Talizumab

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Talizumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target Fc region of IgE
Clinical data
ATC code
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CAS Number
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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.

Contents

History

The 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

TNX-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

The 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

Another 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]

Related Research Articles

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within Roche. Historically, the company is regarded as the world's first biotechnology company.

<span class="mw-page-title-main">Basophil</span> Type of white blood cell

Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. They are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They also produce compounds that coordinate immune responses, including histamine and serotonin that induce inflammation, and heparin that prevents blood clotting, although there are less than that found in mast cell granules. Mast cells were once thought to be basophils that migrated from the blood into their resident tissues, but they are now known to be different types of cells.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

<span class="mw-page-title-main">Food allergy</span> Hypersensitivity reaction to a food

A food allergy is an abnormal immune response to food. The symptoms of the allergic reaction may range from mild to severe. They may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressure. This typically occurs within minutes to several hours of exposure. When the symptoms are severe, it is known as anaphylaxis. A food intolerance and food poisoning are separate conditions, not due to an immune response.

<span class="mw-page-title-main">Omalizumab</span> Monoclonal antibody medication

Omalizumab, sold under the brand name Xolair among others, is an injectable medication to treat severe persistent allergic forms of asthma, nasal polyps, urticaria (hives), and immunoglobulin E-mediated food allergy.

<span class="mw-page-title-main">Allergen immunotherapy</span> Medical treatment for environmental allergies

Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergens in an attempt to change the immune system's response.

<span class="mw-page-title-main">Peanut allergy</span> Type of food allergy caused by peanuts

Peanut allergy is a type of food allergy to peanuts. It is different from tree nut allergies, because peanuts are legumes and not true nuts. Physical symptoms of allergic reaction can include itchiness, hives, swelling, eczema, sneezing, asthma attack, abdominal pain, drop in blood pressure, diarrhea, and cardiac arrest. Anaphylaxis may occur. Those with a history of asthma are more likely to be severely affected.

<span class="mw-page-title-main">FCER1</span>

The high-affinity IgE receptor, also known as FcεRI, or Fc epsilon RI, is the high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotype involved in allergy disorders and parasite immunity. FcεRI is a tetrameric receptor complex that binds Fc portion of the ε heavy chain of IgE. It consists of one alpha, one beta, and two gamma chains connected by two disulfide bridges on mast cells and basophils. It lacks the beta subunit on other cells. It is constitutively expressed on mast cells and basophils and is inducible in eosinophils.

Ibalizumab, sold under the brand name Trogarzo, is a non-immunosuppressive humanised monoclonal antibody that binds CD4, the primary receptor for HIV, and inhibits HIV from entering cells. It is a post-attachment inhibitor, blocking HIV from binding to the CCR5 and CXCR4 co-receptors after HIV binds to the CD4 receptor on the surface of a CD4 cell. Post-attachment inhibitors are a subclass of HIV drugs called entry inhibitors.

Tanox was a biopharmaceutical company based in Houston, Texas. The company was founded by two biomedical research scientists, Nancy T. Chang and Tse Wen Chang in March 1986 with $250,000, which was a large part of their family savings at that time. Both Changs grew up and received college education in chemistry in National Tsing Hua University in Taiwan and obtained Ph.D. degrees from Harvard University. For postdoctoral training, Tse Wen shifted to immunology and did research with Herman N. Eisen at the Center for Cancer Research, M.I.T. The two Changs successively became research managers and worked with a range of monoclonal antibody projects in Centocor, Inc. based in Malvern, Pennsylvania, from 1981 to 1985. The Changs were recruited by Baylor College of Medicine toward the end of 1985 and offered faculty positions in the Division of Molecular Virology. Soon after their arrival, they were encouraged by a high-ranking Baylor official and local business leaders to start a biotech venture in Houston. This was in a period of time when the economy of Houston was in slump as the result of the collapse of the oil industry.

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<span class="mw-page-title-main">Nancy T. Chang</span> Biochemist

Nancy Tang Chang, née Tang Nanshan, is a biochemist who cofounded Tanox in 1986 to address medical needs in the areas of allergy, asthma, inflammation and diseases affecting the human immune system. Tanox took an innovative approach in developing an asthma drug that focused on the allergy-related basis of asthma, Xolair. In June 2003, the U.S. Food and Drug Administration (FDA) approved Xolair, the first biotech product cleared for treating those with asthma related to allergies. Tanox was also active in the development of TNX-355, an antibody for the treatment of HIV/AIDS. In 2007, Tanox was sold to Genentech for $919 million. Dr. Chang grew Tanox from an idea to a substantial publicly traded company, doing innovative science. Following her success with Tanox, she has become an angel investor in health-care entrepreneurships and performs philanthropic work in community health-education projects.

Tse Wen Chang is an immunology researcher, whose career spans across academia and industry. His early research involving the Immunoglobulin E (IgE) pathway and antibody-based therapeutics lead to the development of omalizumab, a medication that has been approved for the treatment of severe allergic asthma and severe chronic spontaneous urticaria. Chang is a cofounder of Tanox, a biopharmaceutical company specialized in anti-IgE therapies for the treatment of allergic diseases. After Tanox's tripartite partnership with Genentech and Novartis was forged in 1996, Chang returned to his alma mater, the National Tsing Hua University in Taiwan and served as the Dean (1996–1999) of the College of Life Sciences. Chang was appointed by the Taiwanese government as President of the Development Center for Biotechnology (DCB) in 2000, and served as a Science and Technology Advisor of the Executive Yuan from 2002 to 2006. From 2006 to 2016, he was tenured as Distinguished Research Fellow at the Genomics Research Center, Academia Sinica. He founded Immunwork, Inc. in 2014.

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References

  1. 1 2 Pollack A (2003-03-13). "Wrangling May Delay Peanut Allergy Drug". The New York Times. ISSN   0362-4331 . Retrieved 2022-10-06.
  2. ↑ 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
  3. ↑ "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.
  4. ↑ "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.
  5. 1 2 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.
  6. 1 2 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.
  7. ↑ 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.
  8. ↑ 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
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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