Addressing challenges of targeting the macrophage checkpoint, CD47. Marie Kosco-Vilbois, PhD CSO

Transcription

1 Addressing challenges of targeting the macrophage checkpoint, CD47 Marie Kosco-Vilbois, PhD CSO 1

2 CD47 is an immune checkpoint Cancer cell Macrophage Activating eat me signal CD47 Inhibitory don t eat me signal CD47 is over expressed in various cancers Helping tumors escape immune surveillance and killing Poor clinical prognosis correlates with levels of CD47 expression 2

3 Four potential mechanisms of action when targeting CD47 Novimmune data Phagocytosis Novimmune data ADCC 3 Liu et al., Nature Medicine Durable Immunity Adapted from Chao et al., Current Opinion in Immun

4 CD47 is an immune checkpoint Cancer cell Macrophage Activating eat me signal CD47 Inhibitory don t eat me signal CD47 is over expressed in various malignancies Helping tumors escape immune surveillance and killing However, CD47 is a ubiquitous cell surface glycoprotein 4

5 Targeting CD47 in cancer Rationale for targeting with bispecific antibodies CD47 CD47 CD47 Tumor Associated Antigen Anti-CD47 mab Binding to all cells - incl. RBC & platelets Anticipated: - poor PK - toxicity CD47/TAA BiAb Selective to malignant cells Prolonged half-life Lower toxicity 5 Anemia, thrombocytopenia and neutropenia observed in animals

6 -bodies Bispecific antibody format Fully human IgG Common heavy chain Two light chains = bispecific (kappa & lambda) Light chains fulfill two important functions: Drive the specificity of each arm Allow efficient purification Properties indistinguishable from an IgG Fischer et al., Nature Commun Expression of unmodified antibody chains Stable expression in CHO cells g/l of -body 6

7 Lead program: NI-1701 CD47/CD19 body Targeting arm Selective for CD19 High affinity Effector arm Disrupts CD47-SIRPα don t eat me signal Right affinity Functional Fc arm Fc-mediated effector functions IgG pharmacokinetics / half-life 7

8 Characterizing the lead candidate Addressing efficacy and safety Non human primates Safety 8

9 Efficacy in vivo Xenograft model Human Raji cells in mice CB17 SCID mice Mice: CB17 SCID Ab treatment: 20 mg/kg 3 times a week from recruitment 9

10 T u m o u r v o lu m e (m m 3 ) Efficacy in vivo Tumor growth controlled by NI IgG1 control Anti-CD19 mab Anti-CD47 monovalent Ab Anti-CD19 monovalent Ab Anti-CD47/CD19 κλ body (NI-1701) D a y p o s t tre a tm e n t Synergistic effect when targeting CD19 combined with CD47 10

11 Studying phagocytosis in vivo Tumor associated macrophages (TAM) Raji Raji GFP+ IgG1 control NI Phagocytosis by flow

12 Tumor growth controlled by NI Is o ty p e c o n tro l N I D a y 1 3 T u m o r h a rv e s t T u m o u r v o lu m e m m * * T u m o u r v o lu m e m m 3 % o f v ia b le to ta l c e lls % o f C D c e lls Yet similar levels of: mouse leukocytes and TAMs D a y s p o s t s ta r t o f tr e a tm e n t D a y 2 3 T u m o r h a rv e s t 5 0 M o u s e C D c e lls in tu m o r F 4 /8 0 + m a c ro p h a g e s Is o ty p e c o n tro l * * N I D a y s p o s t s ta r t o f tr e a tm e n t 0 D 1 3 D D 1 3 D

13 Phagocytosis significantly increased With NI-1701 % o f F 4 / T A M s IgG1 control (D13) F 4 /8 0 + G F P + c e lls F4/80 F4/ Ig G 1 c o n tro l 3 0 ** * N I NI-1701 (D13) 0 D 1 3 D 2 3 With NI-1701: - More TAMs engulf GFP+ tumor cells - More GFP+ tumor cells per TAM 13 GFP

14 In vitro tumor cell killing 14

15 P h a g o c y t o s is % NI-1701 mediates effective phagocytosis Cells from B-CLL patients Method: Patient cells + human MØ + antibodies B -C L L c e lls fr o m p a tie n t s a m p le s ng/ml IgG1 control Rituxi -mab body N I r itu x im a b (a n ti-c D 2 0 ) Ig G 1 is o ty p e c o n tro l n o a n tib o d y 10 10, A n tib o d y c o n c e n tr a tio n (n g / m L ) Phagocytosis index % of M with > 1 fluorescent event red = macrophages green = B-CLL cells 15 B-CLL: B-Chronic Lymphocytic Leukemia

16 Engulfment and elimination of tumor cells + Isotype control + NI-1701 Nalm-6 tumor cells Human macrophages 16

17 Engulfment and elimination of tumor cells Serial killing in the presence of NI-1701 Nalm-6 tumor cells Human macrophages 17

18 NI-1701, safely harnessing CD47 biology 18

19 No RBC agglutination mg/ml Control mab CD47 mab (control) CD47 mab (B6H12) NI

20 Single dose PK study in nonhuman primates Linear kinetics observed at both doses Cynomolgus monkey 3 females per group Dose groups: 1. NI-1701: 0.5 mg/kg 2. NI-1701: 10 mg/kg Route : Intravenous Suggesting no target mediated-clearance 20

21 Dose range finding toxicology study Cynomolgus monkey 3 animals/ group (2F + 1M) 6 animals in total Dose groups: 1. Control 2. NI > 100 mg/kg Route : Intravenous 21

22 Hematology No hematological toxicity after 4 doses <100mg/kg Red blood cells Platelets Hemoglobin Hematocrit 22 DOSING DAYS

23 Manufacturing clinical supply NI

24 Productivity during cell line generation Using GS-CHO system Post lab scale stage Total IgG titer at harvest: 2 to 4 g/l body % at harvest: 42 to 46% harvest: Total IgG body body Mono Mono body titer: 0.9 to 2.0 g/l 24

25 Platform purification process 25

26 Purification process performance Lab scale data Process step Purity % recovery % Aggregates % Overall % MabSelect Sure n.d.* CaptoL n.d.* LambdaFabSelect CHT UF/DF *n.d.: not determined Excellent overall recovery (gram/liter) High purity (>99%) Low aggregates ( 1%)

27 Bispecific antibody pipeline NI-1701 (CD47xCD19) Hit Identification Lead Optimisation Lead Candidate Preclinical Development CTA H NI-1801 (CD47xMSLN) NI-1901 (Undisclosed) NI-2001 (Undisclosed) NI-2101* (Undisclosed) CD3 retargeting 27 *Partnered with Baxalta

28 Targeting CD47, an immune checkpoint, with bodies Exploits the don t eat me signal hijacked by cancer cells Unleashing phagocytosis to enhance killing While avoiding expected toxicity and rapid elimination Human macrophage (red) eating patient tumor cells (green) when incubated with NI-1701 Complements T cell targeting strategies such as other checkpoint inhibitors, CAR Ts, BiTEs Alone or in combination, has the potential to further increase the proportion of cancer patients with durable responses 28

29 Acknowledgements Numerous collaborators in our departments of: Research Experimental Science & Translational Medicine Bioprocess R&D Clinical Science University of Glasgow, UK Dr. Alison Michie Dr. Emilio Cosimo 29