Basic Immunology IITargeted therapy
Basic Immunology IITargeted therapy
Ratanavadee Nanagara, M.D.
Allergy-Immunology-Rheumatology UnitDepartment of MedicineKhonKaen University
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
avoid Ag exposure antimicrobial
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
Antimalarial drug
change pH in
phagosome
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
HLA-DR
TcR TcRTcR
CD3
CD4CD4CD2LFA-3
ICAM-1
Ag
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
APC TH
CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)
Cytotoxic T lymphcyte-associated antigen 4= immunoregulatory protein
? RA refractory to TNF- inhibitor? RA subset …. phase III? SLE mice
CD40
CTLA4-Ig - CTLA4-Fc - LEA29Y
CTLA4-Ig - CTLA4-Fc - LEA29Y
LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)
CD40LCD40L
azathioprine
BCD40
HLA-DR
TcR TcRTcR
CD3
CD4CD4
CD2LFA-3
ICAM-1
Ag
APC TH
CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)
CD40 CD40LCD40L
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
Anti CD40L mAb( IDEC-131, hu5c8, BG9588, Biogen )
Anti CD40L mAb( IDEC-131, hu5c8, BG9588, Biogen )
RA
T
B
CD40
SLEB
CD40
B CD
40 B
CD40
LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)
thrombosis !
CD40 on platelets??
HLA-DR
TcR TcRTcR
CD3
CD4CD4
CD2LFA-3
ICAM-1
Ag
APC TH
CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)
CD40
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
efalizumabefalizumab: humanized mAb CD11a: humanized mAb CD11a
psoriasis
LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)
CD40LCD40L
HLA-DR
TcR TcRTcR
CD3CD3
CD4CD4
CD2LFA-3
ICAM-1
Ag
APC TH
CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)
CD40
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)
CD40LCD40L
Anti-CD3 : HuOKT31 (Ala-Ala)Anti-CD3 : HuOKT31 (Ala-Ala)
HLA-DR
TcR TcRTcR
CD3CD3
CD4CD4
CD2CD2LFA-3
ICAM-1
Ag
APC TH
CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)
CD40
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)
CD40LCD40L
CD2 antagonist : Alefacept (Biogen Idec, phase II)CD2 antagonist : Alefacept (Biogen Idec, phase II)
Signal Transduction
HLA-DR
stimulusspecificreceptor
signal transduction transcriptiontranslation
proteins
Receptor associating
proteins
Protein kineasepathways
Translocation oftranscription factors
mRNAmRNA
post-transcription
HLA-DR
stimulusspecificreceptor
signal transduction transcriptiontranslation
proteins
Receptor associating
proteins
Protein kineasepathways
Translocation oftranscription factors
mRNAmRNA
post-transcription
MAPK inhibitor Scio-469 (oral )
phase IIb
MAPK inhibitor Scio-469 (oral )
phase IIb
RANKL
AMG162 Humanized Ab
AMG162 Humanized Ab
Antiresorptive during bone remodeling
siRNATNF blockademouse model
siRNATNF blockademouse model
Calcineurin
inhibitor
Calcineurin
inhibitor
JNK inhibitorJNK inhibitor
TRAF inhibitorTRAF inhibitor
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
CAMPATH-1HCAMPATH-1H
Profound peripherallymphopenia
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
IL-2 DAB IL-2DAB IL-2
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
Rituximebanti-CD20Rituximebanti-CD20
B
CD20
immaturematurenaive
B
CD20
memory
B
CD20
P
Plasma cell
Rituximebanti-CD20Rituximebanti-CD20
B-cell depletion
Autoimmune with antibody production
refractory Wegener granulomatosis, SLE with AIHA, ITP
essential mixed cryoglobulinemia, RA (? RF+ve)
B
CD20
CD40CD80 B-cell repair
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8IVIG
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
Biologic response modifier
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
ET-1®TGF-
TNF- - soluble p75-TNFR type II (etanercept)
- chimeric human: mouse mAb (infliximab)
- humanized mAb (adalimumab)
- converting enzyme inhibitors (GW3333)
in developing:
- PEGylated anti TNF- Fab’ fragment (CDP-870, UCB, phase III RA)
- PEGylated soluble TNF receptor type I (Pegsunercept, Amgen, phase II)
- TNF- antisense inhibitor (ISIS-104838, Isis Pharma, phase II)
- oral TNF inhibitor (AGIX4207, AtheroGenics, phas II)
Biologic response modifier
IL-1 recombinant IL-1R antagonist (anakinra)
soluble IL-1R type II
IL-1 Trap (recombinant IL-1R I – IgG Fc)
IL-1 converting enzyme inhibitor (caspase-1)
IFNrecombinant IFN- recombinant IFN-
IL-6 IL-6 mAb soluble IL-6R humanized anti IL-6 R mAb (Atlizumab, MRA,
Roache/Ghugai phase I, II)
IL-12 anti IL-12 mAb (ABT874/J-695, Abbott/Cambridge Ab Tech, phase II)
IL-15 anti IL-15 mAb (HuMAX-IL-15/AMG-714, Immunex/Genmab, phase II)
Biologic response modifier
Chemokines & Growth factors
IL-18 recombinant human IL-18 binding protein
IL-8 humanized CXCL8 / IL-8 Ab
CCR1 oral CCR1-antagonist
ET-1 ET-1 receptor antagonist (Bosentan)
TGF- anti-TGF-
VEGF soluble VEGFR1-Fc
Signal p38 MAPK pathway inhibitor (vx-745)
transduction c-Jun-N terminal kinase (JNK) inhibitor
calcineurin inhibition (post receptor signaling)
signaling repressor (CIS3/SOCS3)
Alternative targets of cytokine modifying Rx
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
block adhesionmolecules
HLA DR+
CD 44LFA-1
CLA
P & E Selectin (CD62)
ICAM-1
ICAM-2VCAM-1 (CD106)
VLA-4(CD49/29)
Anti-human-ICAM-1 Ab (enlimomab)Anti-human-ICAM-1 Ab (enlimomab)
ADHESION MOLECULES
mAb E-selectinmAb E-selectin
humanized anti–v3
(integrin mAb)
humanized anti–v3
(integrin mAb)
Humanized 4-1, 4-7 mAb (Natalizumab)
2ME2 (2 methoxyextradiol) antiangiogenesis
anti VCAM-1anti VCAM-1
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
Anti-inflammatory agents
NO synthetaseSuperoxide dismutase
Good luck
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