Transcript Document 7389285

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
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
Review team
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
Statisticians:
Kyung Lee-stat reviewer
Boguang Zhen-stat team leader
Facilities reviewer:
Ann deMarco
DSI/BiMo:
Dianne Tesch
DDMAC:
Catherine Gray
DDRE:
Hyon Kwon
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
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
T cell activation requires signals from TCR
and costimulatory molecules
CD28
TCR
B7
MHC + peptide
activated T cell Antigen presenting cell
CTLA4 – a CD28 homologue that
binds to B7 with higher affinity than CD28
CD28
B7
TCR
T cell
MHC + peptide
Antigen presenting cell
CTLA4 extracellular domain (B7-binding domain) is
fused to IgG1 Fc
to create soluble CTLA4-Ig
B7
CTLA4
IgG1 Fc
CTLA4-Ig
CTLA4-Ig binds to B7 molecules and inhibits
CD28-B7 interactions; suppresses T cell response
CD28
TCR
T cell
B7
MHC + peptide
Antigen presenting cell
Additional possible mechanisms of action to consider:
B7 engaged by CTLA4-Ig directly signals to dendritic cells
Suppresses T cell response
INF-g
tryptophan
B7
IDO
IDO
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
kynurenine
T cell proliferation
is inhibited
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
Binding to
Fc receptors
Phagocytosis/clearance
of opsonized cells
The paradox: CTLA4-Ig may disrupt critical pathways
required for maintenance of immune tolerance
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
CD28-B7 interactions are essential for both thymic development
of Tregs and for their peripheral homeostasis
% CD4+CD25+ thymocytes
Decreased development of Tregs
In the thymus in B7 knockout mice
Decrease in Tregs (CD4+CD25+) cells
in lymph nodes of wildtype mice treated
with CTLA4Ig for 10 days
4
3
2
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?
Activated T cells express CTLA4:
CTLA4 transduces a negative signal to T cells and
functions to attenuate the immune response
B7
CD28
TCR
T cell
MHC + peptide
Antigen presenting cell
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
TCR
T cell
MHC + peptide
Antigen presenting cell
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