Trillium Therapeutics : AACR 2018 Abstract 2709

AACR # 2709

TTI-622 (SIRPα-IgG4 Fc), a CD47-Blocking Innate Immune Checkpoint Inhibitor, Suppresses Tumor Growth and Demonstrates

Enhanced Efficacy in Combination with Anti-Tumor Antibodies in Both Hematological and Solid Tumor Models

Gloria H. Y. Lin1, Natasja Nielsen Viller1, Marilyse Charbonneau1, Laura Brinen1, Tapfuma Mutukura1, Karen Dodge1, Simone Helke1, Vien Chai1, Violetta House1, Vivian Lee1, Hui Chen1, Alison O'Connor1,

Debbie Jin1, Rene Figueredo2,3, Saman Maleki Vareki2,3, Mark Wong1, Emma Linderoth1, Lisa D. S. Johnson1, Xinli Pang1, James Koropatnick2,3, Jeff Winston1, Penka S. Petrova1, Robert A. Uger1

1Trillium Therapeutics Inc., Mississauga, ON, Canada, 2London Regional Cancer Program, London Health Sciences Centre, Lawson Health Research Institute, London, ON, Canada, 3Department of Oncology, University of Western Ontario, London, ON, Canada

TTI-622 (SIRPα-IgG4 Fc): A Novel Biologic that Blocks the

CD47 "Do Not Eat" Signal

•  CD47 binds to SIRPα on the surface of macrophages and delivers a "do not eat" signal to suppress phagocytosis.

•  Tumor cells frequently overexpress CD47 and exploit this pathway to evade macrophage-mediated destruction.

•  TTI-622 (human SIRPα linked to a human IgG4) is a soluble decoy receptor that neutralizes the suppressive effects of CD47 and promotes macrophage-mediated phagocytosis of tumor cells.

•  Previous studies have shown that blockade of the CD47-SIRPα pathway using TTI-621, a soluble SIRPα-IgG1 Fc fusion protein, triggers macrophage phagocytosis of tumor cells in vitro, and potently inhibits tumor growth in vivo.

•  In this study, the in vitro and in vivo efficacy of TTI-622, a soluble SIRPα-Fc variant protein containing an IgG4 Fc tail, was evaluated in multiple model systems.

Both Early and Delayed Administration of TTI-622 Decrease Tumor Growth and Improve Survival in a DLBCL

Xenograft Tumor Model

Toledo cells were implanted subcutaneously into the right flank of NOD.SCID mice (n=9 mice per group) on day 0. Mice were dosed intraperitoneally (IP) with TTI-622 at 10 mg/kg or control Fc on day 10 (A) or day 19 (B). Mice were sacrificed when at least one tumor dimension exceeded 15 mm. The study terminated on day 63. Statistical analysis of the tumor growth curves was performed using t-test comparing tumor volumes at day 35 (A) and day 40 (B). Survival curves were analyzed by Log-rank test. Where indicated, *** p ≤ 0.001, **** p ≤ 0.0001.

TTI-622 Enhances the Efficacy of Cetuximab

(anti-EGFR mAb) in a Head and Neck Squamous Cell Carcinoma Xenograft Model

Tumor Measurements

Survival

Tumor Volume (mm3)

Percent survival

0

20

40

60

0

20

40

60

Days post inoculation

Vehicle ****TTI-622

Days post inoculationVehicle

****

Cetuximab

****

****

TTI-622 *****Cetuximab

***

*Cetuximab + TTI-622

***

***

Cetuximab + TTI-622

TTI-622 Dosing schedule Cetuximab Dosing schedule

FaDu cells were implanted subcutaneously into the right flank of NOD.SCID mice (n=8 mice per group) on day 0. Mice were randomized on day 7 and received IP injections of TTI-622 10 mg/kg and/or cetuximab 3 mg/kg as indicated by the inverted triangles (left). Statistical analysis of the tumor growth curves was performed using one-way ANOVA with Tukey's multiple comparison test comparing tumor volumes at day 29 and survival curves were analyzed by Log-rank test (corrected for multiple comparisons). Where indicated, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, **** p ≤ 0.0001.

TTI-622 Potentiates the Efficacy of Daratumumab

(anti-CD38 mAb) in Burkitt Lymphoma and Multiple Myeloma Xenograft Models

Daudi (Birkitt Lymphoma)

Daudi cells (Birkitt lymphoma) were implanted subcutaneously into the right flank of NOD.SCID mice (n=9-11 mice per group). Mice were randomized on day 3 and received IP injections of TTI-622 10 mg/kg and/or daratumumab 10 mg/kg as indicated by the inverted triangles (left). Statistical analysis of the tumor growth curves was performed using one-way ANOVA with Tukey's multiple comparison test comparing tumor volumes at day 32 and survival curves were analyzed by Log-rank test (corrected for multiple comparisons). Where indicated, * p ≤ 0.05, *** p ≤ 0.001

MM.1S (Multiple Myeloma)

Tumor measurements

Survival

1500

Tumor Volume (mm3)

1000

500

Percent survival

0

0

20

40

60

0

20

40

60

80

100

Days post inoculationVehicle

Days post inoculation

Vehicle

**TTI-622

**

*TTI-622

DaratumumabDaratumumab + TTI-622TTI-622 Dosing scheduleDaratumumab Dosing schedule

***

Daratumumab

Daratumumab + TTI-622

MM.1S cells (multiple myeloma) were implanted subcutaneously into the right flank of NOD.SCID mice (n=9-10 mice per group). Mice were randomized on day 11 and received IP injections of TTI-622 10mg/kg and/or daratumumab 10 mg/kg as indicated by the inverted triangles (left). Statistical analysis of the tumor growth curves was performed using one-way ANOVA with Tukey's multiple comparison test comparing tumor volumes at day 26 and survival curves were analyzed by Log-rank test (corrected for multiple comparisons). Where indicated, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001

Conclusions

•  TTI-622 potently induces phagocytosis of a broad panel of tumor cells derived from patients with both hematological and solid tumors.

•  Unlike CD47-blocking antibodies, TTI-622 binds minimally to human erythrocytes and does not induce hemagglutination in vitro.

•  TTI-622 preferentially induces phagocytosis of tumor cells over platelets in a competitive phagocytosis assay.

•  In a DLBCL xenograft tumor model, both early and delayed treatments resulted in statistically significant decreases in tumor growth, and improved survival relative to treatment with control Fc.

•  TTI-622 potentiates the efficacy of cetuximab and daratumumab in solid and hematological xenograft tumor models, respectively.

•  Based on these data, a clinical study of TTI-622 in patients with advanced lymphoma or myeloma is being initiated.