Plasma cells

1. Professor David Baker
(david.baker@qmul.ac.uk)
Targeting B and Plasma Cells in
CNS inflammatory Disease
8th Hellenic Academy of Neuroimmunology
1
Slides available www.ms-res.org

2. but are used here to help identify mechanisms of disease activity
• Compounds in red are not (currently) indicated for multiple sclerosis,
• The content and slides were all designed and made by David Baker
Disclosures
• Although considered to be irrelevant, D. Baker has received compensation
in the past 3 years from:
• Contributor: MS blog (www.ms-res.org)
InMune Bio, Lundbeck, Merck, Novartis,
Jannsen, Roche, Teva.
• David Baker is not a neurologist and is not clinically qualified
2

3. B Cells and Plasma Cells
Secondary Lymphoid
Tissues
Primary Lymphoid
Tissues
Mantle zone
Plasma cell
Memory
B cell
Germinal Centre
Cells
Germinal
Centres
Germinal Centre
Light Zone
Lymphoid
Tissues
Simplified B cell Lineage1
Dendritic
Cell
1. Baker et al. Ebiomed 2017; 16:41. 2 Baker et al. Mult Scler Rel Dis 2019; 30:176. 3. http://histolab.e-line.nu/ 4.Margoni M et al. J Neurol. 2021 Aug 11:1–19. doi: 10.1007/s00415-
021-10744-x, 5. Baker et al. Brain 2019 141:2834. 6. Aguis et al. Mult scler 25:235-245. 7. Cree et al. Lancet 2019 394:1352, 8. Krejcik et al. Blood 2016:128:384, 9. Borstel et al.
Front Immunol 2019. doi.org/10.3389/fimmu.2019.02221 10. Jagannath et al. Clin Lymphoma Myeloma Leul 2019; 19:372 11. Lonial et al. Lancet Oncol 21:207
3

4. Secondary Lymphoid
Tissues
Primary Lymphoid
Tissues
Mantle zone
Plasma cell
Memory
B cell
Germinal Centre
Cells
Germinal
Centres
Germinal Centre
Light Zone
Lymphoid
Tissues
Dendritic
Cell
T cell
area
Germinal
Centre
(GC)
GC
GC
Follicle
Deoxycytidine kinase expression2
CD138 plasma cell expression3
Simplified B cell Lineage1
1. Baker et al. Ebiomed 2017; 16:41. 2 Baker et al. Mult Scler Rel Dis 2019; 30:176. 3. http://histolab.e-line.nu/ 4.Margoni M et al. J Neurol. 2021 Aug 11:1–19. doi: 10.1007/s00415-
021-10744-x, 5. Baker et al. Brain 2019 141:2834. 6. Aguis et al. Mult scler 25:235-245. 7. Cree et al. Lancet 2019 394:1352, 8. Krejcik et al. Blood 2016:128:384, 9. Borstel et al.
Front Immunol 2019. doi.org/10.3389/fimmu.2019.02221 10. Jagannath et al. Clin Lymphoma Myeloma Leul 2019; 19:372 11. Lonial et al. Lancet Oncol 21:207
B Cells and Plasma Cells
4

5. Secondary Lymphoid
Tissues
Primary Lymphoid
Tissues
Tositumomab
Ibritumomab
Rituximab4
Ublituximab4
Ocrelizumab4
Obinutuzumab
Ofatumumab4
Rituximab4,5
Ublituximab4
B cell Targeting
CD20 B cells
1. Baker et al. Ebiomed 2017; 16:41. 2 Baker et al. Mult Scler Rel Dis 2019; 30:176. 3. http://histolab.e-line.nu/ 4.Margoni M et al. J Neurol. 2021 Aug 11:1–19. doi: 10.1007/s00415-
021-10744-x, 5. Baker et al. Brain 2019 141:2834. 6. Aguis et al. Mult scler 25:235-245. 7. Cree et al. Lancet 2019 394:1352, 8. Krejcik et al. Blood 2016:128:384, 9. Borstel et al.
Front Immunol 2019. doi.org/10.3389/fimmu.2019.02221 10. Jagannath et al. Clin Lymphoma Myeloma Leul 2019; 19:372 11. Lonial et al. Lancet Oncol 21:207
Simplified B cell Lineage1
Used off-label in a variety of neurological and non-neurological autoimmune conditions5
5

6. Secondary Lymphoid
Tissues
Primary Lymphoid
Tissues
Tositumomab
Ibritumomab
Rituximab4
Ublituximab4
Ocrelizumab4
Obinutuzumab
Ofatumumab4
Rituximab4,5
Ublituximab4
B cell Targeting
CD20 B cells
1. Baker et al. Ebiomed 2017; 16:41. 2 Baker et al. Mult Scler Rel Dis 2019; 30:176. 3. http://histolab.e-line.nu/ 4.Margoni M et al. J Neurol. 2021 Aug 11:1–19. doi: 10.1007/s00415-
021-10744-x, 5. Baker et al. Brain 2019 141:2834. 6. Aguis et al. Mult scler 25:235-245. 7. Cree et al. Lancet 2019 394:1352, 8. Krejcik et al. Blood 2016:128:384, 9. Borstel et al.
Front Immunol 2019. doi.org/10.3389/fimmu.2019.02221 10. Jagannath et al. Clin Lymphoma Myeloma Leul 2019; 19:372 11. Lonial et al. Lancet Oncol 21:207
Simplified B cell Lineage1
Used off-label in a variety of neurological and non-neurological autoimmune conditions5
Inhibition of relapses in Neuromyelitis Optica by treating to memory B cell repopulation
Kim et al. JAMA Neurol 2013 70:1110, Kim et al. Neurochem Int 2019: 130:104347
Off label rituximab
5

7. Secondary Lymphoid
Tissues
Primary Lymphoid
Tissues
B cell Targeting
• Selective increase in plasmablasts with the CD19intermediate, CD27high, CD38high ,CD180−
phenotype in Neuromyelitis Optica1
• Interleukin 6 (IL-6) promotes anti-aquaporin 4 (AQP4) autoantibody production from
plasmablasts in Neuromyelitis Optica1
• Tocilizumab (humanized IgG1) and Satralizumab (Humanized IgG2) inhibit
the soluble and membrane interkleukin-6 receptor2,3
IL-6 receptor expression by B cells4
Toclizumab may delete IgG+ B cells5
1.Chihara et al. Proc Natl Acad Sci 108:3701 2.Araki et al. Mod Rheumatol 2013; 23:827 3.Yamamura et al. N Eng J Med 2019: 381:2114. 4. www.genomicscape.com Probe 226333-
at. 5 Roll et al. Arthritis Rheum. 2011, 63, 1255. 6. Enspryng, SpMC. 2021 EU.
Satralizumab
indicated for
neuromyelitis optica
spectrum disorder
who are
AQP4-IgG positive6
6

8. Secondary Lymphoid
Tissues
Primary Lymphoid
Tissues
B cell Targeting
Inebilizumab6,7
CD19 B cells
Simplified B cell Lineage1
1. Baker et al. Ebiomed 2017; 16:41. 2 Baker et al. Mult Scler Rel Dis 2019; 30:176. 3. http://histolab.e-line.nu/ 4.Margoni M et al. J Neurol. 2021 Aug 11:1–19. doi: 10.1007/s00415-
021-10744-x, 5. Baker et al. Brain 2019 141:2834. 6. Aguis et al. Mult scler 25:235-245. 7. Cree et al. Lancet 2019 394:1352, 8. Krejcik et al. Blood 2016:128:384, 9. Borstel et al.
Front Immunol 2019. doi.org/10.3389/fimmu.2019.02221 10. Jagannath et al. Clin Lymphoma Myeloma Leul 2019; 19:372 11. Lonial et al. Lancet Oncol 21:207
Approved for Neuromyelitis Optica in United States of Amercia
European Medicine Agency authorisation in progress
7

9. Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
B cell Targeting
Daratumumab8
CD38 B cells
Cell expression of CD388
CD38
Cell
counts
B cell expression of CD389
CD38
CD27
Memory
Immature Plasmablasts
CD38high
CD38+ve
CD27+ve
CD27-ve
Simplified B cell Lineage1
1. Baker et al. Ebiomed 2017; 16:41. 2 Baker et al. Mult Scler Rel Dis 2019; 30:176. 3. http://histolab.e-line.nu/ 4.Margoni M et al. J Neurol. 2021 Aug 11:1–19. doi: 10.1007/s00415-
021-10744-x, 5. Baker et al. Brain 2019 141:2834. 6. Aguis et al. Mult scler 25:235-245. 7. Cree et al. Lancet 2019 394:1352, 8. Krejcik et al. Blood 2016:128:384, 9. Borstel et al.
Front Immunol 2019. doi.org/10.3389/fimmu.2019.02221 10. Jagannath et al. Clin Lymphoma Myeloma Leul 2019; 19:372 11. Lonial et al. Lancet Oncol 21:207
*
*
*
*
8

10. Secondary Lymphoid
Tissues
Primary Lymphoid
Tissues
B cell Targeting
Plasma cells
Indatuximab (CD138)
ravtansine10
Belantamab (CD269)
mafodin11
Simplified B cell Lineage1
1. Baker et al. Ebiomed 2017; 16:41. 2 Baker et al. Mult Scler Rel Dis 2019; 30:176. 3. http://histolab.e-line.nu/ 4.Margoni M et al. J Neurol. 2021 Aug 11:1–19. doi: 10.1007/s00415-
021-10744-x, 5. Baker et al. Brain 2019 141:2834. 6. Aguis et al. Mult scler 25:235-245. 7. Cree et al. Lancet 2019 394:1352, 8. Krejcik et al. Blood 2016:128:384, 9. Borstel et al.
Front Immunol 2019. doi.org/10.3389/fimmu.2019.02221 10. Jagannath et al. Clin Lymphoma Myeloma Leul 2019; 19:372 11. Lonial et al. Lancet Oncol 21:207
9

11. Oligoclonal Bands
Plasma Cell Niches
C=CSF, S= serum T1= time point 1, T2= time point 2, Pt= patient. Courtesty of Prof. Giovannoi
• Oligoclonal immunoglobulin diagnostic feature of multiple sclerosis1
1.Dobson & Giovannoni Eur J Neurol 2019; 26:27. 2. Matute-Blanch et al. Brain; 2018; 124:10853 Linder et al. Brain 2018.3. Greenfield AL et al. JCI Insight. 2019 Feb 12. pii:126599
4. Agahozo et al. mult scler 2016; 9:110. 5 Spadaro et al. Ann Neurol 2018;84:315.
• Oligoclonal immunoglobulin is compartmentalised in CNS1
• Oligoclonal immunoglobulin can be pathogenic4,5
• Oligoclonal immunoglobulin present early in RIS2
• Oligoclonal immunoglobulin is persistent3
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
CNS central nervous system
RIS radiologically isolated syndrome
NMO neuromyelitis optica
NMOSD MMO spectrum disorders
10

12. CD20
Ectopic follicles in brain sulci in MS3
Plasma Cell Niches
Intra-meningeal
B cells4.5
Lesion
Ectopic follicles in people
with SPMS are Associated
with disease progression 2,3
1. Serafini B et al. Brain Pathol 2004;14:164 2.Serafini B et al. J Neuropathol Exp Neurol. 2010; 69:677, 3. Magliozzi R et al. Brain. 2007;130:1089. . 4.Frischer et al. Brain. 2009;132:1175,
5. Jan & Yong Nat Rev Immunol 2021 :doi: 10.1038/s41577-021-00652-6
B Cell Rich Aggregate in people
with progressive MS1
B Cell Follicles in Central Nervous System in MS
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
11

13. Plasma Cell Niches
1. Baker et al. EBioMed 2017 16:41. 2.Pryce & Baker 2018 25:131.
INFLAMMATORY PENUMBRA IN MS
MYELIN Proteolipid protein = BROWN
DEMYELINATION
PERIVASCULAR
LESION
RELAPSING MS
Cells = haematoxylin = BLUE
Advanced
Multiple sclerosis
Relapsing Multiple sclerosis
Pathogenesis of Multiple Sclerosis1,2
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
12

14. • PATHOLOGY
Antibodies within Lesions with activated Complement1,2
• AUTOANTIBODY
Binding to Central Nervous System Targets3
Present in 28/108 pwMS reacting to 30 different targets.
• PATHOGENICITY
Pathogenic effects of antibodies in vitro and in animals5,6
Autoantibodies often bind to intracellular targets.
These may be secondary to Tissue Destruction.4
Antibodies
• THERAPY
Benefit from Plasma Exchange in Subset of PwMS7,8
Complément Déposition2
1. Lucchinetti et al. Ann Neurol 2000;55:458; 2.Breij et al. Ann Neurol 2008;63:16. 3. Prineas & Paratt Mult scler 2018;24:610; 4. Willis et al. Front Immunol. 2015;6:600
5. Agahozo et al. mult scler 2016; 9:110. 6 Spadaro et al. Ann Neurol 2018;84:315. 7 Keegan et al. Lancet Neurol 2005;366:579, 8. Stock et al. 2018. 75:428. 9. Breij et al.
Ann Neurol 2008 63:16. 10. Jan & Yong Nat Rev Immunol 2021 :doi: 10.1038/s41577-021-00652-6. 11.Rommer & Zettl Curr Pharm Des 2021 doi:
10.2174/1381612827666210920151231
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
13
Post-mortem analysis suggests most lesions represent type 1 & II lesions9
• Aquaporin 4/Myelin-specific antibodies feature of NMO and NMOSD10,11
NMO neuromyelitis optica
NMOSD neuromyelitis optica spectrum
disorder

15. B cell Targeting of Current DMT
B cell Lineage1
Anti-CD20 B cell antibodies injected directly in to the CNS
1. Monson et al. Arch Neurol 2005 62: 62:258 . 2.Petereit et al. Acta Neurol Scand. 2008;117:399 3.Topping et al. Mult Scler Relat Disord. 2016;6:49, 4. Cross et al. J Neuroimmunol.
2006;180:6 5 Svenningsson et al. Neurol Neuroimmunol Neuroinflamm 2015; 2:e79.6. Ferrari et al. Mult Scler Int 2021. https://doi.org/10.1155/2021/8813498 6. Bergman et al. J
Neurol 2021 268:651
Intra-ventricular did not stop progression6
Intravenous. No evidence for rapid depletion of CNS B cells but
rapidly inhibits disease and cellular response months after infusion1,2
Intra-thecal anti-CD20 did not inhibit the intrathecal B cell response
and rapidly entered the circulation depleting peripheral B cells3.
Disease and cellular response after infusion inhibited4-5
No effect on progression6
Antibodies need to target cells and also need the
depleting mechanism to be present
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
DMT disease modifying treatment.
14

16. 1.Baker et al. Ebiomed 2017; 16:41
2. Baker et al. Eur J Neurol 2020: 27:221
Treatment B Memory Cell
in Blood
Availability to Enter
the CNS
Relapse Rate
Atacicept
Tabalumab
Glatiramer acetate
IFN β
Teriflunomide
Daclizumab*
Dimethyl fumarate
Fingolimod
Mitoxantrone
Natalizumab
rituximab
Ocrelizumab
Cladribine
Alemtuzumab
HSCT
Increased
Increased
Reduced
Reduced
Reduced
Reduced*
Reduced
Reduced
Reduced
Increased
Reduced
Reduced
Reduced
Reduced
Reduced
Increased
Increased
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Increased/No Effect
No Effect
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
DEPLETION OF MEMORY B CELLS1,2
Lower
Efficacy
Higher
Efficacy
No
Efficacy
Hierarchy
*Licensed in the US, Germany, Austria and France ^Licensed in Europe # Unlicensed in Europe (not EMA approved)
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
B cell Targeting of Current DMT
DMT disease modifying treatment.
* Data not from
multiple sclerosis.
15

17. Weak Expression of DMT Targets by Plasma Cells1-4
Plasma Cell targeting of Current DMT
B Cell Maturation Antigen (BCMA/CD269)
Syndecan-1/ CD138 Brutons Tyrosine Kinase
CD19
Membrane Spanning 4 A1 (CD20) Integrin alpha four subunit
CD52 Deoxycytidine
kinase
Sphingosine-1-phosphate receptor
Fingolimod target
Cladribine target
Alemtuzumab target
Ocrelizumab/rituximab target Natalizumab target
Inebilizumab target
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
DMT disease modifying treatment.
1.www.genomicscape.com scape 2. Jourdan et al. J Immunol. 2011;187:3931. 3 Jourdan et al. Blood. 2009; 114:5173. 4. Caron G et al. J Immunol. 2009; 182:7595
5. Alavijeh et al. NeuroRx 2005, 2, 554–571. 6. Baker et al. Mult Scler rel Disord 2019:36:19
16
N MC PB PC
N MC PB PC
N MC PB PC
N MC PB PC
N MC PB PC
N MC PB PC
N MC PB PC
N MC PB PC
N MC PB PC
N = naïve/mature cell
MC = memory B cell
PB = plasmablasts
PC = plasma cell

18. Weak Expression of DMT Targets by Plasma Cells1-4
Plasma Cell targeting of Current DMT
• Relative Lack of Effect on Oligoclonal Bands within CNS6
• Relative Lack of Effect on Childhood Past/Infection Immunity
• Potential Lack of Immediate Effect on Bone Marrow Plasma Cells
• Relative Lack of Effect on Vaccination Immunity
• Potential Lack of Immediate Effect on CNS Plasmablasts/Plasma Cells
Protein Therapeutics will have poor CNS penetration5
1.www.genomicscape.com scape 2. Jourdan et al. J Immunol. 2011;187:3931. 3 Jourdan et al. Blood. 2009; 114:5173. 4. Caron G et al. J Immunol. 2009; 182:7595
5. Alavijeh et al. NeuroRx 2005, 2, 554–571. 6. Baker et al. Mult Scler rel Disord 2019:36:19
• Slow inhibition via destruction of Plasma cell Niche/Growth Support
Implications for Infection-related Immunity
• Relative Lack of Effect on COVID-19 related Vaccination Immunity
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
DMT disease modifying treatment
CNS central nervous system.
17

19. Plasma cell
Relative
mRNA
Expression
(arbituray
units)
0
2000
4000
6000
8000
10000
CD52
CD20
Deoxycytidine kinase
Spingosine-1-phosphate 1 receptor
Memory B cell
Naive B cell
Weak Expression of DMT Targets by Plasma Cells1-5
Plasma Cell targeting of Current DMT
• Alemtuzumab (CD52) does not remove childhood infection responses or inhibit the
generation of novel vaccine responses at 6 months post-infusion1. The majority
(>80%) of people can make anti-drug antibody responses within 1 month of infusion2
• Ocrelizumab (CD20) does not remove pre-treatment childhood infections responses3.
• Cladribine (Deoxycytidine kinase) does not inhibit pre-treatment Varicella zoster vaccine
responses4. Limited depletion of peripheral blood CD138 positive cells5 . Does not remove
childhood infection responses6
1.Mcarthy et al. Neurology 2013; 81:872 2. Baker et al. JAMA Neurol 2017; 74:961. 3..Ziemssen T, et al. P 2 Clin Neurophysiol 2017; 128:e326 4 Roy & Borschert P059
ACTRIMS2021. 5. Moser et al. Ann Clin Transl Neurol. 2020;7:2199. Moser et al. Biomedicines 2021 9:1584
Data extracted from www.biogps.org
portal using the Primary Cell Atlas for
CD52 (probe 34210_at) , CD20
(probe 228599_at), Deoxycytidine
kinase (probe DCK Probe
203302_at), S1P1 (probe 204642_at)
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
DMT disease modifying treatment.
18

20. Limited inhibition of SARS-CoV-2 Vaccination responses1
Plasma Cell targeting of Current DMT
• Ocrelizumab (CD20) removes antibody producing cell precursors2
Pre-existing immunity not immediately reduced3.
• Most Current MS DMT do not block COVID-19 vaccine responses1
Therefore there is limited direct targeting of plasma cells .
COVID-19 vaccine responsiveness in treated people with MS1
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
DMT disease modifying treatment.
19
1.Tallantyre et al. MedRXiv https://doi.org/10.1101/2021.07.31.21261326. 2 Baker et al. Clin Exp Immunol. 2020; 202:149 3..Ziemssen et al. P 2 Clin
Neurophysiol 2017; 128:e326. 4. Fernández-Díaz et al. Mult Scler Relat Disord. 2020;45:102402

21. Limited inhibition of SARS-CoV-2 Vaccination responses1
Plasma Cell targeting of Current DMT
• Ocrelizumab (CD20) removes antibody producing cell precursors2
Pre-existing immunity not immediately reduced3.
• Most Current MS DMT do not block COVID-19 vaccine responses1
Therefore there is limited direct targeting of plasma cells .
COVID-19 vaccine responsiveness in treated people with MS1
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
DMT disease modifying treatment.
20
1.Tallantyre et al. MedRXiv https://doi.org/10.1101/2021.07.31.21261326. 2 Baker et al. Clin Exp Immunol. 2020; 202:149 3..Ziemssen et al. P 2 Clin
Neurophysiol 2017; 128:e326. 4. Fernández-Díaz et al. Mult Scler Relat Disord. 2020;45:102402

22. Ablative Haematopoietic Stem Cell therapy (HSCT)1
Plasma Cell targeting of Current DMT
1.Muraro P et al. Nat. Neurol Rev 2017; 13:391; 2. Burt RK et al. JAMA 2019; 321:165-174, 3. Atkins HL et al. Lancet 2016; 388:576-585. 4. Brinkman et al. J Clin Immunol 2007
27:647. 5,Saiz et al. Neurol 2001 56:1084. 6.Larsson et al. Mult Scler. 2020;26:1351. 7. Bowen et al. Transplant. 2012;47:946.8. Atkins Bone Marrow Transplant 2010; 45:1671. 9
Mariottni et al. Mult Scler 2021 :27:27:61
• Oligoclonal Bands are often not Inhibited5-7
• Relapsing MS is strongly inhibited1-3
• Non-relapsing Progressive MS may not be halted8
• Past Immunity inhibited requiring re-vaccination4
HSCT procedure1
Depletion of most T and B cells and the
Innate Immune Response (Anti-thymocyte
globulin (ATG)/Alemtuzumab/
BEAM (bis-chloroethynitrosourine,
etoposide, arabinoside, melphalen)
G-CSF granulocyte colony stimulating factor
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
DMT disease modifying treatment.
21

23. Plasma Cell targeting Agents
Agents approved for multiple myeloma1 & CNS Lymphoma2
1.https://www.nhs.uk/conditions/multiple-myeloma/treatment/ 2.https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/primary-cns
3.https://www.cancer.gov/about-cancer/treatment/drugs/multiple-myeloma (all accessed 12:9:21). Tooze Front Immunol 2013 | https://doi.org/10.3389/fimmu.2013.00460
5.Baker et al. Mult Scler Relat Disord. 2019;35:19. 6.Baker et al. Ebiomed 2017; 16:41 7.Baker et al. Mult Scler Relat Disord. 2021;53:103057
Chemotherapy ± Steroids
Thalidomide, Lenalidomide, Pomalidomide
Proteosome Inhibitors: Bortezomib, Carfilzomib, Ixazomib
Anti-CD38: Daratumab, Isatuximab
Histone Deactylase Inhibitor: Panbinostat
Stem Cell Therapy
> 45 FDA approved agents for multiple myeloma3
• Agents should not be proliferation dependent. Plasma cells are post-mitototic4,5
• Agents should not augment the peripheral memory B cell response5-7
• Agents should be CNS penetrant, as target is in the CNS in MS7
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
CNS central nervous system
FDA Food & Drug Administration.
DMT disease modifying treatment.
22

24. Plasma Cell targeting Agents
Anti-Plasma Cell Targeting Antibodies ± chemotherapy
1.Lonial S et al. Lancet Oncol. 2020;21:207. 2.Jagannath et al. Clin Lymphoma Myeloma Leul 2019; 19:372. 3. Dimopoulous et al. New Eng J Med 2020 375:1319
4. Dimopoulous et al. New Eng J Med 2020 375:1319. 5 Dhillon Drugs 2020:80:905. 6.Pepinsky et al. J. Pharmacol. Exp. Ther. 2011339, 519–529. 7. Baker et al.Eur J Neurol.
2020;27:221-228.
Anti-CD38: Daratuzumab4
Anti-CD38: Isatuximab (apoptosis including antibody)5
(Plasma cells, plasma blasts, naïve/mature B cells)
Anti-CD138 (Syndecan-1): Indatuximab ravtansine2
(Plasma cells) Chimeric antibody linked to maytansinoid (microtubule cytostatic)
Anti-CD269 (BCMA/TNFRSF17) Belantamab mafodotin1
(Plasma cells + plasmablasts) Human IgG1 + monomethyl auristatin (cytostatic) + side effects
keratopathy/ corneal disease
Anti-CD319 (SLAM7) Elotuzumab (Natural killer cell killing augmenting)3
(Plasma cell, plasmablasts)Signalling lymphocyte activation molecular family member 7
Antibodies have poor-penetration (<0.1%) into the CNS6
Anti-plasma/naive cell targeting agents may not inhibit MS7
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
BCMA B cell maturation antigen
SLAM signalling lymphocyte
activation molecule.
23

25. Plasma Cell targeting Agents
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
B Cell Maturation Antigen (CD269 TNFRSF13C) CAR-T Therapy1
• CNS-penetrant
• CNS-Non Memory B cell augmenting
Side Effects
Cytokine release syndrome,&
Neurotoxicity
Chimeric Antigen Receptor (CAR) T BCMA CAR-T idecabtagene vicleucel2
CD8
Isolation
expansion
CAR gene
(Antibody variable chains
+ T cell signalling molecule)
CAR-T cells
Irreversible/Non Selective
CD19 CAR-T (tisagenlecleucel2 lisocabtagene maraleucel3; Axicabtagene ciloleucel4)
Feng & Sun Scand J Immunol. 2020;92:e12910 2. Munshi et al. N Engl J Med 384:705 2. Liu et al. Drugs Today 53:597 3. Qin et al. J Immunother 43:107 4.Neelapu et al. N Engl J
med 377:2531.
BCMA B cell maturation antigen
SLAM signalling lymphocyte
activation molecule.
24

26. Plasma Cell targeting Agents
APRIL A proliferation ligand,
BAFF B cell activating factor
1. Baker et al. Eur J Neurol. 2020;27:221-228. 2.Kappos et al. Lancet Neurol. 2014;13:353-63.3.Bossen & Schneider. Semin Immunol. 2006; 18:263-275, . Isenberg et al. Ann
Rheum Dis 2016 75:323
Tabalumab anti-BAFF did not inhibit Multiple Sclerosis1
Atacicept anti-BAFF/APRIL did not inhibit Multiple Sclerosis1,2
No Effect
No Effect
Worsening
Tabalumab Inhibit CD38+ naïve cells and
Atacicept Immunoglobulin levels1-5
Do not inhibit deplete memory B cells1,2
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
25

27. Plasma Cell targeting of Current DMT
1.Baker et al. Ebiomed 2017; 16:41 2.Baker et al. Mult Scler Relat Disord. 2021;53:103057 3. Anolik et al. J Immunol 2008 180:688. 4. Canete et al. Ann Rheumat Dis 2009:68:7514.
5. Koo et al. J Intern Med 2020: 465. 6. Andersson et al. Ann Rheum Dis 2006 65:1237
Anti-Tumour Necrosis Factor inhibits Rheumatoid Arthritis but not MS1,2
Anti-Tumour Necrosis Factor inhibits Joint associated Ectopic Follicles3,4
Would a CNS-penetrant TNF inhibitor be useful?
Anti-Tumour Necrosis Factor inhibits joint TNF but not inhibit central TNF5,6
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
MS multiple sclerosis
TNF Tumour necrosis factor
DMT disease modifying treatment.
26

28. Agents approved for multiple myeloma1
Plasma Cell targeting agents
• CNS-penetrant2,3
TNF-inhibitors4,5
Thalidomide, Lenalidomide, Pomalidomide
1.https://www.nhs.uk/conditions/multiple-myeloma/treatment. 2. Rubenstein et al. Blood Adv. 2018:2:15952. 3. Vestermark et al. Ecancermedicalsci 2008:2:91 4.Moreira et al. J Exp
Med. 1993;177:1675. 5. De Sanctis et al. Recent Pat Inflamm Allergy Drug Discov. 2010;4:144. 6.Baker et al. Mult Scler Relat Disord. 2021;53:103057. 7. Ghermezi et al. Clin Adv
Hematol Oncol 2019; 17:5004.7.Fox et al. N Eng J Med 379:846 . 8.Schenkein. Clin.Lymphoma 2002; 3:49–55 9. Mullard Nat Med. 2012 Jan 6;18(1):7..
• CNS-penetrant6
TNF-inhibitors6
Phosphodiesterase 4 inhibitors. Ibudilast7
• CNS-penetrant6
TNF-inhibitors6
Janus kinase inhibitors. Baricitinib6.
Approved agents that inhibit TNF6
Ruxolitinib (poor CNS penetration) in myeloma7
Proteosome Inhibitors8. • CNS-penetrant7
Bortezomib (poor CNS penetration)7
Marizomib7,8 Ixazomib9
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
TNF Tumour necrosis factor
27

29. Brutons Tyrosine Kinase (BTK) Inhibitors
Plasma Cell targeting agents
BTK inhibitors can be cytotoxic to B cell lymphoma and leukemia cells1
Ibrutinib, acalabrutinib, zanubrutinib approved for B cell lymphoma/leukaemia1-4
Tirabrutinib active for lymphoma4
BTK is expressed in B cells, macrophages/monocytes and not T cells5
Bruton’s Tyrosine Kinase Gene Expression5
Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Autoimmune
Ectopic Lymphoid
Follicle
1.Smith Ongogene 2017:36:2045; 2 Byrd et al. N Eng J Med 2016:374:323, 3. Tam et al. Clin Adv Hematol Oncol 2019:17:32-34. 4. Munakata et al. Cancer Sci 2019:110:1686
5. www.biogps.org. Probe 205504_at.. 6. Montalban et al. N Engl J Med 2019; 380:2406. 7. Reich et al. Eur J Neurol. 2020; 27 (Suppl. 1), 1–102. O4010
8. Cohen et al. ACR/ARP 2019 Abstract 929 9. Scaramozza et al. ECRIMS 2020. P0186, 9. Diagram by 葉智海 https://commons.wikimedia.org/w/index.php?curid=87312786
BTK Brutons tyrsosine kinase.
BTK involved in signaling through the B cell and the Fcγ receptors6
BTK gene mutation leads to X-linked agammaglobulinemia1,
Block in pre-B cell differentiation lack of B cells/antibody levels1
PIP3
28

30. Brutons Tyrosine Kinase (BTK) Inhibitors (BTKi)
Plasma Cell targeting agents
1.Smith Ongogene 2017:36:2045; 2 Byrd et al. N Eng J Med 2016:374:323, 3. Tam et al. Clin Adv Hematol Oncol 2019:17:32-34. 4. Munakata et al. Cancer Sci 2019:110:1686
5. www.biogps.org. Probe 205504_at.. 6. Hopkins et al. J Med Chem 2021 doi.org/10.1021/acs.jmedchem.1c00926. 7. Montalban et al. N Engl J Med 2019; 380:2406. 8. Reich et al. Eur
J Neurol. 2020; 27 (Suppl. 1), 1–102. O4010 9 Cohen et al. ACR/ARP 2019 Abstract 929 10. Bame et al. Clin Transl Immunol 2021 10:e1295, 11. Dhillon Drugs 2021 81:503. 12.
Correale et al. Mult scler Rel Diso 56:103264
BTK Brutons tyrsosine kinase.
BTK inhibitors are being trials in relapsing and Progressive multiple sclerosis6-9
• EVOBRUTINIB. Second generation (G2) BTKi. Completed phase II in phase III
(NCT04338022) relapsing MS6,7
• TOLEBRUTINIB. SG2 BTKi. Completed phase II in phase III
(NCT04410991/NCT04458051/NCT04458051) relapsing for MS/PPMS/SPMS6,8
• FENEBRUTINIB. Second generation BTKi in Phase III in relapsing/PPMS
(NCT04586010/NCT04586023/NCT04544449)6.9
• BIIB091. Reversible second generation BTKi. Completed phase I in healthy
individuals in development for MS6,10.
• ORELABRUTINIB. Irreversible BTKi. Phase II trial (NCT04711148) in relapsing
Remitting MS11
*
*
*
*
*Brain penetration12
PIP3
29

31. Primary Lymphoid
Tissues
Secondary Lymphoid
Tissues
Safety of Ixazomib Targeting Plasma Cells
in Multiple Sclerosis (SIZOMUS)
Plasma Cell targeting agents
Autoimmune
Ectopic Lymphoid
Follicle
Primary Outcomes:
Proportion of oligoclonal Band IgG negative subjects
will be compared between active (n=48) and placebo arm (n=24)
Adverse Events
• Relapsing Multiple Sclerosis
• Progressive Multiple Sclerosis
Primary Safety Complete:
Trial : NCT03783416
Clinical Trial
30

32. Conclusions
Many agents can be used as to target Normal/Transformed Antibody Producing Cells1
• Antibody Producing Cells may be Pathogenic
• Antibody Producing Cells may produce Anti-Inflammatory (IL-10)Cytokines2,3
1.Baker et al. Mult Scler Rel Dis 2019; 35:19. 2. Flemming et al. Nat Rev Immunol 2018: 18:540; Fillatreau Biomed J 2019:42:233
4 Cunniffe et al. J Neurol Neurosurg Psychiatry. 2021; 92:295
The action of inhibiting Antibody Producing Cells in the CNS of MS is Unexplored
Are Antibody Producing B Cells a useful target in Progressive Multiple Sclerosis?4
31

33. Thank you for Listening
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