TNX-901
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Talizumab (TNX-901) is a
humanized monoclonal antibody Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal ant ...
that was under development by
Tanox 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 ti ...
in Houston, Texas as a new-concept therapeutic for allergic diseases. The unique anti-IgE antibody was designed to target
immunoglobulin E Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isoform") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε ...
(
IgE Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isoform") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε ...
) and IgE-expressing
B lymphocytes B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
specifically, without binding to IgE already bound by the
high affinity IgE receptor 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 ...
s on
mast cells A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a ...
and
basophils 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 reactio ...
. Talizumab was tested in clinical trials at
National Jewish Medical and Research Center National Jewish Health is an American academic hospital/clinic in Denver, Colorado, doing research and treatment in respiratory, cardiac, immune and related disorders. It is an internationally respected medical center that draws people from man ...
and other medical centers and allergy clinics across the U. S. and shown to be able to prevent
allergic reaction 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 Allergic rhinitis, hay fever, Food allergy, food al ...
s to accidental exposure to peanuts, which is contained in many kinds of foods.


History

The
U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(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 Houston ( ) is the List of cities in Texas by population, most populous city in the U.S. state of Texas and in the Southern United States. Located in Southeast Texas near Galveston Bay and the Gulf of Mexico, it is the county seat, seat of ...
-based Tanox, started by two biomedical scientists,
Nancy T. Chang Chang Tang Chang (née Tang Nanshan; ; born 1950), also known by her English name Nancy Chang, is a Taiwanese biochemist. She co-founded the biopharmaceutical company Tanox in 1986. She also developed the asthma drug Xolair. In June 2003, the U.S. ...
and
Tse Wen Chang Tse Wen Chang (, born August 25, 1947) is a Taiwanese immunologist. His early research involving the Immunoglobulin E (IgE) pathway and antibody-based therapeutics lead to the development of omalizumab (also known as Xolair), a medication that h ...
, in 1986. There was a
legal dispute Legal proceeding is an activity that seeks to invoke the power of a tribunal in order to enforce a law. Although the term may be defined more broadly or more narrowly as circumstances require, it has been noted that " e term ''legal proceedings'' ...
whether Tanox had the right to independently develop TNX-901 under the tripartite partnership formed by Tanox,
Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...
, and
Genentech Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It operates as an independent subsidiary of holding company Roche. Genentech Research and Early Development operates as an independent cent ...
in 1996. Trials of TNX-901 for treating extreme peanut sensitivity, which affect children especially, were unfortunately mired in legal battles. In the original collaborative agreement signed between Tanox and
Ciba-Geigy Novartis AG is a Swiss multinational pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by revenue in 2024. Novartis manufactures the drugs ...
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 Right of first refusal (ROFR or RFR) is a contractual right that gives its holder the option to enter a business transaction with the owner of something, according to specified terms, before the owner is entitled to enter into that transactio ...
. (Note Ciba-Geigy merged with
Sandoz Sandoz Group AG is a Swiss company that focuses on generic pharmaceuticals and biosimilars. Prior to October 2023, it was part of a division of Novartis that was established in 2003, when Novartis united all of its generics businesses under the ...
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 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. Omalizumab is a recombi ...
(trade name
Xolair 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. Omalizumab is a recombin ...
) 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 Peanut allergy is a type of food allergy to peanuts. It is different from tree nut allergy, tree nut allergies, because peanuts are legumes and not true Nut (fruit), nuts. Physical symptoms of allergic reaction can include pruritus, itchiness, h ...
, 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 Arbitration is a formal method of dispute resolution involving a third party neutral who makes a binding decision. The third party neutral (the 'arbitrator', 'arbiter' or 'arbitral tribunal') renders the decision in the form of an 'arbitrati ...
. 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. The media hailed the success of the trials, but expressed outcry over the fate of the TNX-901 program on peanut allergy. 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.


Mechanism

TNX-901 is a humanized anti-IgE antibody with a unique set of binding specificity to human IgE. 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 A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a ...
and
basophils 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 reactio ...
, which bear on their surface
high affinity IgE receptor 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 ...
s, 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. 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 A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
, 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 Ind or IND may refer to: General * Independent (politician), a politician not affiliated to any political party * Independent station, used within television program listings and the television industry for a station that is not affiliated with ...
(“
Investigational New Drug The United States Food and Drug Administration's Investigational New Drug (IND) program is the means by which a pharmaceutical industry, pharmaceutical company obtains permission to start human clinical trials and to ship an experimental drug inte ...
”) approval from the U.S. FDA to be tested in human subjects. Under the collaborative agreement between Tanox and Ciba-Geigy, c GMP-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 Southampton is a port City status in the United Kingdom, city and unitary authority in Hampshire, England. It is located approximately southwest of London, west of Portsmouth, and southeast of Salisbury. Southampton had a population of 253, ...
, UK in 1991–1992, 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. 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. 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, 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. Omalizumab is a recombin ...
(
omalizumab 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. Omalizumab is a recombi ...
). 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.


References


External links

* {{Monoclonals for immune system Monoclonal antibodies Experimental monoclonal antibodies