title: Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala).
abstract: Dimeric Fc receptor (FcR) nonbinding anti-CD3 antibodies have been developed to minimize toxicities associated with classical anti-CD3 monoclonal antibodies (e.g., OKT3). Studies with murine analogs of non-FcR-binding antibodies have shown reduced mitogenicity compared to OKT3. In a trial of an FcR nonbinding humanized anti-CD3 mAb hOKT3gamma1(Ala-Ala) for treatment of patients with type 1 diabetes, we found significant increases in IL-10 and IL-5 in the serum of 63% and 72% of patients, respectively, and TNF-alpha and IL-6 levels that were lower than those previously reported following OKT3 therapy. The activation signal delivered by hOKT3gamma1(Ala-Ala) was associated with calcium signaling and cytokine production by previously activated human cells in vitro. However, the production of IL-10, compared to IFN-gamma on a molar basis, was greater after culture with hOKT3gamma1(Ala-Ala) than with OKT3. Flow cytometric studies confirmed that OKT3 induced IFN-gamma and IL-10 production, but hOKT3gamma1(Ala-Ala) induced only detectable IL-10 production in CD45RO(+) cells. Moreover, in vivo, we found IL-10(+)CD4(+) T cells after drug treatment. These cells were heterogeneous but generally CD45RO(+), CTLA-4(-), and expressed CCR4. A subgroup of these cells expressed TGF-beta. Thus, the non-FcR binding anti-CD3 mAb, hOKT3gamma1(Ala-Ala) delivers an activation signal to T cells that is quantitatively and qualitatively different from OKT3. It leads to the generation of T cells that might inhibit the autoimmune response and may be involved in the beneficial effect on beta cell destruction in Type 1 diabetes.
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine and Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. kh318@columbia.edu
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Burton
authors.forename: Fleur
authors.initials: F
authors.lastname: Francois
authors.forename: Ena
authors.initials: E
authors.lastname: Poumian-Ruiz
authors.forename: Mariela
authors.initials: M
authors.lastname: Glandt
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism; D017252:CD3 Complex / Q000096:biosynthesis*; D002118:Calcium / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation; D016853:Muromonab-CD3 / Q000737:chemistry*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D011961:Receptors, Fc / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015850:Interleukin-6; D016853:Muromonab-CD3; D011961:Receptors, Fc; D014409:Tumor Necrosis Factor-alpha; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D002118:Calcium