11/8/2022 0 Comments Brian sheridan minitube3,6 Multiple direct and indirect effects related to blocking IL-2 association with CD25 may be responsible for the immune modulatory activities of daclizumab, including direct inhibitory effects on secretion of inflammatory cytokines expansion of regulatory CD56 bright natural killer (NK) cell activities inhibition of the sustained expression of the T-cell expressed co-stimulatory molecule CD40L and reductions in the priming of antigen naïve T cells as a consequence of inhibiting trans-presentation of IL-2 by antigen-presenting cells. 4,5 Both forms of daclizumab prevent IL-2 binding to CD25, thereby reducing IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling, such as effector T cells implicated in the pathology of MS. 3 A second form, known as daclizumab high-yield process (DAC HYP), has completed pivotal clinical trials and received approval as a treatment for multiple sclerosis under the name ZinbrytaTM. Food and Drug Administration in 1997 for the prophylaxis of acute organ rejection in patients receiving renal transplants, to be used in combination with an immunosuppressive regimen that included cyclosporine and corticosteroids, but later withdrawn from the marketplace for commercial reasons, not for safety reasons. 1,2 Different forms of daclizumab have been developed. The substantive glycosylation differences between the two antibody forms and corresponding greater Fc-mediated effector activities by Zenapax, including cell killing activity, manifest as a difference in the biological function and pharmacology between DAC HYP and Zenapax.ĭaclizumab is a humanized monoclonal antibody of the human IgG1 isotype that binds specifically to CD25, the α subunit of the human high-affinity interleukin-2 (IL-2) receptor. Incubation of each antibody with peripheral blood mononuclear cells also caused the down-modulation of CD16 expression on NK cells and the CD16 down-modulation was greater for Zenapax in comparison to that observed for DAC HYP. The ADCC activity required natural killer (NK) cells, but not monocytes, suggesting the effects were mediated through binding to Fc-gamma RIII (CD16). Although neither antibody elicited complement-dependent cytotoxicity in vitro, DAC HYP antibody had significantly reduced levels of antibody-dependent cell-mediated cytotoxicity (ADCC). Comparison of the physicochemical properties of the two antibody forms revealed the glycosylation profile of DAC HYP differs from Zenapax in both glycan distribution and the types of oligosaccharides, most notably high-mannose, galactosylated and galactose-α-1,3-galactose (α-Gal) oligosaccharides, resulting in a DAC HYP antibody material that is structurally distinct from Zenapax. He started his career with the Central Intelligence Agency.īrian earned a bachelor’s degree in political science from Boston College, a master of science degree in foreign service from Georgetown University, and a master of business administration degree from the University of Chicago.The CD25-binding antibody daclizumab high-yield process (DAC HYP) is an interleukin (IL)-2 signal modulating antibody that shares primary amino acid sequence and CD25 binding affinity with Zenapax®, a distinct form of daclizumab, which was approved for the prevention of acute organ rejection in patients receiving renal transplants as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. He also worked for the Department of Defense in a variety of leadership roles, culminating in service as assistant secretary of defense, special operations and low intensity conflict. Prior to GDIT, Brian was the general manager of Bechtel’s defense and security business line, where he was responsible for leading complex engineering and construction projects and managing the operations of advanced technology test facilities. Brian previously served as vice president and general manager of the Joint, Air Force, Naval and Coalition sector within the defense division. Department of Defense and other government customers. He oversees the delivery of mission-critical services and solutions to the U.S. Brian Sheridan is GDIT’s senior vice president for the defense division, reporting to President Amy Gilliland.
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