Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

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