Otelixizumab Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:458269768
Type:mab
Mab Type:mab
Source:xizu/a
Target:CD3E
Cas Number:881191-44-2
Atc Prefix:none
Unii:I5HF2X04PB
Kegg:D08959
Chemspiderid:none
C:6448
H:9954
N:1718
O:2016
S:42

Otelixizumab, also known as TRX4, is a monoclonal antibody,[1] which is being developed for the treatment of type 1 diabetes and other autoimmune diseases. The antibody is being developed by Tolerx, Inc. in collaboration with GlaxoSmithKline and is being manufactured by Abbott Laboratories.[2] [3]

Mechanism of action

Otelixizumab is one of several investigational monoclonal antibodies that target CD3, a T lymphocyte receptor involved in normal cell signaling. More specifically, otelixizumab targets the epsilon chain of CD3. Data suggest that the drug works by blocking the function of effector T cells, which mistakenly attack and destroy insulin-producing beta cells, while stimulating regulatory T cells, which are understood to protect against effector T cell damage, thus preserving the beta cells' normal ability to make insulin.[4]

Proof of concept was established in a randomized, placebo-controlled Phase 2 study. These data demonstrated otelixizumab's ability to preserve beta cell function, as measured by C-peptide, in patients up to 18 months after dosing, as well as reduce the need for delivered insulin to maintain glucose control.[5] [6]

Clinical progress

The efficacy and safety of otelixizumab for the treatment of autoimmune type 1 diabetes was studied in a pivotal Phase 3 study called DEFEND (Durable-response therapy Evaluation For Early or New-onset type 1 Diabetes). DEFEND was a randomized, placebo-controlled Phase 3 trial designed to enroll approximately 240 adult patients, age 18 to 45, with newly diagnosed autoimmune type 1 diabetes. DEFEND was conducted at multiple centers in North America and Europe. The trial was designed to evaluate whether a single course of otelixizumab, administered not more than 90 days after the initial diagnosis, would reduce the amount of administered insulin required to control blood glucose levels by inhibiting the destruction of beta cells.[7] The trial failed to show efficacy of the treatment.[8]

Orphan drug status

Otelixizumab has been granted "orphan drug" status by the U.S. Food and Drug Administration.[9]

Chemistry

As a monoclonal antibody, otelixizumab consists of two heavy chains and two light chains. The heavy chains are humanized γ1 (gamma-1) chains from rats, making otelixizumab an immunoglobulin G1. The light chains are chimeric human/rat λ (lambda) chains.[10]

Notes and References

  1. Bolt S, Routledge E, Lloyd I, Chatenoud L, Pope H, Gorman SD, Clark M, Waldmann H . The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties . European Journal of Immunology . 23 . 2 . 403–11 . February 1993 . 8436176 . 10.1002/eji.1830230216 . 25876507 .
  2. Web site: Windhover Information "GSK buys rights to Tolerx's diabetes antibody otelixizumab" . 2009-04-13 . https://web.archive.org/web/20110718061511/http://sis.windhover.com/buy/abstract.php?id=200720729 . 2011-07-18 . dead .
  3. News: TolerRx Inc., of Cambridge, Mass., entered an agree- ment with Abbott Park, Ill.-based Abbott Laboratories for the manufacturing of TolerRx's TRX4 monoclonal antibody . Bioworld Today . 16 . 228 . 20 November 2005 . Thomson Bioworld . 6 . 2 December 2009.
  4. Chatenoud L, Bluestone JA . CD3-specific antibodies: a portal to the treatment of autoimmunity . Nature Reviews. Immunology . 7 . 8 . 622–32 . August 2007 . 17641665 . 10.1038/nri2134 . 11868182 .
  5. Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L . 6 . Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes . The New England Journal of Medicine . 352 . 25 . 2598–608 . June 2005 . 15972866 . 10.1056/NEJMoa043980 . free .
  6. Kaufman A, Herold KC . Anti-CD3 mAbs for treatment of type 1 diabetes . Diabetes/Metabolism Research and Reviews . 25 . 4 . 302–6 . May 2009 . 19319985 . 10.1002/dmrr.933 . 36595661 . free .
  7. Web site: DEFEND is a Phase 3 clinical study . https://web.archive.org/web/20090220000208/http://defendagainstdiabetes.com/ . 20 February 2009 .
  8. Web site: Tolerx, Inc. and GlaxoSmithKline (GSK) Announce Phase 3 Defend-1 Study of Otelixizumab in Type 1 Diabetes Did Not Meet Its Primary Endpoint . Biospace . https://web.archive.org/web/20110929033328/http://www.biospace.com/news_story.aspx?StoryID=213614&full=1 . 2011-09-29 .
  9. Web site: N.E. drug makers find individual paths into growing diabetes arena . Mass High Tech . May 16, 2008 . April 13, 2009 . https://web.archive.org/web/20090215102021/http://www.masshightech.com/stories/2008/05/12/focus1-NE-drug-makers-find-individual-paths-into-growing-diabetes-arena.html . February 15, 2009 . dead .
  10. Recommended INN List 60 . https://web.archive.org/web/20120307220615/http://apps.who.int/medicinedocs/index/assoc/s14915e/s14915e.pdf . dead . March 7, 2012 . WHO Drug Information . 22 . 3 . 2008 .

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