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Engineered antibody therapeutics
Advanced Drug Delivery Reviews 58 (2006) 631 – 632 www.elsevier.com/locate/addr
Preface
Engineered antibody therapeuticsB
Monoclonal antibodies are entering their third decade as scientific entities and it has been a decade since the introduction of the first chimeric therapeutic antibody. This issue will strive to review the current state of, at least a portion of, what is a growing and ever more exciting field both scientifically and medically. The theme focuses mainly on the use of naked antibodies and leaves a comprehensive overview of the complex topic of using antibodies to target radioactive or toxic compounds for another issue, although these are touched on in several of the chapters including Daugherty and Mrsny’s article on antibody formulation and Trachsel and Neri’s article on vascular targeting. This issue will also focus almost entirely on issues related to the pre-clinical development of antibodies to be used for clinical or diagnostic use, clearly just one of the potential scientific, medical, or industrial uses of engineered antibodies. These chapters can then be grouped under 4 broad categories: the engineering of the antibody protein to optimize its performance in the clinic; the manufacturing and formulation of antibodies that meet regulatory requirements for human drugs and commercial requirements for cost of goods; the development of better pre-clinical animal models to predict antibody behavior in the clinic; and some ideas concerning interesting areas opening up in the field of monoclonal antibody uses. I will briefly discuss each of these areas below and the contributions in this issue. One of the initial barriers to the success of antibody therapies was the human host immune response to the B
This preface is part of the Advanced Drug Delivery Reviews theme issue on bEngineered Antibody therapeuticsQ Vol. 58/5–6 2006. 0169-409X/$ - see front matter D 2006 Published by Elsevier B.V. doi:10.1016/j.addr.2006.05.001
administration of murine antibodies, which limited these to one or two doses. It was only with the ability to use molecular biology tools to create antibodies with predominantly human sequence that multi-dose, and thus more efficacious, therapies became possible. Dr. Presta reviews in detail the different ways in which antibodies can be made less immunogenic. The desirability of and need for increased binding affinity and methods of achieving such increases, as well as antibody fragments are also discussed in the first two chapters. Drs. Wark and Hudson review in detail the current state of the art of in vitro and in vivo mutagenesis methodologies, which are rapidly evolving to make finely tuned changes in antibodies faster and easier than ever. Finally, antibodies as a class are one of the few drugs that can have two distinctly different types of actions: host effector-mediated, and antibody-target mediated. Dr. Presta reviews what is known about the host effector mediating functions of the antibody molecules and what has been done to engineer the molecules to optimize these functions. The first recombinant products brought to market were hormones such as growth hormone and insulin or enzymes like plasminogen activator that were dosed in the mg/dose range. With antibodies came the need to create the capacity to produce recombinant proteins to give grams/patient doses weekly for long periods of time to tens of thousands of patients per year. This required the development of entirely new technologies in recombinant protein expression, fermentation, and purification, coupled with the ability to develop formulations that provide stable sterile solutions, at very high concentrations of protein, over years of storage, for intraveneous administration of
632
Preface 58 (2006) 631 – 632
the drugs. The progress in these areas, which has made commercial monoclonal antibodies as therapies possible, are reviewed by Drs. Birch and Racher and Drs. Daugherty and Mrsny. Equally important has been the hand in hand development of regulatory oversight of the manufacturing and development of this entirely new class of therapeutics. As with any new area, this is an iterative process with the regulatory strategies evolving as our understanding of the biochemistry of the antibody molecule, the biology of the immune system, and the clinical response of patients to a range of antibody therapeutics grows more complex and complete. This area, at least as it evolved in the US, is reviewed by Drs. Kozlowski and Swann of the US Federal Drug Administration. One of the continuing challenges in the area of monoclonal antibodies is the development of better animal models for both safety and efficacy. Mouse and other rodent models have been developed and used for cytotoxic small molecule chemotherapies. These are not very specific so toxicity can be observed in rodents, although drug metabolism, and therefore, metabolite toxicity, in these species may be very different from that in humans. These models have been developed with rapidly growing tumors that will respond well to cytotoxic small molecules that act on dividing cells, although these drugs frequently have not worked as well in the clinic as in the animal models. The species specificity of the antibody effector and target interactions present special challenges in creating animal models that will accurately predict safety and efficacy of these proteins and their interactions with the chemotherapeutic molecules that they are used with clinically. Dr. Pegram presents a case study illustrating this challenging area. Even though we are now firmly entrenched economically in the era of the antibody, with antibodies expected to contribute the majority of growth in cancer therapies over the next decade, I feel we are just at the beginning of the road that will lead to the complete range of the applications of antibodies to
medical technology and treatment. While penicillin was considered a bwonder drugQ in the 1950s neither the huge variety of antibiotics now available nor any idea that they might be useful in treating diseases such as ulcers and heart disease could have been foreseen. Antibodies too are really just beginning to be fully understood biochemically, biologically, and clinically and we can expect many more exciting applications to emerge in the coming decades. Therefore, in the last section we take a closer look at just two areas where the natural biology of the antibody has led, and may continue to lead, into exciting new therapeutic areas. The treatment of cancer by antibodies which primarily attack and modify the cancer environment is illustrated in the review of anti-angiogenic, vascular targeting Mabs and Mabs which mediate endothelial cell transcytosis. This chapter by Drs. Trachsel and Neri takes us on an interesting review of the field from the marketed antibodies Avastin and Lucentis to speculations on novel new targets to kill tumor vasculature. Finally, in a short and pithy chapter Drs. Vollmers and Brandlein challenge some pre-conceptions about IgMs and carbohydrate antigens’ role in immune surveillance and potential for immunotherapy for cancer. I would like to thank all of the contributors for their contributions to this special edition. Most of all, I thank the scientists, physicians, and patients who have been part of the basic research, applied pharmaceutical research, and clinical research that has brought this field to the state that it has currently reached in a relatively short time, although it never seems short enough as long as patients stand in need of better therapies to treat their disease. Jennie P. Mather Theme Editor Raven Biotechnologies, Inc., 1140 Veterans Blvd. South San Francisco, CA 94080 USA E-mail address: [email protected]
Preface
Engineered antibody therapeuticsB
Monoclonal antibodies are entering their third decade as scientific entities and it has been a decade since the introduction of the first chimeric therapeutic antibody. This issue will strive to review the current state of, at least a portion of, what is a growing and ever more exciting field both scientifically and medically. The theme focuses mainly on the use of naked antibodies and leaves a comprehensive overview of the complex topic of using antibodies to target radioactive or toxic compounds for another issue, although these are touched on in several of the chapters including Daugherty and Mrsny’s article on antibody formulation and Trachsel and Neri’s article on vascular targeting. This issue will also focus almost entirely on issues related to the pre-clinical development of antibodies to be used for clinical or diagnostic use, clearly just one of the potential scientific, medical, or industrial uses of engineered antibodies. These chapters can then be grouped under 4 broad categories: the engineering of the antibody protein to optimize its performance in the clinic; the manufacturing and formulation of antibodies that meet regulatory requirements for human drugs and commercial requirements for cost of goods; the development of better pre-clinical animal models to predict antibody behavior in the clinic; and some ideas concerning interesting areas opening up in the field of monoclonal antibody uses. I will briefly discuss each of these areas below and the contributions in this issue. One of the initial barriers to the success of antibody therapies was the human host immune response to the B
This preface is part of the Advanced Drug Delivery Reviews theme issue on bEngineered Antibody therapeuticsQ Vol. 58/5–6 2006. 0169-409X/$ - see front matter D 2006 Published by Elsevier B.V. doi:10.1016/j.addr.2006.05.001
administration of murine antibodies, which limited these to one or two doses. It was only with the ability to use molecular biology tools to create antibodies with predominantly human sequence that multi-dose, and thus more efficacious, therapies became possible. Dr. Presta reviews in detail the different ways in which antibodies can be made less immunogenic. The desirability of and need for increased binding affinity and methods of achieving such increases, as well as antibody fragments are also discussed in the first two chapters. Drs. Wark and Hudson review in detail the current state of the art of in vitro and in vivo mutagenesis methodologies, which are rapidly evolving to make finely tuned changes in antibodies faster and easier than ever. Finally, antibodies as a class are one of the few drugs that can have two distinctly different types of actions: host effector-mediated, and antibody-target mediated. Dr. Presta reviews what is known about the host effector mediating functions of the antibody molecules and what has been done to engineer the molecules to optimize these functions. The first recombinant products brought to market were hormones such as growth hormone and insulin or enzymes like plasminogen activator that were dosed in the mg/dose range. With antibodies came the need to create the capacity to produce recombinant proteins to give grams/patient doses weekly for long periods of time to tens of thousands of patients per year. This required the development of entirely new technologies in recombinant protein expression, fermentation, and purification, coupled with the ability to develop formulations that provide stable sterile solutions, at very high concentrations of protein, over years of storage, for intraveneous administration of
632
Preface 58 (2006) 631 – 632
the drugs. The progress in these areas, which has made commercial monoclonal antibodies as therapies possible, are reviewed by Drs. Birch and Racher and Drs. Daugherty and Mrsny. Equally important has been the hand in hand development of regulatory oversight of the manufacturing and development of this entirely new class of therapeutics. As with any new area, this is an iterative process with the regulatory strategies evolving as our understanding of the biochemistry of the antibody molecule, the biology of the immune system, and the clinical response of patients to a range of antibody therapeutics grows more complex and complete. This area, at least as it evolved in the US, is reviewed by Drs. Kozlowski and Swann of the US Federal Drug Administration. One of the continuing challenges in the area of monoclonal antibodies is the development of better animal models for both safety and efficacy. Mouse and other rodent models have been developed and used for cytotoxic small molecule chemotherapies. These are not very specific so toxicity can be observed in rodents, although drug metabolism, and therefore, metabolite toxicity, in these species may be very different from that in humans. These models have been developed with rapidly growing tumors that will respond well to cytotoxic small molecules that act on dividing cells, although these drugs frequently have not worked as well in the clinic as in the animal models. The species specificity of the antibody effector and target interactions present special challenges in creating animal models that will accurately predict safety and efficacy of these proteins and their interactions with the chemotherapeutic molecules that they are used with clinically. Dr. Pegram presents a case study illustrating this challenging area. Even though we are now firmly entrenched economically in the era of the antibody, with antibodies expected to contribute the majority of growth in cancer therapies over the next decade, I feel we are just at the beginning of the road that will lead to the complete range of the applications of antibodies to
medical technology and treatment. While penicillin was considered a bwonder drugQ in the 1950s neither the huge variety of antibiotics now available nor any idea that they might be useful in treating diseases such as ulcers and heart disease could have been foreseen. Antibodies too are really just beginning to be fully understood biochemically, biologically, and clinically and we can expect many more exciting applications to emerge in the coming decades. Therefore, in the last section we take a closer look at just two areas where the natural biology of the antibody has led, and may continue to lead, into exciting new therapeutic areas. The treatment of cancer by antibodies which primarily attack and modify the cancer environment is illustrated in the review of anti-angiogenic, vascular targeting Mabs and Mabs which mediate endothelial cell transcytosis. This chapter by Drs. Trachsel and Neri takes us on an interesting review of the field from the marketed antibodies Avastin and Lucentis to speculations on novel new targets to kill tumor vasculature. Finally, in a short and pithy chapter Drs. Vollmers and Brandlein challenge some pre-conceptions about IgMs and carbohydrate antigens’ role in immune surveillance and potential for immunotherapy for cancer. I would like to thank all of the contributors for their contributions to this special edition. Most of all, I thank the scientists, physicians, and patients who have been part of the basic research, applied pharmaceutical research, and clinical research that has brought this field to the state that it has currently reached in a relatively short time, although it never seems short enough as long as patients stand in need of better therapies to treat their disease. Jennie P. Mather Theme Editor Raven Biotechnologies, Inc., 1140 Veterans Blvd. South San Francisco, CA 94080 USA E-mail address: [email protected]