Otelixizumab

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Otelixizumab
Monoclonal antibody
TypeWhole antibody
SourceChimeric/humanized hybrid (rat/human)
TargetCD3E
Clinical data
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6448H9954N1718O2016S42
Molar mass145145.09 g·mol−1
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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).[7] 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.[8] The trial failed to show efficacy of the treatment.[9]

Orphan drug status

Otelixizumab has been granted "orphan drug" status by the U.S. Food and Drug Administration.[10]

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.[11]

References

  1. ^ Bolt S, Routledge E, Lloyd I, Chatenoud L, Pope H, Gorman SD, Clark M, Waldmann H (February 1993). "The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties". European Journal of Immunology. 23 (2): 403–11. doi:10.1002/eji.1830230216. PMID 8436176. S2CID 25876507.
  2. ^ "Windhover Information "GSK buys rights to Tolerx's diabetes antibody otelixizumab"". Archived from the original on 2011-07-18. Retrieved 2009-04-13.
  3. ^ "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" (PDF). Bioworld Today. Vol. 16, no. 228. Thomson Bioworld. 20 November 2005. p. 6. Retrieved 2 December 2009.
  4. ^ Chatenoud L, Bluestone JA (August 2007). "CD3-specific antibodies: a portal to the treatment of autoimmunity". Nature Reviews. Immunology. 7 (8): 622–32. doi:10.1038/nri2134. PMID 17641665. S2CID 11868182.
  5. ^ Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, et al. (June 2005). "Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes". The New England Journal of Medicine. 352 (25): 2598–608. doi:10.1056/NEJMoa043980. PMID 15972866.
  6. ^ Kaufman A, Herold KC (May 2009). "Anti-CD3 mAbs for treatment of type 1 diabetes". Diabetes/Metabolism Research and Reviews. 25 (4): 302–6. doi:10.1002/dmrr.933. PMID 19319985. S2CID 36595661.
  7. ^ Clinical trial number NCT00678886 for "Trial of Otelixizumab for Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-1 (DEFEND-1)" at ClinicalTrials.gov
  8. ^ "DEFEND is a Phase 3 clinical study". Archived from the original on 20 February 2009.
  9. ^ "Tolerx, Inc. and GlaxoSmithKline (GSK) Announce Phase 3 Defend-1 Study of Otelixizumab in Type 1 Diabetes Did Not Meet Its Primary Endpoint". Biospace. Archived from the original on 2011-09-29.
  10. ^ "N.E. drug makers find individual paths into growing diabetes arena". Mass High Tech. May 16, 2008. Archived from the original on February 15, 2009. Retrieved April 13, 2009.
  11. ^ "Recommended INN List 60" (PDF). WHO Drug Information. 22 (3). 2008. Archived from the original (PDF) on March 7, 2012.