Mechanism of action of anti CD38 antibodies

Transcription

1 Mechanism of action of anti CD38 antibodies Tuna Mutis, MD, PhD Dept. of Hematology, VU University Medical Center Amsterdam, NL

2 Conflict of Interest: T. Mutis Received research grants from Genmab & Janssen Pharmaceutics

3 CD38 S.Deaglio. FMalavazi, purinergic Signalling :431

4 High and uniform Expression of CD38 in Multiple Myeloma cells Appendix Prostate Seminal vesicles Purkinje cells Lung smooth muscle T cells B cells Monocytes NK cells Multiple Myeloma Cells

5 Targeting CD38-by antibodies MOR202 (IgG1) MorphoSys Daratumumab Isatuximab Daratumumab (IgG1) Janssen Biotech Anti-tumor effector mechanisms of CD38 antibodies MM cell MOR202 Daratumumab Isatuximab Isatuximab (IgG1) Sanofi-Aventis MOR202 Daratumumab Isatuximab Isatuximab Daratumumab

6 daratumumab-mediated ADCC and CDC against MM cells from newly diagnosed or relapsed/refractory patients

7 CD38 expression levels of primary MM cells are associated their susceptibility toward daratumumab-mediated ADCC and CDC. IS Nijhof et al. Leukemia (2015) 29,

8 Ps increase at the time of progression during DARA Complement inhibitory Protein expression Levels may influence Daratumumab responses in patients: CIPs Increase at the time of progression during DARA treatment IS Nijhof et al. Blood (2016) 128(7): Nijhof Blood 2016

9 What are the effects of DARA on CD38 + immune cell populations? T cells B cells NK cells Multiple Myeloma Cells Monocytes

10 CD4 and CD8 T cells increase during DARA treatment

11 Immunomodulatory Effects of Daratumumab in Multiple Myeloma J. Krejcik, T. Casneuf, I. S. Nijhof, B. Verbist, J. Bald, T. Plesner, K. Syed, K. Liu, N. W. van de Donk, B. M. Weiss, T. Ahmadi, H. M. Lokhorst, T. Mutis, and A. K. Sasser. Blood 128 (3): , 2016

12 A subset of Tregs constitutively express high levels of CD38

13 The CD38 high Tregs are more suppressive than CD38 neg Tregs

14 The CD38 high Tregs are depleted by DARA treatment

15 CD38 high CD24 high Bregs are also depleted by DARA Gating strategy CD19+ CD3- B cells C D 3 8 C D At baseline CD CD % 1.1% CD3 CD38 high CD24 high Bregs C D During dara treatment 0.1% 2.5% CD24

16 Granulocytic-like MDSCs are also CD38 high and are depleted by DARA CD38 expression (CD11b + CD14 - HLA-DR - cells) MDSCs Isotype control DARA

17 CD8/CD4 and CD8/Treg ratios increase during DARA treatment CD8+/CD4+ CD8+/Treg Peripheral blood Bone Marrow

18 HLA-DR+ Activated T cells increase during DARA treatment

19 Naïve T cells decrease, Memory T cells increase during DARA treatment

20 % o f p ro life ra tin g T c e lls % % IF N - p ro d u c tio n ( v a lu e s ) A p t 1 V G P R p t 2 C R p t P R p t 4 * T cell responses to viral proteins and allo antigens increase during DARA treatment * * P R n s 0.0 B a s e lin e w e e k 4 w e e k 8 w e e k B a s e lin e w e e k 4 w e e k 8 R e la p s e 0.0 B a s e lin e w e e k 4 w e e k 8 R e la p s e B a s e lin e w e e k 4 w e e k 8 R e la p s e p t 5 P D p t 6 M R p t n s 0.2 p t 1 V G P R p t 2 C R p t B 0.1 n o sam ple B a s e lin e w e e k 4 w e e k 8 R e la p s e B a s e lin e w e e k 4 w e e k 8 R e la p s e B a s e lin e w e e k 4 w e e k 8 R e la p s e p t 1 p t V G P R B a s e lin e w e e k 4 w e e k 8 w e e k 1 0 * B a s e lin e w e e k 4 w e e k 8 w e e k * C R B a s e lin e w e e k 4 w e e k 8 R e la p s e n s B a s e lin e w e e k 4 w e e k 8 R e la p s e * * P R * P R * B a s e lin e w e e k 4 w e e k 8 R e la p s e B a s e lin e w e e k 4 P - - p t 5 P D p t 6 M R p t 7 n e g a tiv e c o n tro l + C E F a llo g e n e ic re a c tio n n s n s a llo g e n e ic re a c tio n n o t p e rfo rm e d 0.3 P R * IF N - p ro d u c tio n ( v a lu e s ) A p t 4 1.0

21 T cell responses become more clonal during DARA treatment Clonal expansion is more pronounced in Responders vs Nonresponders clonal expansion in non-responders vs responders

22 Clonal expansion is generally an antigen driven process: an example High Clonality of Virus-Specific T Lymphocytes Defined by TCR Usage in the Brains of Mice Infected with West Nile Virus Kitaura et al JI:

23 Daratumumab modulates immune responses by J. Krejcik et al Blood 128 (3): , 2016

24 Isatuximab (SAR650984) also depletes CD38++ Tregs Xiaoyan Feng et al. Clin.Cancer Res / Tregs express higher levels of CD38 Foxp3 expression correlates with CD38 expression in Tregs Isatuximab and its F(ab) 2 fragments deplete Tregs by apoptosis induction

25 Daratumumab combined with anti PD-L1 antibodies improve the antitumor response in a lung cancer murine model. L. Chen et al J Clin Oncol 35, 2017 (suppl 7S; abstract 79) Tumor volume, tumor mass, and lung metastases were diminished dramatically The percentage of CD8 + effector T cells increased markedly, The percentage of CD4 + regulatory T cells and myeloid-derived suppressor cells decreased significantly.

26 Daratumumab interferes with tumor (CLL) cell migration and in vivo homing A. Matas-Céspedes, et al. Clin. Cancer Res (6);

27 Daratumumab Team Inger Nijhof Berris van Kessel Jakub Krejcik Preclinical In vivo Models Anton Martens Richard Groen Willy Noort Regina de Jong-Korlaar Henk Jan Prins Susan van Veen Clinical Team Niels van de Donk Henk Lokhorst Sonja Zweegman Acknowledgments Janssen Team Tineke Casneuf Bie Verbist Jaime Bald Brendan Weiss Thamatan Ahmadi Kate Sasser Veijle Team Torben Plesner Funding/Support Janssen Pharmaceutics KWF WCR (former AICR) Genmab