTH). It works by primarily stimulating bone formation, at least for a limited period of time. About 4 years later, rhPTH(1 – 84), the full length PTH molecule, was approved in Europe, but not the US, for the treatment of osteoporosis. In 2010, the first and so far only monoclonal antibody for osteoporosis, denosumab, was approved. This is a fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor-κB ligand, a cytokine member of the tumor necrosis factor family that is the principal mediator of osteoclastic bone resorption. A limitation of all of these agents is the coupling of bone resorption and formation, whereby increases or decreases of one aspect of bone remodeling inevitably leads to a move in the same direction by the other, although not necessarily of the same magnitude.

Investigational compounds in advanced stages of clinical development include odanacatib, a cathepsin K inhibitor; abaloparatide, a novel synthetic peptide analog of PTH related protein with potent anabolic activity; and another anabolic agent, romosozumab, a humanized monoclonal antibody to sclerostin [6]. Mechanistically, some of these investigational agents appear to be breaking new ground by dissociating the coupling of bone resorption and formation, at least transiently, in ways that had not previously been imagined [7]. This has led to suggestions of different ways of classifying osteoporosis treatments, such as ‘predominantly antiresorptive,’ ‘predominately bone forming,’ and ‘others’ [8]. Novel ways of combining approved drugs, with the potential for added clinical benefit, are also being explored [9]. We are now perhaps approaching the ‘holy grail’ of osteoporosis therapy, where bone resorption is decreased while formation is increased [10]. With newer treatments for osteoporosis come opportunities for improvement in the balance of benefits and risks of therapy and better reducing the global burden of osteoporotic fractures.

In other disease states, particularly cancers and chronic inflammatory diseases, great advances have also been achieved. The biological approaches to cancer therapy are many and varied. Bacillus Calmette–Guérin was the first biological therapy to be approved by the FDA. When inserted directly into the bladder, it stimulates an immune response against bladder cancer cells. Monoclonal antibodies can stimulate an immune response that destroys cancer cells such as non-Hodgkin’s lymphoma cells and B cell chronic lymphocytic leukemia cells. Other monoclonal antibodies interfere with the action of proteins that are necessary for tumor growth. Vaccines may stimulate an immune response to tumor cells. Oncolytic virus therapy that might directly destroy cancer cells is being investigated. The most downloaded EOBT article to date [11] is a review of progress in the investigation of antibody–drug conjugates, an exciting emerging strategy for cancer treatment that addresses the need to deliver a highly cytotoxic drug to the desired point of action. Biological agents targeted to pro-inflammatory cytokines or molecules involved in the activation, differentiation, and maturation of B cells have revolutionized the treatment of rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and systemic lupus erythematosus.

With the human genome project reaching its goal of mapping the full human genome in 2003, the development of gene therapy was propelled from a conceptual phase into an arena of active clinical investigation, with emerging therapeutic applications and substantial investment by the pharmaceutical industry. Pharmacogenomics, the study of the role of genetics in drug response, may provide the ultimate in personalized medicine by allowing drug therapy to be selected according to the genetic makeup of individual patients. The rising tide of gene therapy and other technologies with potential clinical applications, such as stem cell therapy, nanotherapy and bioengineering of organs, has been accompanied by controversies regarding ethics, public interest, and autonomy, all of which should be aired and discussed in the public arena [12].

With so many advances in the study of biological therapies, there is a need for rapid communication among researchers, clinicians, policy makers, bio-ethicists, and others to stay current. This journal represents an important platform for keeping stakeholders in this vast and expanding field well-informed. It was a pioneer in the presentation of translational medicine for biological therapy, from bench to bedside. When first launched in 2001, EOBT was published every 2 months, advancing to 8 issues per year in 2002 and becoming monthly in 2004. The impact factor, a measure of the average number of citations of recent journal articles, has risen from 2.014 in 2002 to 3.653 in 2013, suggesting a rising interest in viewing published articles and greater attractiveness for authors wishing to have a strong platform for presenting their data. The number of citations of EOBT articles has risen from 179 in 2002 to 3535 in 2013. Over the past 5 years, the rejection rate for submitted manuscripts has almost doubled to about 25%, consistent with greater selectivity and higher quality of publications. In the first issue of EOBT in 2001, J Desmond Fitzgerald presciently wrote in the Foreword that “biological therapy has only come of age in the last 20 years but now is poised to make a major impact on therapeutics” [13]. This was the rationale for creating this journal. I am pleased to report that this assessment was fully correct. There have indeed been major advances in biological therapies since the journal was launched, and EOBT can be justly proud to have played and continuing to play such an important role.

Declaration of interest

In the past year, EM Lewiecki has received research grant support from Amgen, Eli Lilly and Merck. He has received consulting fees from Amgen, Eli Lilly, Merck, Radius Health, AgNovos Healthcare, Theranova, Alexion, NPS and AbbVie. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.