huOKT3gamma in T1DM

Diabetes Mellitus, or Type 1 Diabetes (T1DM), is an autoimmune disorder in which one’s T cells destroy the insulin-producing pancreatic b cells. (5) Insulin is necessary for the metabolism of glucose and a balance between insulin and glucose must be maintained to avoid either hyperglycemia or hypoglycemia.
b cells account for about 60% of the cells are produced in the islets of the pancreas. The onset of T1DM occurs when one’s b cells have nearly all been destroyed. Once this occurs treatment with exogenous insulin to maintain the proper insulin-glucose balance is required. Food intake must be carefully monitored carefully as is affects this balance.
The monitoring devices, delivery methods and the daily management of T1DM has become more streamlined and convenient, it still requires insulin in the right amounts at the right intervals. The advent of “closed loop” systems would, in essence, act as an artificial pancreas but would still require exogenous insulin. There are two other options that offer promise of dramatically changing treatment. One is islet cell transplantation which restores the pancreas’s ability to produce b cells and thereby endogenous insulin. A second option, and the focus here, is the preservation of islet cell function – the production of b cells which produce insulin. This necessitates interfering in the process that results in b cell destruction as close to onset of frank diabetes as possible.
Anti-rejection therapies used in organ transplantation are a possibility because of their effect on autoimmune responses. One agent with promise has been used in renal and renal-pancreatic transplants: huOKT3g which interferes in the events leading to autoimmune destruction of b cells. (3) huOKT3g is an ati-CD3 antibody; CD 3 is a group of proteins that associates with T-cell receptors to generate an activation signal in T lymphocytes that results in the destruction of b cells. huOKT3g is a humanized, nonmitogenic, Fc receptor non-binding OKT3 antibody. (3) This means that it is an antibody derived from a mouse in which the genetic information for six complimentarity determining regions (CDRs) has been grafted within a human IgG1 monoclonal antibody. (1) This reduces the amount of mouse material to £ 10%. The antibody is nonmitogenic because it contains no substances that signal a cell to divide which would trigger mitosis. (1) In addition, the CH2 region of the IgG1 has been altered by site-directed mutagenesis which changes Fc receptor binding activity which also eliminates T cell activation. Studies have shown that these manipulations of the antibody result in it retaining its immunosuppressive properties, but not its immune activating properties.(1) The most encouraging thing about huOKT3g treatment (by infusion) is that its effect on b cell preservation persists for at least a year post-infusion. Current trials are testing whether reinfusion at 1 year can further extend the preservation of b cells.

References:
Woodle ES, Bluestone JA, Zivin RA, Jolliffe LK, Auger j, Xu D, Thistlethwaite JR, Humanized, Nonmitogenic OKT3 Antibody, huOKT3g (Ala-Ala): Initial clinical Experience, Transplantation Proceedings, 30, 1369-1370, 1998.
Seegan GW, Smith CA, Schumaker VN, Changes in quaternary structure of IgG upon reduction of the interheavy-chain disulfide bond, Proceedings National Academy of Sciences, Vol. 76, No 2. 907-911, February 1979.
Woodle ES, Xu D, Zivin RA, Auger J, Charette J, Olaughlin R, Peace D, Jolliffe LK, Haverty T, Bluestone JA, Thistlethwaited JR, Phase I Trial of Humanized, Fc Receptor Nonbinding OHT3 Antibody, huOKT3[gamma[ in the Treatment of Acute Renal Allograft Rejection, Transplantation, Vol. 68(5), 608-616, 15 September 1999
Chatenoud L, Primo J, Bach, JF, CD3 Antibody-Induced Dominant Self Tolerance in Overtly Diabetic NOD Mice, The Journal of Immunology, 22-1767, 2947-2954, 1997.
Herold KC, Hagopian W, Auger JA, Poumian E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA, Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus, NEJM, 346, No 22, May 30, 2002.