Otelixizumab

Otelixizumab
Monoclonal antibody
Type Whole antibody
Source Chimeric/humanized hybrid (rat/human)
Target CD3E
Clinical data
ATC code none
Identifiers
CAS Number 881191-44-2 N
ChemSpider none
UNII I5HF2X04PB YesY
KEGG D08959 YesY
Chemical and physical data
Formula C6448H9954N1718O2016S42
Molar mass 145.1 kg/mol
 NYesY (what is this?)  (verify)

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, S., Clark, M. & Waldmann, H. (1993). The generation of humanized, non-mitogenic CD3 monoclonal antibody which retains in-vitro immunosuppressive properties. Europ. J. Immunol. 23, 403-411.
  2. ↑ Windhover Information “GSK buys rights to Tolerx's diabetes antibody otelixizumab”
  3. ↑ (PDF). Thomson Bioworld. 30 November 2005. p. 6 http://www.bioworld.com/img/bwt11302005sample.pdf. Retrieved 2 December 2009. Missing or empty |title= (help)
  4. ↑ Chatenoud, L; Bluestone, JA (2007). "CD3-specific antibodies: a portal to the treatment of autoimmunity.". Nature Reviews Immunology. 7 (8): 622–32. doi:10.1038/nri2134. PMID 17641665.
  5. ↑ Chatenoud, L.; Vandemeulebroucke, E; Ziegler, AG; Mathieu, C; Kaufman, L; Hale, G; Gorus, F; Goldman, M; Walter, M (June 2005). "Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes". N Engl J Med. 352 (25): 2598–608. doi:10.1056/NEJMoa043980. PMID 15972866.
  6. ↑ Kaufman, A; Herold, KC (24 March 2009). "Anti-CD3 mAbs for treatment of type 1 diabetes.". Diabetes Metab Res Rev. 25 (4): 302–6. doi:10.1002/dmrr.933. PMID 19319985.
  7. ↑ From ClinicalTrials.gov, a Service from the U.S. National Institutes of Health
  8. ↑ www.DefendAgainstDiabetes.com
  9. ↑ Biospace:Tolerx, Inc. and GlaxoSmithKline (GSK) Announce Phase 3 Defend-1 Study of Otelixizumab in Type 1 Diabetes Did Not Meet Its Primary Endpoint
  10. ↑ Mass High Tech, May 16, 2008, “N.E. drug makers find individual paths into growing diabetes arena”
  11. ↑ "Recommended INN List 60" (PDF). WHO Drug Information. 22 (3). 2008.
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