1 / 17

Abatacept (hCTLA4-Ig) For the Treatment of Rheumatoid Arthritis:

Abatacept (hCTLA4-Ig) For the Treatment of Rheumatoid Arthritis:. Product Attributes and Mechanism of Action Joy Williams, Ph.D. Arthritis Advisory Committee September 6, 2005. Abatacept BLA. Continuous Marketing Application (Rolling submission of BLA) Unit: Date of

brayton
Download Presentation

Abatacept (hCTLA4-Ig) For the Treatment of Rheumatoid Arthritis:

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Abatacept (hCTLA4-Ig) For the Treatment of Rheumatoid Arthritis: Product Attributes and Mechanism of Action Joy Williams, Ph.D. Arthritis Advisory Committee September 6, 2005

  2. Abatacept BLA Continuous Marketing Application (Rolling submission of BLA) Unit: Date of submission: Pharmacology and Toxicology reviewable unit 11/15/04 Clinical pharmacology and biopharmaceutics Full clinical reviewable unit 12/20/04 Chemistry, Manufacturing and Controls (CMC) reviewable unit 3/31/05 PDUFA action date for BLA 125118 (Abatacept): 12/31/05

  3. Review team Statisticians: Kyung Lee-stat reviewer Boguang Zhen-stat team leader Facilities reviewer: Ann deMarco DSI/BiMo: Dianne Tesch DDMAC: Catherine Gray DDRE: Hyon Kwon Regulatory Project manager: Erik Laughner Product reviewers: Joy Williams, chair Elizabeth Shores Susan Kirshner Ennan Guan Edward Max Barbara Rellahan Clinical reviewers: Keith Hull – Chair, clinical reviewer Jeffrey Siegel –Team leader Mark Walton-Director Pharm/Tox: Anita O'Connor-toxicology reviewer Anil Rajpal-Pharm reviewer Hannan Guan

  4. Abatacept (CTLA4-Ig) homodimer CTLA-4 domain: Extracellular sequence of human CTLA-4 IgG1 Fc domain: Hinge, CH2 and CH3 regions of human IgG1 Fc sequence

  5. Abatacept manufacturing process Abatacept is produced as a secreted protein in large scale culture of Chinese hamster ovary cell line Series of purification/viral clearance steps Final formulation Abatacept for Injection, 250 mg/vial sterile, non-pyrogenic lyophile for intravenous administration following reconstitution with Sterile Water for Injection; supplied with non-siliconized syringe Excipients: maltose monohydrate, sodium phosphate monobasic, Sodium chloride, hydrochloric acid, sodium hydroxide

  6. T cell activation requires signals from TCR and costimulatory molecules B7 CD28 TCR MHC + peptide activated T cell Antigen presenting cell

  7. CD28 B7 CTLA4 TCR MHC + peptide CTLA4 – a CD28 homologue that binds to B7 with higher affinity than CD28 Antigen presenting cell T cell

  8. CTLA4 extracellular domain (B7-binding domain) is fused to IgG1 Fc to create soluble CTLA4-Ig B7 CTLA4 IgG1 Fc CTLA4 extracellular domain CTLA4-Ig

  9. CTLA4-Ig binds to B7 molecules and inhibits CD28-B7 interactions; suppresses T cell response CD28 B7 TCR MHC + peptide Antigen presenting cell T cell

  10. B7 engaged by CTLA4-Ig directly signals to dendritic cells Suppresses T cell response Additional possible mechanisms of action to consider: INF-g tryptophan B7 IDO IDO kynurenine IDO Grohmann et al. Nat Immunol. 3:1097-101 Mellor et al. JI 171:1652-5 Boasso et al. Blood 105: 1574-81 Munn et al. JI 172: 4100-10 T cell proliferation is inhibited

  11. Additional possible mechanisms of action to consider: Potential functions of the IgG1 Fc portion of abatacept Resulting in elimination of B7-expressing cells and suppression of T cell response B7 expressing cell ? Antibody-dependent Cellular cytoxicity (ADCC) CTLA4 ? IgG1 Fc Phagocytosis/clearance of opsonized cells Binding to Fc receptors

  12. The paradox: CTLA4-Ig may disrupt critical pathways required for maintenance of immune tolerance

  13. T regulatory cells are critical components in the maintenance of peripheral tolerance to tissue-specific self-antigens T regulatory cell Effector T cell B7-CTLA4 Self-antigen Antigen presenting cell In both humans and mice, absence of T regulatory cells is associated with aggressive autoimmunity

  14. CD28-B7 interactions are essential for both thymic development of Tregs and for their peripheral homeostasis Decrease in Tregs (CD4+CD25+) cells in lymph nodesofwildtype mice treated with CTLA4Ig for 10 days Decreased development of Tregs In the thymus in B7 knockout mice 4 3 2 % CD4+CD25+ thymocytes 1 0 wildtype B7 knockout Williams et al. (not published) Tang et al. JI 171: 3348-52 In certain inbred mouse strains, autoimmune disease is exacerbated in the absence of B7 or CD28 due to loss of Tregs Implications for development of fetal immune system during gestation?

  15. Activated T cells express CTLA4: CTLA4 transduces a negative signal to T cells and functions to attenuate the immune response B7 CD28 CTLA4 TCR MHC + peptide Antigen presenting cell T cell

  16. Activated T cells express CTLA4: CTLA4 transduces a negative signal to T cells and functions to attenuate the immune response; CTLA4-Ig may interfere with this process B7 CD28 CTLA4 TCR MHC + peptide Antigen presenting cell T cell

  17. Abatacept (CTLA4-Ig) Mechanism of Action Summary Mechanisms of action that may function to ameliorate RA: Blocking CD28 costimulation Induction of suppressor antigen-presenting cells (via IDO) Depletion of B7-expressing cells Mechanisms of action that may exacerbate autoimmunity: Inhibition of T regulatory (CD4+CD25+) cell maintenance/development Inhibition of endogenous CTLA4 signals

More Related