Milstein and Kohler: Monoclonal Antibodies.

César Milstein (1927-2002) was born in Bahía Blanca, Argentina. He was a chemistry student educated at the University of Buenos Aires, obtaining his degree in biochemistry in 1952. He completed his PhD in 1957 at the same University and also received the British Council research scholarship to the biochemistry department at the University of Cambridge. Under the direction of the distinguished biochemist Frederick Sanger, Milstein completed a second dissertation, a study of the enzyme, earning his PhD in 1960 and joining the scientific staff of the Medical Research Council (MRC). He then worked at the National Institute of Microbiology in Buenos Aires from 1961 to 1963 until political turmoil led him to resign and return to Cambridge to work with Sanger at the newly formed MRC Laboratory of Molecular Biology. Now, he shifted his focus from enzymes to antibodies. By the early 1970s, he was an internationally recognized leader in the field and was able to attract talented, young researchers, including Georges Köhler, to the MRC. In 1983, Milstein was named head of the Protein and Nucleic Acid Chemistry Division of the MRC, a position he held until his retirement in 1995. He died in Cambridge, England, in 2002 at the age of 74.

A tale of the monoclonal anti-CD20 antibodies, in tribute to prof. Waclaw Szybalski (1921-2020).

Technical advances that lead to the era of targeted therapeutics demanded several milestones that were reached in the second half of the previous century. Professor Waclaw Szybalski was the first one to perform a stable gene transfer in eukaryotic cells. To do so, he used his own designed system consisting of HPRT-deficient cells and HAT selective medium. Moreover, the first-ever hybridoma cells were also constructed by Waclaw Szybalski's team. These spectacular achievements made him not only a forerunner of gene therapy, but also became a foundation for immunotherapy, as hybridoma and their selection by the HPRT-HAT system turned into a crucial technical step during production of monoclonal antibodies (mAbs). Herein, we present a story of anti-CD20 mAbs, one of the most successful lines of anticancer drugs. When looking back into history, the prototypic mAb rituximab was considered the biggest step forward in the therapy of B-cell malignancies. Nowadays, the second and third generations of anti-CD20 mAbs are approved in clinical use and numerous breakthrough studies on immune effector mechanisms were conducted with the aforementioned immunotherapeutics as a model.

The history of the antibody as a tool.

Antibodies are essential tools in modern science and medicine, however the history leading to the use of antibodies as tools has not been well-described. The objective of this paper is to analyze the history of immunology from smallpox inoculation to the production of monoclonal antibodies, and to identify turning points in immunological theory leading to the emergence of antibody-tools. In the early 1700's, Western medicine adopted smallpox inoculation from Turkey, along with the idea of acquired immunity. The Germ Theory of disease had to replace spontaneous generation and miasma theory in the 1880's, however, before inoculation could successfully be applied to other diseases. Inquiry into acquired immunity led to the idea of the "antibody" in the 1890's, and the use of antiserum to identify bacteria. Immunostaining was invented in 1942 by repurposing antibody-dye conjugates originally intended as antibiotics. Monoclonal antibody-producing hybridomas were similarly invented in 1975 by repurposing techniques from virology and genetics.

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development.

The tutorial introduces the readers to the fundamentals of antibody pharmacokinetics (PK) in the context of drug development. Topics covered include an overview of antibody development, PK characteristics, and the application of antibody PK/pharmacodynamics (PD) in research and development decision-making. We also discuss the general considerations for planning a nonclinical PK program and describe the types of PK studies that should be performed during early development of monoclonal antibodies.

[Humanization of Murine Monoclonal anti-hTNF Antibody: The F10 Story].

Tumor necrosis factor (TNF) is a proinflammatory cytokine implicated in pathogenesis of multiple autoimmune and inflammatory diseases. Anti-TNF therapy has revolutionized the therapeutic paradigms of autoimmune diseases and became one of the most successful examples of the clinical use of monoclonal antibodies. Currently, anti-TNF therapy is used by millions of patients worldwide. At the moment, fully human anti-TNF antibody Adalimumab is the best-selling anti-cytokine drug in the world. Here, we present a story about a highly potent anti-TNF monoclonal antibody initially characterized more than 20 years ago and further developed into chimeric and humanized versions. We present comparative analysis of this antibody with Infliximab and Adalimumab.

From the discovery of monoclonal antibodies to their therapeutic application: an historical reappraisal.

Vertebrate make billions of different antibodies, each with a binding site that recognizes a specific region of a macromolecule. The hybridoma technique allows monoclonal antibodies, highly specific antibodies produced in the laboratory by a variety of methods. In the last 35 years since the first process for creating monoclonal antibodies was introduced, their application have improved the growing biotechnology industry, but the most important application concerns the therapy of human malignancies.

Selective immunotoxic lesions of basal forebrain cholinergic neurons: twenty years of research and new directions.

The advent of the selective cholinergic toxin, 192 IgG-saporin, dramatically shaped subsequent research on the role of the basal forebrain in learning and memory. In particular, several articles (including the authors' 1995 Behavioral Neuroscience paper; M. G. Baxter, D. J. Bucci, L. K., Gorman, R. G. Wiley, & M. Gallagher, 1995) revealed that selective removal of basal forebrain cholinergic neurons had surprisingly little effect on spatial learning and memory. Here, as part of the series commemorating the 30th anniversary of Behavioral Neuroscience, we describe how our earlier findings prompted a reconsideration of the cholinergic contribution to cognitive function and also led to several new research directions, including renewed interest in basal forebrain GABA-ergic neurons and cholinergic contributions to neurocognitive development. The authors also describe how the successful use of 192 IgG-saporin led to the development and popularity of a wide range of selective new neurotoxic agents. Finally, they consider the utility of the permanent lesion approach in the wake of new transgenic and optogenetic methods.

Selective immunotoxic lesions of basal forebrain cholinergic cells: effects on learning and memory in rats.

Male Long-Evans rats were given injections of either 192 IgG-saporin, an apparently selective toxin for basal forebrain cholinergic neurons (LES), or vehicle (CON) into either the medial septum and vertical limb of the diagonal band (MS/VDB) or bilaterally into the nucleus basalis magnocellularis and substantia innominata (nBM/SI). Place discrimination in the Morris water maze assessed spatial learning, and a trial-unique matching-to-place task in the water maze assessed memory for place information over varying delays. MS/VDB-LES and nBM/SI-LES rats were not impaired relative to CON rats in acquisition of the place discrimination, but were mildly impaired relative to CON rats in performance of the memory task even at the shortest delay, suggesting a nonmnemonic deficit. These results contrast with effects of less selective lesions, which have been taken to support a role for basal forebrain cholinergic neurons in learning and memory.

Is tumor necrosis factor-α friend or foe for chronic heart failure?

Although detrimental effects of tumor necrosis factor-α (TNF-α) have been reported in failing myocardium, clinical trials using TNF-α antagonists did not show the benefit of TNF-α inhibition in patients with chronic heart failure (CHF). The double-edged effects of TNF-α/Toll-like receptors (TLRs)-related proinflammatory cytokines and downstream signal transduction, nuclear factor (NF)-κB activation on failing myocardium are discussed.

Waclaw Szybalski's contribution to immunotherapy: HGPRT mutation & HAT selection as first steps to gene therapy and hybrid techniques in mammalian cells.

In this report we describe Waclaw Szybalski's fundamental contribution to gene therapy and immunotherapy. His 1962 PNAS paper (Szybalska and Szybalski, 1962) documented the first successful gene repair in mammalian cells. Furthermore, this was also the first report on the HAT selection method used later in many applications. Most importantly, somatic cell fusion and HAT selection were subsequently used to develop monoclonal antibody technology, which contributed significantly to the progress of today's medicine.

Monoclonal antibodies as novel neurotherapeutic agents in CNS injury and repair.

Central nervous system (CNS) injury is a complex in which numerous neurochemicals and other vasoactive agents actively contribute towards the development of posttraumatic brain pathology and/or repair mechanisms. A focal trauma to the brain or spinal cord releases several endogenous neurodestructive agents within the CNS, resulting in adverse cellular reactions. Our laboratory is engaged in identifying these endogenous neurodestructive signals in the CNS following injury caused by trauma or hyperthermia. Our observations show that serotonin (5-HT), dynorphin A (Dyn A 1-17), nitric oxide synthase (NOS), and tumor necrosis factor-α (TNF-α) could be potential neurodestructive signals in the CNS injury. Thus, neutralization of these agents using monoclonal antibodies directed against 5-HT, NOS, Dyn A (1-17), and TNF-α in vivo will result in marked neuroprotection and enhance neurorepair after trauma. In addition, a suitable combination of monoclonal antibodies, for example, NOS and TNF-α, when applied 60-90 min after trauma, is capable to enhance neuroprotective ability and thwart cell and tissue injury after spinal cord insult. Taken together, our novel observations suggest a potential use of monoclonal antibodies as suitable therapeutic agents in CNS injuries to achieve neuroprotection and/or neurorepair.

Immunotherapy in clinical medicine: historical perspective and current status.

In humans, the immune system is a complex organ system involving cells and soluble mediators whose function is, essentially, protection. However, disequilibrium in this intricate system leads to disease in itself. To modulate these responses, immunotherapy is now the primary or adjunct treatment of many diseases. In addition, immunologic tests now diagnose several diseases.

The biopharmaceutical industry in China: history and future perspectives.

Biopharmaceuticals reflect the rapid progress achieved in modern biomedical research. This area has also become one of the main criteria for assessing the development level of biotechnology for a particular country. Although it has been only three decades since the first biopharmaceutical, recombinant human insulin, was licensed by the US Food and Drug Administration, the biopharmaceutical industry has become the fastest growing, most dynamic and technology-intensive sector in the biomedical field. Since the licensing of recombinant human interferon α1b in 1989, the biopharmaceutical industry in China has gone through initial developments and gradually entered a period of rapid growth. This paper provides an overview of the status and development trends of biopharmaceuticals in China, and compares them with those observed in developed countries.

From the discovery of vascular endothelial growth factor to the introduction of avastin in clinical trials - an interview with Napoleone Ferrara by Domenico Ribatti.

Napoleone Ferrara and his colleagues at Genentech were the first to isolate and clone vascular endothelial growth factor (VEGF) in 1989. His laboratory has investigated many aspects of VEGF biochemistry and molecular biology. In 1993, Ferrara reported that inhibition of VEGF-induced angiogenesis by specific monoclonal antibodies resulted in dramatic suppression of the growth of a variety of tumors in vivo. These findings provided an important evidence that inhibition of angiogenesis may suppress tumor growth and blocking VEGF action could have therapeutic value for a variety of malignancies. A further development was the design in a rational fashion in 1997 of a humanized anti-VEGF monoclonal antibody (Avastin), now in clinical trials as a treatment for several solid tumors and also outside of cancer, in the treatment of age-related macular degeneration (AMD). Ferrara's work is revolutionizing quality of life for many of the estimated 1.2 million individuals in the US who have wet AMD. Upwards of a million AMD patients worldwide have already received anti-VEGF antibody therapy.