Talizumab (TNX-901) is a humanized monoclonal antibody that was under development by Tanox in Houston, Texas as a new-concept therapeutic for allergic diseases. The unique anti-IgE antibody was designed to target immunoglobulin E (IgE) and IgE-expressing B lymphocytes specifically, without binding to IgE already bound by the high affinity IgE receptors on mast cells and basophils. Talizumab was tested in clinical trials at National Jewish Medical and Research Center and other medical centers and allergy clinics across the U. S. and shown to be able to prevent allergic reactions to accidental exposure to peanuts, which is contained in many kinds of foods.
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| Type | Whole antibody |
| Source | Humanized (from mouse) |
| Target | Fc region of IgE |
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History
editThe U.S. Food and Drug Administration (FDA) "fast-tracked" TNX-901. A drug is given a fast-track status if it meets a medical need not currently being met by any medication. TNX-901 was developed by Houston-based Tanox, started by two biomedical scientists, Nancy T. Chang and Tse Wen Chang, in 1986. There was a legal dispute whether Tanox had the right to independently develop TNX-901 under the tripartite partnership formed by Tanox, Novartis, and Genentech in 1996. Trials of TNX-901 for treating extreme peanut sensitivity, which affect children especially, were unfortunately mired in legal battles.[1][2][3]
In the original collaborative agreement signed between Tanox and Ciba-Geigy in 1990 to co-develop the anti-IgE antibody program, the two companies agreed to select a top candidate for manufacturing process development and clinical trials. The agreement stipulated that Tanox could develop any “left-over” antibody candidate, but when and if Tanox sought a corporate partner to further develop and commercialize the product, Ciba-Geigy would have the right of first refusal. (Note Ciba-Geigy merged with Sandoz to form Novartis in 1996.)
When Genentech joined in the anti-IgE program in 1996, the original 2-way Tanox-Ciba Geigy agreement was expanded to a tripartite agreement. A joint steering committee formed by members from the three companies chose omalizumab (trade name Xolair) developed by Genentech for further development, on the basis that it had a better developed manufacturing process than TNX-901. Tanox took a position that because the original clause concerning its right to develop a left-over candidate was not explicitly removed in the tripartite agreement, it should still have a right to do so with the recognition that its corporate partners, Novartis and Genentech, would still command right of first refusal on the product Tanox developed. Based on this position, Tanox proceeded with a phase II clinical trial of TNX-901 on peanut allergy, with the understanding that this indication was important and urgent, but was not on the top agenda of clinical testing planned by the steering committee.
As the issue on Tanox's right to develop TNX-901 was moved to the legal stage, a judge of a California court remarked that Tanox should have such a right, but then passed the case for arbitration.[4] The arbitration panel eventually ruled the case in favor of the giant partners, Genentech and Novartis, in 2002. The managers of Tanox agonized over the decision, in the midst of very positive results from the phase II studies of TNX-901 on peanut allergy.[5][6] The media hailed the success of the trials, but expressed outcry over the fate of the TNX-901 program on peanut allergy.[1][7][8]
Ten years have passed, since Tanox was forced to put its TNX-901 program on the shelf. In the meantime, a phase II clinical trial of omalizumab on peanut allergy failed to finish, as a couple of patients suffered anaphylactic reactions during the testing for baseline sensitivity for peanut allergens and the trial had to be suspended.[9]
Mechanism
editTNX-901 is a humanized anti-IgE antibody with a unique set of binding specificity to human IgE.[6] The therapeutic anti-IgE antibodies, like TNX-901, were designed to neutralize free IgE in the blood and in interstitial space and to target IgE-expressing B lymphocytes via their surface B cell receptors, without triggering the activation of mast cells and basophils, which bear on their surface high affinity IgE receptors, which are essentially fully occupied and armed by IgE. If an ordinary anti-IgE antibody, which does not possess the unique set of binding specificity of CGP51901 or TNX-901, were injected into a human subject, it would probably invariably induce an extensive scale of mast cell and basophil activation and hence the development of anaphylactic shocks. TNX-901 can intervene with the IgE-mediated allergic pathway at the top of the pathway, and hence prevent the down-stream release of pharmacological mediators from activated basophils and mast cells.[10][11][12] It was also discovered in the early clinical trials that the depletion of IgE in the blood gradually cause the down-regulation of the high-affinity IgE receptors on basophils, mast cells, and dendritic cells, rendering these cells insensitive to allergen activation.
Research
editThe chimeric form of TNX-901, was made prior to TNX-901 by Tanox in 1988-1989 and later referred to as CGP51901 (CGP is an acronym for “Ciba-Geigy Product”) after Tanox established a partnership with Ciba-Geigy in 1990. CGP51901 was the first anti-IgE antibody to receive an IND (“Investigational New Drug”) approval from the U.S. FDA to be tested in human subjects. Under the collaborative agreement between Tanox and Ciba-Geigy, cGMP-grade CGP51901 was manufactured in a 500-liter bioreactor facility in Tanox in Houston, Texas and a Phase I trial on individuals with pollen sensitivity was carried out in Southampton, UK in 1991–1992,[13] and a Phase II trial on patients with severe sensitivity to mountain cedar pollens was performed in three medical centers in Texas in 1994–1995.[14] Based on the safety and efficacy data of these two trials, a “switch-over” study was performed on TNX-901 and subsequently a double-blinded, randomized, placebo-controlled, and multi-center trial of TNX-901 was designed and performed on patients with extreme sensitivity to peanuts.[5]
The clinical trial results indicate that with the administration of TNX-901, patients, who could tolerate an average of half a peanut before the treatment, were able to ingest up to 9 peanuts before they started to have allergic reactions. Therefore, TNX-901 cannot cure peanut allergy, but could protect patients from the often violent and life-threatening reactions upon the accidental exposure to peanut. Note that this clinical study was not done on patients who were known to develop deadly anaphylactic reactions to minute traces of peanut.
Similar drugs
editAnother anti-IgE antibody with identical antigen-binding characteristics is already on the market for allergic asthma and immunoglobulin E-mediated food allergy, under the trade name Xolair (omalizumab). Omalizumab is an anti-IgE monoclonal antibody, which was placed in a development program under a tripartite partnership formed by Tanox, Novartis, and Genentech in 1996. Xolair was originally approved solely to treat severe persistent allergic forms of asthma and nasal polyps, but in February 2024, the FDA approved it also to treat severe food allergy.[15]
References
edit- ^ a b Pollack A (2003-03-13). "Wrangling May Delay Peanut Allergy Drug". The New York Times. ISSN 0362-4331. Retrieved 2022-10-06.
- ^ Hamilton DP. How Genentech, Novartis Stifled A Promising Drug. Wall Street Journal April 5, 2005. http://online.wsj.com/article/0,,SB111265511632497703-search,00.html
- ^ "Trials of an allergy drug Remedy against peanuts is mired in legal battles - International Herald Tribune". Archived from the original on 2007-03-12. Retrieved 2008-03-19.
- ^ "Court Stays Lawsuit Against Tanox, Inc.; Judge Returns Parties to Arbitration. - Free Online Library". Archived from the original on 2016-08-21. Retrieved 2012-09-27.
- ^ a b Leung DY, Sampson HA, Yunginger JW, et al. (2003). "Effect of anti-IgE therapy in patients with peanut allergy". N. Engl. J. Med. 348 (11): 986–93. doi:10.1056/NEJMoa022613. PMID 12637608.
- ^ a b Leung DY, Shanahan WR, Li XM, Sampson HA (2004). "New approaches for the treatment of anaphylaxis". Anaphylaxis. Novartis Foundation Symposia. Vol. 257. pp. 248–60, discussion 260–4, 276–85. doi:10.1002/0470861193.ch20. ISBN 978-0-470-86119-6. PMID 15025403.
- ^ Delayed help for peanut allergy sufferers - A new drug has been shown to offer protection against this sometimes fatal malady. Further testing, however, is stuck in a legal limbo. Business Week March 10, 2003. [1]
- ^ Robbins-Roth C. A David Vs. Goliath Biotech Story, With Goliath Winning. BioWorld Today April 8, 2005. http://www.bioventureconsultants.com/4-8-05_Article.html
- ^ Sampson HA, Leung DY, Burks AW, Lack G, Bahna SL, Jones SM, Wong DA (March 2011). "A phase II, randomized, double blind, parallel group, placebo controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy". J. Allergy Clin. Immunol. 127 (5): 1309–10.e1. doi:10.1016/j.jaci.2011.01.051. PMID 21397314.
- ^ Chang TW, Davis FM, Sun NC, Sun CR, MacGlashan DW Jr, Hamilton RG (February 1990). "Monoclonal antibodies specific for human IgE-producing B cells: a potential therapeutic for IgE-mediated allergic diseases". Bio/Technology. 8 (2): 122–6. doi:10.1038/nbt0290-122. PMID 1369991. S2CID 10510009.
- ^ Chang TW (February 2000). "The pharmacological basis of anti-IgE therapy". Nat. Biotechnol. 18 (2): 157–62. doi:10.1038/72601. PMID 10657120. S2CID 22688959.
- ^ Chang TW, Wu PC, Hsu CL, Hung AF (2007). Anti-IgE Antibodies for the Treatment of IgE-Mediated Allergic Diseases. Advances in Immunology. Vol. 93. pp. 63–119. doi:10.1016/S0065-2776(06)93002-8. ISBN 9780123737076. PMID 17383539.
- ^ Corne J, Djukanovic R, Thomas L, Warner J, Botta L, Grandordy B, Gygax D, Heusser C, Patalano F, Richardson W, Kilchherr E, Staehelin T, Davis F, Gordon W, Sun L, Liou R, Wang G, Chang TW, Holgate S (March 1997). "The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: efficacy, safety, and pharmacokinetics". J Clin Invest. 99 (5): 879–87. doi:10.1172/JCI119252. PMC 507895. PMID 9062345.
- ^ Racine-Poon A, Botta L, Chang TW, Davis FM, Gygax D, Liou RS, Rohane P, Staehelin T, van Steijn AM, Frank W (December 1997). "Efficacy, pharmacodynamics, and pharmacokinetics of CGP 51901, an anti-immunoglobulin E chimeric monoclonal antibody, in patients with seasonal allergic rhinitis". Clin Pharmacol Ther. 62 (6): 675–90. doi:10.1016/S0009-9236(97)90087-4. PMID 9433396. S2CID 28652703.
- ^ "FDA Approves First Medication to Help Reduce Allergic Reactions to Multiple Foods After Accidental Exposure". U.S. Food and Drug Administration (FDA) (Press release). 16 February 2024. Archived from the original on 19 February 2024. Retrieved 19 February 2024.
This article incorporates text from this source, which is in the public domain.
External links
edit- TNX901 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)