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Essay: Monoclonal antibodies—designer medical missiles
Essay Monoclonal antibodies—designer medical missiles Lancet 2006; 368: S48–S49
The printed journal includes an image merely for illustration Marvin J Stone has been Chief of Oncology and Director of the Charles A Sammons Cancer Center at Baylor University Medical Center since 1976. He heads the internal medicine clerkship for third-year medical students and the medical oncology fellowship programme. He is a Master of the American College of Physicians and a past president of the American Osler Society. Charles A Sammons Cancer Center, Baylor University Medical Center and Baylor Research Institute, and Texas Oncology, PA, 3500 Gaston Avenue, Dallas, TX 75246, USA (Prof M J Stone MD) Correspondence to: Prof Marvin J Stone [email protected]
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Marvin J Stone
The immunologist Emil von Behring was awarded the first Nobel Prize in Physiology or Medicine in 1901. The citation read: “For his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths.” Passive antibody therapy thus had an auspicious beginning. Paul Ehrlich’s side-chain theory of antibody formation achieved widespread popularity and was a precursor of F Macfarlane Burnet’s clonal selection hypothesis. Ehrlich stated “The immune substances … in the manner of magic bullets, seek out the enemy.” The British immunologist, Almroth Wright, who developed typhoid vaccine and described opsonins, predicted that “the physician of the future will be an immunisator”. George Bernard Shaw used Wright as the model for the leading character in his play The Doctor’s Dilemma, in which a physician proclaims that the best way to treat all diseases scientifically is to “stimulate the phagocytes. Drugs are a delusion.” Later investigators showed that an immune serum to even a well-defined hapten group consisted of a heterogeneous mixture of antibodies with widely varying affinities. Theories of antibody formation advanced by chemists were of an instructive or template nature. By the mid-20th century, Niels Jerne and Burnet switched the focus to cell selection, shifting from a chemical to a biological orientation. In 1959, Rodney Porter and Gerald Edelman described the multichain polypeptide structure of antibody molecules, now called immunoglobulins, which led to aminoacid sequencing and delineation of the antigenbinding sites. This work, which led to a Nobel Prize, was aided immeasurably by the availability of large amounts of homogeneous immunoglobulins from patients and mice with plasma-cell tumours. Myeloma immunoglobulins, Bence-Jones proteins, and monoclonal macroglobulins had crucial roles in the elucidation of normal immunoglobulin structure, genetics, synthesis, and metabolism. The inducible plasmacytoma BALB/c mouse model developed by Michael Potter in the early 1960s was distributed to investigators worldwide and plasmacytoma cell lines were established. By the late 1960s, functional antibody activity in occasional human myeloma and Waldenström macroglobulin paraproteins had been documented. However, most monoclonal proteins did not have identifiable antigen-binding properties. Moreover, efforts to immunise animals and retain the antibody activity in an emerging monoclonal component were unsuccessful. Immunisation, somatic-cell hybrids, and monoclonal immunoglobulins converged in a remarkable way in 1975. Georges Köhler and César Milstein’s development
of hybridoma technology fundamentally changed immunology. These investigators showed that antibodyproducing cells of virtually any desired specificity could be fused with a myeloma cell line, the result being unlimited amounts of homogeneous (monoclonal) antibodies carrying that specificity. Their letter in Nature’s issue of August 7, 1975, concluded: “It is possible to hybridise antibody-producing cells from different origins. Such cells can be grown in vitro in massive cultures to provide specific antibody. Such cultures could be valuable for medical and industrial use.” Köhler and Milstein were awarded the Nobel Prize in 1984 for this work. Initially monoclonal antibodies were of murine origin. The first to gain regulatory approval for treatment was muromonab, a T-lymphocyte antibody used to prevent rejection of solid-organ transplants. Early attempts to treat patients were hampered by the development of antibodies to mouse proteins. Genetic engineering enabled the development of less immunogenic monoclonal antibodies, which could be given repeatedly. Thus, monoclonal antibodies can be chimeric (with a human immunoglobulin constant region) or humanised (with murine antibody-combining regions in an otherwise >90% human framework). Platforms that use phage, ribosome, or microbial cell display technologies can produce a vast number of high-affinity monoclonal antibodies directed to a wide range of antigens. Fully human monoclonal antibodies can be synthesised by transgenic mice that express the repertoire of human immunoglobulin genes. The diagnostic effect of monoclonal antibodies has been profound. Since the molecules are homogeneous and react with a single epitope, they are well defined and yield reproducible data. Examples of their application include lymphocyte subset analysis for organ transplantation, classification of leukaemias and lymphomas, and diagnosis of various neoplasms. They also have proven valuable as diagnostic imaging agents, especially in the cardiovascular system. Antibody fragments have advantages (smaller fragments can penetrate tissues more easily) but also disadvantages (lower affinity). Bispecific antibodies—simple molecules that can bind two different epitopes—can also be made. Monoclonal antibodies directed against tumours represent a huge leap in targeted anticancer treatment. Though initial progress was slow, their efficacy has been demonstrated in some patients with lymphoma and breast cancer. How monoclonal antibodies kill tumour cells is not clear, but mechanisms including antibodydependent cellular cytotoxicity, complement fixation, signal transduction blockage, and direct induction of apoptosis have roles. The biological properties of a monoclonal antibody, especially antibody-dependent www.thelancet.com Medicine and Creativity Vol 368 December 2006
www.thelancet.com Medicine and Creativity Vol 368 December 2006
Sciecne Photo Library
cellular cytotoxicity, can be augmented or inhibited by the structure of Fc receptors on immune cells. Genetic engineering is being applied to improve effector function and half-life of monoclonal antibodies by selecting for Fc receptor type. The first anticancer monoclonal antibody approved for use in the USA was rituximab, a chimeric anti-CD20 immunoglobulin. Initially approved for use in refractory low-grade non-Hodgkin lymphoma, rituximab is now used for treatment of other lymphomas and lymphocytic leukaemias. It is active as a single agent and in combination with cytotoxic chemotherapy. Rituximab is effective for treatment of post-transplantation lymphoproliferative disorders and certain autoimmune diseases. Trastuzumab binds to the HER2 protein, which is overexpressed in about 20% of patients with invasive breast cancer. This monoclonal antibody is beneficial in metastatic HER2-positive breast cancer and has been shown to reduce disease recurrence when given in combination with chemotherapy in the adjuvant setting. Monoclonal antibodies to epidermal-growth-factor receptor and vascular endothelial growth factor have been approved in the USA for treatment of colorectal and head and neck cancers. Other malignant diseases are likely to be suitable for treatment by monoclonal antibodies as well. For optimum results, each reagent must be studied carefully and methodically in each clinical circumstance, alone and in combination with other modalities. Monoclonal antibodies that modulate inflammatory reactions are effective therapeutic agents for several diseases—for example the TNFα inhibitor, infliximab, in rheumatoid arthritis and Crohn’s disease, adalimumab in rheumatoid arthritis, efalizumab, a T-cell modulator, in psoriasis and abciximab, a platelet inhibitor, that prevents thrombotic complications. Palivizumab can prevent infection with respiratory syncytial virus in highrisk infants. Side-effects consisting of fever, chills, rash, and aching frequently occur with the initial infusion of monoclonal antibody. They are probably due to cytokine release and often can be controlled by slowing the infusion rate; subsequent treatments are better tolerated. Severe adverse events are rare and seem to be more likely with administration of antibodies that stimulate rather than suppress the immune system. Serious reactions have been seen in healthy volunteers who received a humanised superagonist anti-CD28 monoclonal antibody that activated T lymphocytes. Other side-effects such as susceptibility to infections and neoplasms are a continuing cause for concern. Since the toxicity of monoclonal antibodies generally does not overlap with that of cytotoxic chemotherapeutic drugs or radiation, combined therapy has become increasingly applied in oncology. Monoclonal antibodies can be used as the carrier or homing device as well as the effector warhead. They can be linked to drugs, toxins, radionuclides, cytokines, or
enzymes for diagnostic or therapeutic purposes. They provide immediate short-term immunity against viruses and other organisms that can be used as biological weapons. Hundreds of monoclonal antibodies are in clinical or preclinical development, and combinations or “cocktails” with different specificities are being investigated. During the next decade, the number of therapeutic and diagnostic monoclonal antibodies is expected to increase dramatically. Promising approaches combining these reagents with small-molecule inhibitors will be further explored. Production of monoclonal antibodies targeting amplified and mutated proteins will be expanded for patients with cancer. The antibodies will also have a crucial role in proteomics research. One sobering admonition: these agents are expensive. Society will have to grapple with their cost. Their exquisite specificity provides previously unattainable therapeutic potential for cancer, autoimmune disorders, infectious diseases, and cardiovascular disorders. As additional novel targets are recognised, further applications will surely occur. Over the past 31 years, monoclonal antibodies have had an enormous influence on biology and medicine. The ability to produce an unlimited quantity of homogeneous antibody to any antigen has spawned a revolution in science. Though not magic, monoclonal antibodies are bullets that will continue to raise targeted diagnosis and therapy to new levels. If George Bernard Shaw were still alive, he might even write a play about them. Acknowledgments Dedicated to the memory of Jill Stone. I thank Ellen Vitetta, Virginia Pascual, and Alex Tong for valuable comments. Kathleen Shannon assisted expertly with preparation of the essay. I am a shareholder in Texas Oncology PA and US Oncology.
Further reading Stockwin LH, Holmes S. Antibodies as therapeutic agents: vive la renaissance! Expert Opin Biol Ther 2003; 3: 1133–52. Hoogenboom HR. Selecting and screening recombinant antibody libraries. Nat Biotechnol 2005; 23: 1105–16. Waldman TA, Morris JC. Development of antibodies and chimeric molecules for cancer immunotherapy. Adv Immunol 2006; 90: 83–131. Weiner LM. Fully human therapeutic monoclonal antibodies. J Immunother 2006; 29: 1–9. Reichert JM, Dewitz MC. Antiinfective monoclonal antibodies: perils and promise of development. Nat Rev/Drug Discov 2006; 5: 191–95.
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The printed journal includes an image merely for illustration Marvin J Stone has been Chief of Oncology and Director of the Charles A Sammons Cancer Center at Baylor University Medical Center since 1976. He heads the internal medicine clerkship for third-year medical students and the medical oncology fellowship programme. He is a Master of the American College of Physicians and a past president of the American Osler Society. Charles A Sammons Cancer Center, Baylor University Medical Center and Baylor Research Institute, and Texas Oncology, PA, 3500 Gaston Avenue, Dallas, TX 75246, USA (Prof M J Stone MD) Correspondence to: Prof Marvin J Stone [email protected]
S48
Marvin J Stone
The immunologist Emil von Behring was awarded the first Nobel Prize in Physiology or Medicine in 1901. The citation read: “For his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths.” Passive antibody therapy thus had an auspicious beginning. Paul Ehrlich’s side-chain theory of antibody formation achieved widespread popularity and was a precursor of F Macfarlane Burnet’s clonal selection hypothesis. Ehrlich stated “The immune substances … in the manner of magic bullets, seek out the enemy.” The British immunologist, Almroth Wright, who developed typhoid vaccine and described opsonins, predicted that “the physician of the future will be an immunisator”. George Bernard Shaw used Wright as the model for the leading character in his play The Doctor’s Dilemma, in which a physician proclaims that the best way to treat all diseases scientifically is to “stimulate the phagocytes. Drugs are a delusion.” Later investigators showed that an immune serum to even a well-defined hapten group consisted of a heterogeneous mixture of antibodies with widely varying affinities. Theories of antibody formation advanced by chemists were of an instructive or template nature. By the mid-20th century, Niels Jerne and Burnet switched the focus to cell selection, shifting from a chemical to a biological orientation. In 1959, Rodney Porter and Gerald Edelman described the multichain polypeptide structure of antibody molecules, now called immunoglobulins, which led to aminoacid sequencing and delineation of the antigenbinding sites. This work, which led to a Nobel Prize, was aided immeasurably by the availability of large amounts of homogeneous immunoglobulins from patients and mice with plasma-cell tumours. Myeloma immunoglobulins, Bence-Jones proteins, and monoclonal macroglobulins had crucial roles in the elucidation of normal immunoglobulin structure, genetics, synthesis, and metabolism. The inducible plasmacytoma BALB/c mouse model developed by Michael Potter in the early 1960s was distributed to investigators worldwide and plasmacytoma cell lines were established. By the late 1960s, functional antibody activity in occasional human myeloma and Waldenström macroglobulin paraproteins had been documented. However, most monoclonal proteins did not have identifiable antigen-binding properties. Moreover, efforts to immunise animals and retain the antibody activity in an emerging monoclonal component were unsuccessful. Immunisation, somatic-cell hybrids, and monoclonal immunoglobulins converged in a remarkable way in 1975. Georges Köhler and César Milstein’s development
of hybridoma technology fundamentally changed immunology. These investigators showed that antibodyproducing cells of virtually any desired specificity could be fused with a myeloma cell line, the result being unlimited amounts of homogeneous (monoclonal) antibodies carrying that specificity. Their letter in Nature’s issue of August 7, 1975, concluded: “It is possible to hybridise antibody-producing cells from different origins. Such cells can be grown in vitro in massive cultures to provide specific antibody. Such cultures could be valuable for medical and industrial use.” Köhler and Milstein were awarded the Nobel Prize in 1984 for this work. Initially monoclonal antibodies were of murine origin. The first to gain regulatory approval for treatment was muromonab, a T-lymphocyte antibody used to prevent rejection of solid-organ transplants. Early attempts to treat patients were hampered by the development of antibodies to mouse proteins. Genetic engineering enabled the development of less immunogenic monoclonal antibodies, which could be given repeatedly. Thus, monoclonal antibodies can be chimeric (with a human immunoglobulin constant region) or humanised (with murine antibody-combining regions in an otherwise >90% human framework). Platforms that use phage, ribosome, or microbial cell display technologies can produce a vast number of high-affinity monoclonal antibodies directed to a wide range of antigens. Fully human monoclonal antibodies can be synthesised by transgenic mice that express the repertoire of human immunoglobulin genes. The diagnostic effect of monoclonal antibodies has been profound. Since the molecules are homogeneous and react with a single epitope, they are well defined and yield reproducible data. Examples of their application include lymphocyte subset analysis for organ transplantation, classification of leukaemias and lymphomas, and diagnosis of various neoplasms. They also have proven valuable as diagnostic imaging agents, especially in the cardiovascular system. Antibody fragments have advantages (smaller fragments can penetrate tissues more easily) but also disadvantages (lower affinity). Bispecific antibodies—simple molecules that can bind two different epitopes—can also be made. Monoclonal antibodies directed against tumours represent a huge leap in targeted anticancer treatment. Though initial progress was slow, their efficacy has been demonstrated in some patients with lymphoma and breast cancer. How monoclonal antibodies kill tumour cells is not clear, but mechanisms including antibodydependent cellular cytotoxicity, complement fixation, signal transduction blockage, and direct induction of apoptosis have roles. The biological properties of a monoclonal antibody, especially antibody-dependent www.thelancet.com Medicine and Creativity Vol 368 December 2006
www.thelancet.com Medicine and Creativity Vol 368 December 2006
Sciecne Photo Library
cellular cytotoxicity, can be augmented or inhibited by the structure of Fc receptors on immune cells. Genetic engineering is being applied to improve effector function and half-life of monoclonal antibodies by selecting for Fc receptor type. The first anticancer monoclonal antibody approved for use in the USA was rituximab, a chimeric anti-CD20 immunoglobulin. Initially approved for use in refractory low-grade non-Hodgkin lymphoma, rituximab is now used for treatment of other lymphomas and lymphocytic leukaemias. It is active as a single agent and in combination with cytotoxic chemotherapy. Rituximab is effective for treatment of post-transplantation lymphoproliferative disorders and certain autoimmune diseases. Trastuzumab binds to the HER2 protein, which is overexpressed in about 20% of patients with invasive breast cancer. This monoclonal antibody is beneficial in metastatic HER2-positive breast cancer and has been shown to reduce disease recurrence when given in combination with chemotherapy in the adjuvant setting. Monoclonal antibodies to epidermal-growth-factor receptor and vascular endothelial growth factor have been approved in the USA for treatment of colorectal and head and neck cancers. Other malignant diseases are likely to be suitable for treatment by monoclonal antibodies as well. For optimum results, each reagent must be studied carefully and methodically in each clinical circumstance, alone and in combination with other modalities. Monoclonal antibodies that modulate inflammatory reactions are effective therapeutic agents for several diseases—for example the TNFα inhibitor, infliximab, in rheumatoid arthritis and Crohn’s disease, adalimumab in rheumatoid arthritis, efalizumab, a T-cell modulator, in psoriasis and abciximab, a platelet inhibitor, that prevents thrombotic complications. Palivizumab can prevent infection with respiratory syncytial virus in highrisk infants. Side-effects consisting of fever, chills, rash, and aching frequently occur with the initial infusion of monoclonal antibody. They are probably due to cytokine release and often can be controlled by slowing the infusion rate; subsequent treatments are better tolerated. Severe adverse events are rare and seem to be more likely with administration of antibodies that stimulate rather than suppress the immune system. Serious reactions have been seen in healthy volunteers who received a humanised superagonist anti-CD28 monoclonal antibody that activated T lymphocytes. Other side-effects such as susceptibility to infections and neoplasms are a continuing cause for concern. Since the toxicity of monoclonal antibodies generally does not overlap with that of cytotoxic chemotherapeutic drugs or radiation, combined therapy has become increasingly applied in oncology. Monoclonal antibodies can be used as the carrier or homing device as well as the effector warhead. They can be linked to drugs, toxins, radionuclides, cytokines, or
enzymes for diagnostic or therapeutic purposes. They provide immediate short-term immunity against viruses and other organisms that can be used as biological weapons. Hundreds of monoclonal antibodies are in clinical or preclinical development, and combinations or “cocktails” with different specificities are being investigated. During the next decade, the number of therapeutic and diagnostic monoclonal antibodies is expected to increase dramatically. Promising approaches combining these reagents with small-molecule inhibitors will be further explored. Production of monoclonal antibodies targeting amplified and mutated proteins will be expanded for patients with cancer. The antibodies will also have a crucial role in proteomics research. One sobering admonition: these agents are expensive. Society will have to grapple with their cost. Their exquisite specificity provides previously unattainable therapeutic potential for cancer, autoimmune disorders, infectious diseases, and cardiovascular disorders. As additional novel targets are recognised, further applications will surely occur. Over the past 31 years, monoclonal antibodies have had an enormous influence on biology and medicine. The ability to produce an unlimited quantity of homogeneous antibody to any antigen has spawned a revolution in science. Though not magic, monoclonal antibodies are bullets that will continue to raise targeted diagnosis and therapy to new levels. If George Bernard Shaw were still alive, he might even write a play about them. Acknowledgments Dedicated to the memory of Jill Stone. I thank Ellen Vitetta, Virginia Pascual, and Alex Tong for valuable comments. Kathleen Shannon assisted expertly with preparation of the essay. I am a shareholder in Texas Oncology PA and US Oncology.
Further reading Stockwin LH, Holmes S. Antibodies as therapeutic agents: vive la renaissance! Expert Opin Biol Ther 2003; 3: 1133–52. Hoogenboom HR. Selecting and screening recombinant antibody libraries. Nat Biotechnol 2005; 23: 1105–16. Waldman TA, Morris JC. Development of antibodies and chimeric molecules for cancer immunotherapy. Adv Immunol 2006; 90: 83–131. Weiner LM. Fully human therapeutic monoclonal antibodies. J Immunother 2006; 29: 1–9. Reichert JM, Dewitz MC. Antiinfective monoclonal antibodies: perils and promise of development. Nat Rev/Drug Discov 2006; 5: 191–95.
S49