- Email: [email protected]
New treatments and the future role of immunotherapy: anti-IgE
New treatments and the future role of immunotherapy: anti-IgE Bob Lanier, MD
Objective: The review outlines an overview of anti-IgE, along with a description of the production and mechanism of action of the finished molecule. The immunologic effect of the drug and the drug complexes are detailed, and proof of efficacy is offered. The review also speculates about the role of anti-IgE in clinical use, along with potential future therapies, including gene substitution and genetic alteration. Data Sources: The author reviewed literature studying IgE and anti-IgE antibody. Study Selection: The expert opinion of the author was used to select relevant data. Results: The injection of anti-IgE results in four proven reactions: free antibody is bound; not bound antibody is not dislodged to any degree; plasma B cell production of IgE drops; and high-affinity Fc ⑀ RI and low-affinity Fc ⑀ RII on mast cells and basophils are downregulated. Conclusions: Based on observation of clinical reaction, anti-IgE is truly immunotherapy. Current opinion among clinical investigators about the impact of the impending approval of this new drug is that it will not replace standard immunotherapy. How it will fit into the armamentarium of physicians dealing with allergic disease, and protocols for its use, are still being debated. Ann Allergy Asthma Immunol 2001;87(Suppl):68– 69.
The discovery in 1970 of the agent responsible for allergy (IgE) triggered an immediate response among researchers to find an antibody-crippling mechanism to ameliorate the allergic response. Naturally occurring antibodies to IgE were subsequently found, which created a brief flurry of projects designed to induce these antibodies as a therapeutic modality.1–3 This research avenue bore no fruit; efforts were largely abandoned and redirected to create a new entity to cover the combining site of the docking molecule of the antibody. Once covered, the antibody would not be able to attach to mast cells and the body’s own clearance system would take care of removing the now-impotent antibody. Nothing would be changed in the immune system except that the allergic antibody would be prevented from attachLanier Education and Research Network, Fort Worth, TX. Received for publication November 10, 2000. Accepted for publication November 15, 2000.
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ing to the mast cell. This is the basis of the new monoclonal antibody vaccine. Work using the mouse model for making specific anti-IgE antibodies began to appear in the medical literature in the late 1980s with a number of new findings in the early 1990s. By 1995, human trials were well underway and a buzz of excitement began to be heard coming from the physicians conducting clinical trials across the country.4 Both Tannox Biosystems in Houston (combined with Novartis), and Genentech in San Francisco produced molecules that worked. Cooperation between Tannox, Novartis, and Genentech, after extended litigation, eventually produced the study compound Rhumab E-25 or Omaluzumab. The production of anti-IgE begins with the injection of our human allergic antibody into mice. Mice, being naturally irritated by the injection of this foreign protein, react with a polyclonal antibody response. The B lymphocytes producing these antibodies are removed and a hybridoma is cre-
ated with fusion of the antibodies to myeloma cells. This hybridoma cell clone continually produces large quantities of identical monoclonal antibodies because they come from only one type of cell. Over a period of time, the products from each cell line are analyzed for the desired properties and are further cultured to extend the quantity of anti-IgE. Early experiments with mouse-derived antibodies revealed a brisk human anti-mouse immune response which negated the therapeutic potential. A recombinant process was used to cleave off all but the basic docking portion, which was inserted into a human protein (humanization). Less than 5% of nonhuman protein remains in the final product and only four amino acid groups in the entire molecule are not found in normal human tissue. When anti-IgE is injected, it mercilessly hunts and disables allergic antibody by creating a complex that prevents IgE binding to high-affinity Fc ⑀ RI and low-affinity Fc ⑀ RII on mast cells and basophils. Oddly enough, though, the complex retains its full antiparasitic capacity, and in some studies, the case can be made for enhanced antiparasitic activity.5 In extensive testing and human trials, no evidence of disease has been found related to this anti-IgE complex. In radio tagging studies, urinary excretion was the primary route of elimination of radioactivity; ⬎90% of the radioactivity found in urine was not associated with protein. The lack of specific tissue uptake and blood cell association and the slow clearance of Rhumab E25:IgE complexes were consistent with low-avidity interaction of small complexes with Fc ␥ receptors of leukocytes and the reticuloendothelial
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
system. There has been no complement fixation noted.6,7 There are four proven reactions that occur as a result of the injection of anti-IgE: 1) free antibody is bound; 2) bound antibody is not dislodged to any degree; 3) plasma B cell production of IgE drops; 4) and high-affinity Fc ⑀ RI and low-affinity Fc ⑀ RII on mast cells and basophils are downregulated.8 Anti-IgE is truly immunotherapy (IT). Since anti-IgE has been proven to reduce IgE levels in multiple trials, recent clinical trials have attempted to verify the clinical importance of the phenomenon in patients known to be symptomatic despite the best approved pharmaceutical-based control programs. Asthma patients (334) aged 6 to 12 years, already receiving corticosteroid therapy, were given either subcutaneous anti-IgE every 2 to 4 weeks, or placebo. Patients were closely followed for ⬎ 28 weeks in two phases: 1) a 16-week stable treatment period where patients had either anti-IgE or placebo added to their current therapy and 2) a 12-week steroid reduction period. In this study, steroids were discontinued altogether in ⬎50% of the patients on anti-IgE, and 71% in half the patients on placebo therapy. Headache (80 of 225 anti-IgE vs 33 of 109 placebo) and upper respiratory infection (78 of 225 anti-IgE patients vs 33 of 109 placebo) were the most frequently reported adverse events. The percentages for one or more adverse events were similar in each group: 89% of anti-IgE and 87% for placebo. There were no drug-related adverse events.
VOLUME 87, JULY, 2001
Whereas IgE levels tended to return to the exact former levels within 6 months of discontinuation, it is the anecdotal observation of many investigators that a number of these children remain asymptomatic on minimal medications for 1 year. The dose of the anti-IgE is dependent on the serum level of the person factored for body weight. A large person with an increased blood volume will need a larger and more frequent dose. A smaller person with a lower blood volume will require a smaller and less frequent dose. The vaccine is now given every 2 to 6 weeks, and may be given for an indefinite period of time. The impending approval of this agent has provoked some concern among practicing allergists. “Will this drug replace standard IT?” The consensus opinion from clinical investigators is “no.” But how this drug fits into the armamentarium of physicians is a hotly debated topic. If this drug eliminates the need for skin tests (“It doesn’t matter what you are allergic to, this gets it all”) and consequent IT (“Both standard IT and anti-IgE are expensive; we can’t do them both”), the basis for the profession of allergy is threatened. Some allergists relate the coming of anti-IgE as analogous to typewriter manufacturers watching the first computers roll off the assembly line, or dentists finding fluoride in toothpaste. Other physicians look at anti-IgE as an exciting tool in the further evolution of standardized antigen IT. Protocols for using anti-IgE as the preparation for expedited IT are already being considered.
REFERENCES 1. Quinti I, Brozek C, Wood N, et al. Circulating IgG autoantibodies to IgE in atopic syndromes. J Allergy Clin Immunol 1986;77:586 –594. 2. Fiebiger E, Stingl G, Maurer D. AntiIgE and anti-Fc ⑀ RI autoantibodies in clinical allergy. Curr Opin Immunol 1996;8:784 –789. 3. Hellman L. Is vaccination against IgE possible? Adv Exp Med Biol 1996; 409:337–342. 4. Shields RL, Whether WR, Zioncheck K, et al. Inhibition of allergic reactions with antibodies to IgE. Int Arch Allergy Immunol 1995;107:308 –312. 5. Korenaga M, Watanabe N, Tada I. Effects of anti-IgE monoclonal antibody on a primary infection of Strongyloides ratti in mice. Parasitol Res 1991;77:362–363. 6. Fox JA, Hotaling TE, Struble C, et al. Tissue distribution and complex formation with IgE of an anti-IgE antibody after intravenous administration in cynomolgus monkeys. J Pharmacol Exp Ther 1996;279:1000 –1008. 7. Liu J, Lester P, Builder S, Shire SJ. Characterization of complex formation by humanized anti-IgE monoclonal antibody and monoclonal human IgE. Biochemistry 1995;34: 10474 –10482. 8. Saini SS, MacGlashan DW Jr, Sterbinsky SA, et al. Down-regulation of human basophil IgE and FC ⑀ RI ␣ surface densities and mediator release by anti-IgE-infusions is reversible in vitro and in vivo. J Immunol 1999;162: 5624 –5630.
Requests for reprints should be addressed to: Bob Lanier, MD 5925-B Lovell Avenue Fort Worth, TX 76107 E-mail: [email protected]
69
Objective: The review outlines an overview of anti-IgE, along with a description of the production and mechanism of action of the finished molecule. The immunologic effect of the drug and the drug complexes are detailed, and proof of efficacy is offered. The review also speculates about the role of anti-IgE in clinical use, along with potential future therapies, including gene substitution and genetic alteration. Data Sources: The author reviewed literature studying IgE and anti-IgE antibody. Study Selection: The expert opinion of the author was used to select relevant data. Results: The injection of anti-IgE results in four proven reactions: free antibody is bound; not bound antibody is not dislodged to any degree; plasma B cell production of IgE drops; and high-affinity Fc ⑀ RI and low-affinity Fc ⑀ RII on mast cells and basophils are downregulated. Conclusions: Based on observation of clinical reaction, anti-IgE is truly immunotherapy. Current opinion among clinical investigators about the impact of the impending approval of this new drug is that it will not replace standard immunotherapy. How it will fit into the armamentarium of physicians dealing with allergic disease, and protocols for its use, are still being debated. Ann Allergy Asthma Immunol 2001;87(Suppl):68– 69.
The discovery in 1970 of the agent responsible for allergy (IgE) triggered an immediate response among researchers to find an antibody-crippling mechanism to ameliorate the allergic response. Naturally occurring antibodies to IgE were subsequently found, which created a brief flurry of projects designed to induce these antibodies as a therapeutic modality.1–3 This research avenue bore no fruit; efforts were largely abandoned and redirected to create a new entity to cover the combining site of the docking molecule of the antibody. Once covered, the antibody would not be able to attach to mast cells and the body’s own clearance system would take care of removing the now-impotent antibody. Nothing would be changed in the immune system except that the allergic antibody would be prevented from attachLanier Education and Research Network, Fort Worth, TX. Received for publication November 10, 2000. Accepted for publication November 15, 2000.
68
ing to the mast cell. This is the basis of the new monoclonal antibody vaccine. Work using the mouse model for making specific anti-IgE antibodies began to appear in the medical literature in the late 1980s with a number of new findings in the early 1990s. By 1995, human trials were well underway and a buzz of excitement began to be heard coming from the physicians conducting clinical trials across the country.4 Both Tannox Biosystems in Houston (combined with Novartis), and Genentech in San Francisco produced molecules that worked. Cooperation between Tannox, Novartis, and Genentech, after extended litigation, eventually produced the study compound Rhumab E-25 or Omaluzumab. The production of anti-IgE begins with the injection of our human allergic antibody into mice. Mice, being naturally irritated by the injection of this foreign protein, react with a polyclonal antibody response. The B lymphocytes producing these antibodies are removed and a hybridoma is cre-
ated with fusion of the antibodies to myeloma cells. This hybridoma cell clone continually produces large quantities of identical monoclonal antibodies because they come from only one type of cell. Over a period of time, the products from each cell line are analyzed for the desired properties and are further cultured to extend the quantity of anti-IgE. Early experiments with mouse-derived antibodies revealed a brisk human anti-mouse immune response which negated the therapeutic potential. A recombinant process was used to cleave off all but the basic docking portion, which was inserted into a human protein (humanization). Less than 5% of nonhuman protein remains in the final product and only four amino acid groups in the entire molecule are not found in normal human tissue. When anti-IgE is injected, it mercilessly hunts and disables allergic antibody by creating a complex that prevents IgE binding to high-affinity Fc ⑀ RI and low-affinity Fc ⑀ RII on mast cells and basophils. Oddly enough, though, the complex retains its full antiparasitic capacity, and in some studies, the case can be made for enhanced antiparasitic activity.5 In extensive testing and human trials, no evidence of disease has been found related to this anti-IgE complex. In radio tagging studies, urinary excretion was the primary route of elimination of radioactivity; ⬎90% of the radioactivity found in urine was not associated with protein. The lack of specific tissue uptake and blood cell association and the slow clearance of Rhumab E25:IgE complexes were consistent with low-avidity interaction of small complexes with Fc ␥ receptors of leukocytes and the reticuloendothelial
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
system. There has been no complement fixation noted.6,7 There are four proven reactions that occur as a result of the injection of anti-IgE: 1) free antibody is bound; 2) bound antibody is not dislodged to any degree; 3) plasma B cell production of IgE drops; 4) and high-affinity Fc ⑀ RI and low-affinity Fc ⑀ RII on mast cells and basophils are downregulated.8 Anti-IgE is truly immunotherapy (IT). Since anti-IgE has been proven to reduce IgE levels in multiple trials, recent clinical trials have attempted to verify the clinical importance of the phenomenon in patients known to be symptomatic despite the best approved pharmaceutical-based control programs. Asthma patients (334) aged 6 to 12 years, already receiving corticosteroid therapy, were given either subcutaneous anti-IgE every 2 to 4 weeks, or placebo. Patients were closely followed for ⬎ 28 weeks in two phases: 1) a 16-week stable treatment period where patients had either anti-IgE or placebo added to their current therapy and 2) a 12-week steroid reduction period. In this study, steroids were discontinued altogether in ⬎50% of the patients on anti-IgE, and 71% in half the patients on placebo therapy. Headache (80 of 225 anti-IgE vs 33 of 109 placebo) and upper respiratory infection (78 of 225 anti-IgE patients vs 33 of 109 placebo) were the most frequently reported adverse events. The percentages for one or more adverse events were similar in each group: 89% of anti-IgE and 87% for placebo. There were no drug-related adverse events.
VOLUME 87, JULY, 2001
Whereas IgE levels tended to return to the exact former levels within 6 months of discontinuation, it is the anecdotal observation of many investigators that a number of these children remain asymptomatic on minimal medications for 1 year. The dose of the anti-IgE is dependent on the serum level of the person factored for body weight. A large person with an increased blood volume will need a larger and more frequent dose. A smaller person with a lower blood volume will require a smaller and less frequent dose. The vaccine is now given every 2 to 6 weeks, and may be given for an indefinite period of time. The impending approval of this agent has provoked some concern among practicing allergists. “Will this drug replace standard IT?” The consensus opinion from clinical investigators is “no.” But how this drug fits into the armamentarium of physicians is a hotly debated topic. If this drug eliminates the need for skin tests (“It doesn’t matter what you are allergic to, this gets it all”) and consequent IT (“Both standard IT and anti-IgE are expensive; we can’t do them both”), the basis for the profession of allergy is threatened. Some allergists relate the coming of anti-IgE as analogous to typewriter manufacturers watching the first computers roll off the assembly line, or dentists finding fluoride in toothpaste. Other physicians look at anti-IgE as an exciting tool in the further evolution of standardized antigen IT. Protocols for using anti-IgE as the preparation for expedited IT are already being considered.
REFERENCES 1. Quinti I, Brozek C, Wood N, et al. Circulating IgG autoantibodies to IgE in atopic syndromes. J Allergy Clin Immunol 1986;77:586 –594. 2. Fiebiger E, Stingl G, Maurer D. AntiIgE and anti-Fc ⑀ RI autoantibodies in clinical allergy. Curr Opin Immunol 1996;8:784 –789. 3. Hellman L. Is vaccination against IgE possible? Adv Exp Med Biol 1996; 409:337–342. 4. Shields RL, Whether WR, Zioncheck K, et al. Inhibition of allergic reactions with antibodies to IgE. Int Arch Allergy Immunol 1995;107:308 –312. 5. Korenaga M, Watanabe N, Tada I. Effects of anti-IgE monoclonal antibody on a primary infection of Strongyloides ratti in mice. Parasitol Res 1991;77:362–363. 6. Fox JA, Hotaling TE, Struble C, et al. Tissue distribution and complex formation with IgE of an anti-IgE antibody after intravenous administration in cynomolgus monkeys. J Pharmacol Exp Ther 1996;279:1000 –1008. 7. Liu J, Lester P, Builder S, Shire SJ. Characterization of complex formation by humanized anti-IgE monoclonal antibody and monoclonal human IgE. Biochemistry 1995;34: 10474 –10482. 8. Saini SS, MacGlashan DW Jr, Sterbinsky SA, et al. Down-regulation of human basophil IgE and FC ⑀ RI ␣ surface densities and mediator release by anti-IgE-infusions is reversible in vitro and in vivo. J Immunol 1999;162: 5624 –5630.
Requests for reprints should be addressed to: Bob Lanier, MD 5925-B Lovell Avenue Fort Worth, TX 76107 E-mail: [email protected]
69