Post on 22-Jul-2015
The original anti-CD20
•Binds to CD20,leading to cell death and B cell depletion
•Significant off-label use
•Failed PIII studies in SLE and LN (trial design issues)
The original anti-CD20
•Binds to CD20,leading to cell death and B cell depletion
•Significant off-label use
•Failed PIII studies in SLE and LN (trial design issues)
B cellB cell
rituximab
CD20
Rituximab
Roche/GenentechPhase III
2nd generation anti-CD20
•BELONG trial in LN suspended due to infections
2nd generation anti-CD20
•BELONG trial in LN suspended due to infections
ocrelizumab
B cellB cell
CD20
GenentechBiogen-Idec
Ocrelizumab
Anti-CD22
Binds to CD22 (“an inhibitory B cell co-receptor”) •Cell death & partial B cell depletion•Anti-activation of B cells (“negative B cell signaling”)
Anti-CD22
Binds to CD22 (“an inhibitory B cell co-receptor”) •Cell death & partial B cell depletion•Anti-activation of B cells (“negative B cell signaling”)
B cellB cell
CD22
epratuzumab
Epratuzumab
UCBPhase III
BlyS blockade
Binds to soluble BlyS* (a B cell survival cytokine) blocking it from binding to the TACI° receptor•Inhibits B cell hyperactivity & activation•Blocks differentiation into plasma cells•Some B cell depletion
*B lymphocyte stimulator °Transmembrane activator and calcium-modulating cyclophilin ligand interactor;
BlyS blockade
Binds to soluble BlyS* (a B cell survival cytokine) blocking it from binding to the TACI° receptor•Inhibits B cell hyperactivity & activation•Blocks differentiation into plasma cells•Some B cell depletion
*B lymphocyte stimulator °Transmembrane activator and calcium-modulating cyclophilin ligand interactor;
B cellB cell
Soluble BlyS
TACIreceptor
Belimumab
Membrane-bound BlyS
Belimumab (benlysta)
HGS/GSK
Complete BlyS blockade
•Blocks BOTH soluble and membrane-bound BlyS from binding to TACI and activating the B cell•Will be available in SQ formulation
Complete BlyS blockade
•Blocks BOTH soluble and membrane-bound BlyS from binding to TACI and activating the B cell•Will be available in SQ formulation
LY2127399
LillyPhase III
B cellB cell
Soluble BlyS
TACIreceptor
Membrane-bound BlyS
LY2127399
Complete BlyS blockade
•Fusion protein: a BAFF* binding domain + Ig constant portion•Binds both soluble and membrane-bound BlyS•Will be available in a SQ formulation
Complete BlyS blockade
•Fusion protein: a BAFF* binding domain + Ig constant portion•Binds both soluble and membrane-bound BlyS•Will be available in a SQ formulation
Blisibimod
AntheraPIIb
B cellB cell
Soluble BlyS
TACIreceptor blisimibod
Membrane-bound BlyS
*B cell activating factor
Complete BlyS blockade
•Fusion protein of the TACI* receptor + Ig constant portion•Binds BlyS OR APRIL° preventing B cell activation by either ligand•PII halted in lupus nephritis; trial in SLE ongoing
*Transmembrane activator and CAML interactor (calcium-modulator and cyclophilin ligand)°A proliferation-inducing ligand
Complete BlyS blockade
•Fusion protein of the TACI* receptor + Ig constant portion•Binds BlyS OR APRIL° preventing B cell activation by either ligand•PII halted in lupus nephritis; trial in SLE ongoing
*Transmembrane activator and CAML interactor (calcium-modulator and cyclophilin ligand)°A proliferation-inducing ligand
Atacicept
MerckPIII
B cellB cell
TACIreceptor
Membrane-bound BlyS
BlyS
Atacicept
APRIL
Anti-interferon α
•Anti-IFNα receptor2 Moab•Biomarker test for IFNα gene signature (personlized medicine)
• Relationship between levels and disease activity has been demonstrated
•Both IV and SQ being studied
Anti-interferon α
•Anti-IFNα receptor2 Moab•Biomarker test for IFNα gene signature (personlized medicine)
• Relationship between levels and disease activity has been demonstrated
•Both IV and SQ being studied
Sifalimumab
AZ/MedimmunePII
pDCpDC
Cytokines and tissue damage
Differentiation, autoantibodies
B cellB cellT cellT cell
sifalimumab
Anti-interferon α
•Anti-IFNα receptor2 moab•Biomarker test for IFNα gene signature
• Relationship between levels and disease activity has been demonstrated
•Both IV and SQ being studied
Anti-interferon α
•Anti-IFNα receptor2 moab•Biomarker test for IFNα gene signature
• Relationship between levels and disease activity has been demonstrated
•Both IV and SQ being studied
Rontalizumab
Roche/GenentechPII
pDCpDC
Cytokines and tissue damage
Differentiation, autoantibodies
B cellB cellT cellT cell
Rontalizumab
Co-stimulatory blockade
•Fusion protein of CTLA-4* + Ig constant portion•Binds with CD80/86 on B cell, thereby blocking the ability to bind to CD28 on T cell•“T cell inhibition”•Ongoing PII/III trials for lupus nephritis; PII for SLE halted
*Cytotoxic T-lymphocyte-antigen 4
Co-stimulatory blockade
•Fusion protein of CTLA-4* + Ig constant portion•Binds with CD80/86 on B cell, thereby blocking the ability to bind to CD28 on T cell•“T cell inhibition”•Ongoing PII/III trials for lupus nephritis; PII for SLE halted
*Cytotoxic T-lymphocyte-antigen 4
Abatacept
BMSPII-III
B cellB cell T cellT cell
CD80
CD86
CD28
abatacept
T cell modulation
•CD4 T cell modulation•“Modulates rather than immunosuppresses”•May have potential to be used with other lupus agents b/c of lack of B cell action•Trial endpoints: reduction in anti-dsDNA antibodies & increase in IL-10
T cell modulation
•CD4 T cell modulation•“Modulates rather than immunosuppresses”•May have potential to be used with other lupus agents b/c of lack of B cell action•Trial endpoints: reduction in anti-dsDNA antibodies & increase in IL-10
Forigermod (Lupuzor)
CephalonPIIb
T cellT cell
CD4
Anti-proliferative
•Anti-proliferative, inhibiting de novo synthesis of guanosine nucleotides (RNA)•T and B cells are more dependent on this pathway than other cell types•Off label use•In study in lupus nephritis, flare rate was 16% vs. 32% with AZT
Anti-proliferative
•Anti-proliferative, inhibiting de novo synthesis of guanosine nucleotides (RNA)•T and B cells are more dependent on this pathway than other cell types•Off label use•In study in lupus nephritis, flare rate was 16% vs. 32% with AZT
Mycophenolate mofetil (Cellcept)
Roche
B cellB cell T cellT cell
Anti-proteosome
•Proteasomes degrade intracellular proteins in a regulated manner •Inhibition of the normal degradation of intracellular proteins leads to disruption of cellular proliferation and cell death
Anti-proteosome
•Proteasomes degrade intracellular proteins in a regulated manner •Inhibition of the normal degradation of intracellular proteins leads to disruption of cellular proliferation and cell death
Proteosome inhibition
PI
Proteasomes
Anti-proteosome
•Plasmacytoid dendritic cells express TLR7 and TLR9•When bound by ligands, they produce a large amount of IFN-α
Anti-proteosome
•Plasmacytoid dendritic cells express TLR7 and TLR9•When bound by ligands, they produce a large amount of IFN-α
TLR inhibition
Dynavax/othersPI