MSC-1 — ANTI-LIF MONOCLONAL ANTIBODY ■■ First-in-class, humanized IgG1 monoclonal antibody■■ Binds to LIF with high affinity and specificity■■ Functions as a potent LIF antagonist■■ Inhibits downstream pSTAT3 in vitro and in vivo■■ Drives reprogramming of TME through modulation of immunosuppressive macrophages and of several immune cell types

LIF

JAK

gp130

MSC-1

LIFR

Stat3

M2 Macrophages

T-regs

NK cells

CD4+ and CD8+ cells

MSC-1

Self-renewal(CIC)

TeffTreg

Myeloid/M2

LIF

LIF

Nor

mal

ized

MSD

Sig

nal

0.25

0.20 IC50 2.5 nm

0.15

0.10

0.05

0.00-2 -1 0 1 2 3

MSC-1 (log nM)

HCC1954 pSTAT3

Representative IC50 dose-inhibition curve of LIF-induced pSTAT3 with MSC-1 treatment in HCC1954 breast cancer cell line

BACKGROUND AND PRECLINICAL

LEUKEMIA INHIBITORY FACTOR (LIF)■■ A multi-functional cytokine and part of the IL-6 family of cytokines■■ Binds to its specific receptor (LIFR) and recruits gp130 to form high affinity receptor complex■■ Activates downstream signaling pathways that regulate proliferation and survival

– Induces JAK/STAT3, PI3K/AKT and MAPK signaling pathways■■ Complex role in tumor development and progression

– Increases the migration and invasion abilities of tumor cells and promotes metastasis – Described role in regulating multiple immune cell types found within TME, including T-eff, T-reg, Th17 cells, as well as Myeloid cells

■■ Promotes the activity of cancer initiating cells (CICs)■■ Increases resistance to anti-cancer therapy (chemotherapy and radiation therapy)

Scientific World Journal, 2013

A.Blood

IFN-γ

Tumormicroenvironment

IL-6LIF

M2d/TAM

M-CSFCD115

M1

Immunotherapy © Future Science Group (2011)

IFN-γ

B.

Figure A. Schema of the proposed LIF signaling pathway. LIF triggers activation of JAK/STAT and MAPK pathways independently, resulting in different cell-responses: increase of invasiveness and proliferation, respectively.3

Figure B. IL-6 and LIF are involved in the local differentiation of monocytes into M2d, a new subclass of immunosuppressive macrophages that are functionally and phenotypically similar to TAM.4

A Phase 1, First-in-Human, Open Label, Dose Escalation, Dose Expansion Study of MSC-1, a Humanized Anti-LIF Monoclonal Antibody, in Patients with

Relapsed/Refractory Metastatic Solid Tumors David Hyman1, Irene Braña2, Anna Spreafico3, Naimish Pandya4, Kimberly Hoffman4, Robin Hallett4, Patricia Giblin4, Angus Sinclair4,

Judit Anido4, Isabel Huber-Ruano4, Ada Sala2, Monica Pascual2, Vanessa Chiganças2, Jeanne Magram4, Robert Wasserman4, Joan Seoane2

1Memorial Sloan Kettering Cancer Center, New York, NY; 2Vall D’Hebron Institute of Oncology, Barcelona, Spain; 3Princess Margaret Cancer Center, Toronto, Canada; 4Northern Biologics, Inc. Toronto, Canada

Presented at the Society for Immunotherapy of Cancer (SITC) 32nd Annual Meeting, November 8–12, 2017, National Harbor, MD

SITC 2017Abstract P506

ROLE IN MALIGNANCY■■ LIF is highly expressed in a sub-set of many solid tumors ■■ LIF over-expression correlates to poor prognosis

GBM NSCLC

LIF

H-S

core

Ovarian CA

Low

LIF

Hig

h LI

F

CRC Pancreatic Ca

0

100

200

300

0

100

200

300

0

100

200

300

0

100

200

300

0

100

200

300

MonthsMonths Since Initial Diagnosis Local Recurrence-free Survival (years)00 20 40 60 80 100 120 50 100 150 200 250

50

60

70

80

90

100

0

20

40

60

80

100

HR=1.357 (0.96–1.92)p=0.041

p=0.016p=0.001

A.

C.

B.

100

50

00 50 100 150

Perc

ent

Surv

ival

Months

High LIFLow LIF

High LIFLow LIF

High LIFLow LIF

100

50

0 0

0.25

0.50

0.75

1.00

0 20 40 60 80 100

Perc

ent

Surv

ival

Perc

ent

Surv

ival

Perc

ent

Surv

ival

Cum

ulat

ive

Surv

ival

Prob

abili

ty o

f Sur

viva

l

Months Breast Relapse-free Survival (years)

High LIFLow

High LIFLow LIF

p<0.001p<0.001

0 20 40 60 80 100

p=0.0039

LIF negative stainingLIF positive staining

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8

Colon

Lung Breast

NasopharyngealGBM

Head and Neck

IHC with an anti-LIF polyclonal antibody evaluating different tumor types (Red bars represent mean +/- SEM). LIF was highly expressed in a subset of GBM, NSCLC, Ovarian, Colorectal and Pancreatic tumors.

High LIF expression correlates with poor prognosis. A) High LIF transcript levels are associated with poor outcome in GBM (Internal data) and Colon cancer (Yu 2014); B) High circulating serum LIF protein levels correlates with poor outcome in Nasopharyngeal cancer (Liu 2013); C) High intratumoral LIF protein expression correlates with poor outcome in Head and Neck, Lung and Breast cancers (Albrengues 2014, Li 2014).

©2017 Northern Biologics, Inc. All rights reserved.

101 College Street TMDT 11-301Toronto, ON M5G 1L7 Canada

http://northernbiologics.com/wp-content/uploads/2017/11/SITC-2017.pdf

MSC-1 IN SYNGENEIC MODELS■■ MSC-1 inhibits tumor growth in mutiple syngeneic models

Control rMSC-1

Control rMSC-1

Control rMSC-1

OvarianID8

NSCLCKLN205

ColonCT26

Vehicle rMSC-1 shLIF#1 shLIF#20

4x107

3x107

2x107

1x107Tota

l Flu

x (p

/s)

0

8x106

6x106

4x106

2x106Tota

l Flu

x (p

/s)

Abd

omin

al V

olum

e (m

m3 )

Abd

omin

al V

olum

e (m

m3 )

p=0.07

**(p=0.001)

****(p<0.0001)

****(p<0.0001)

Vehicle rMSC-10

500

1000

1500

2000

2500 ***

Tum

or V

olum

e (m

m3 )

Tum

or V

olum

e (m

m3 )

Vehicle rMSC-10

2000

4000

6000

8000

10000

5 10 15 20

ControlrMSC-1

Days after Inoculation

shLIF #1shLIF #2

ControlrMSC-1

ControlrMSC-1

30 35 40250

2000

4000

6000

8000

Days after Inoculation

Days after Inoculation10 15 20

0

500

1000

1500

Tumor growth in rMSC-1 and control treated mice in three syngeneic models: KLN205 NSCLC tumor (orthotopic), ID8 Ovarian tumor (peritoneum), and CT26 Colon cancer (SQ).

MSC-1 REPROGRAMS TUMOR MICROENVIRONMENT■■ MSC-1 increases frequency of intratumoral immune cells and activation status

Control (PBS) rMSC-10

1

2

3

4

Control (PBS) rMSC-1

% C

D45

+

*(p=0.02)

Vehicle rMSC-10.0

0.1

0.2

0.3

% C

D3+ C

D4+

**(p=0.008)

Vehicle rMSC-1

Control (PBS) rMSC-1 Vehicle rMSC-1 Vehicle rMSC-1

0.0

0.5

1.0

1.5

2.0

% C

D3+ C

D8+

**(p=0.008)

0.00

0.02

0.04

0.06

0.08

0.10

% C

D3– C

D49

b+

**(p=0.008)

0.000

0.005

0.010

0.015

0.020

% C

D4+ C

D69

+

**(p=0.008)

0.000

0.005

0.010

0.015

0.020

% C

D8+ C

D69

+

**(p=0.008)

N=5 N=5 N=5 N=5 N=5 N=5

N=5 N=5 N=5 N=5 N=5 N=5

Immune cell infiltrates in ID8 tumors from rMSC-1 or control treated mice. Tumors were harvested at d40 post implantation and analyzed by flow cytometry. Similar results were observed in the KL205 and CT26 models.

■■ MSC-1 decreases immunosuppressive M2 macrophages

Vehicle

****

rMCS-1

% C

D20

6+ / IB

A1+ C

ells 100

80

60

40

20

0Vehicle

****

rMCS-1

% C

CL22

+ / IB

A1+ C

ells 100

80

60

40

20

0

Cont

rol

rMSC

-1

Cont

rol

rMSC

-1

CD206 IBA-1 MERGE DAPI CCL22 IBA-1 MERGE DAPIPatient 1 Patient 1

Human GBM organotypic slices were incubated with rMSC-1 for 72 hrs and stained using double immunofluorescence for (A) CD206 (MRC1) or (B) CCL22 with IBA-1. Representative images of the immunofluorescence are shown (scale bar, 50 µm). Similar results were observed using three patients. CD206/IBA-1 and CCL22/IBA-1 expression ratios were calculated and are shown besides the representative images. Results graphed are the mean ± SEM of all patients with statistical significance (****) p<0.0001 as analyzed by the unpaired T-test.

STUDY RATIONALE■■ LIF is a pleotropic cytokine over-expressed in multiple solid tumors and hypothesized to play a role in tumor growth, progression and resistance to standard anti-cancer treatments■■ It is hypothesized that in patients with advanced solid tumors, treatment with MSC-1 will lead to effective blocking of LIF signaling and reprogramming of the tumor microenvironment causing increased immune-mediated anti-tumor effect■■ It is further hypothesized that administration of MSC-1 will be sufficiently well tolerated to enable further development subsequent to the completion of this Phase 1 study

KEY STUDY OBJECTIVESPRIMARY OBJECTIVE ■■ To evaluate the safety and tolerability of MSC-1 in patients with advanced solid tumors■■ To determine the recommended dose for MSC-1 monotherapy■■ To assess the preliminary anti-tumor activity, as measured by ORR, of MSC-1 according to RECIST 1.1 criteria

SECONDARY OBJECTIVES■■ To characterize the PK and immunogenicity of MSC-1■■ To assess efficacy parameters in patients with advanced solid tumors, including DCR & PFS by RECIST 1.1

KEY EXPLORATORY OBJECTIVES■■ To explore the relationships between PK, pharmacodynamics and MSC-1 exposure to patient safety and anti-tumor activity■■ To assess whether high tumor LIF expression correlates with anti-tumor activity of MSC-1■■ To characterize pharmacodynamic effects of MSC-1 in the periphery and in the tumor ■■ To characterize impact of MSC-1 treatment on exploratory biomarkers

STUDY DESIGN■■ Open-label, Phase 1 study enrolling advanced solid tumor patients ■■ The study will be conducted in an accelerated-titration 3 + 3 design ■■ Flat dose of MSC-1 administered intravenously once Q3W

DOSE ESCALATION(all comer solid tumors)

MTD / OBD

DOSE EXPANSION(LIF-High)

NSCLC BasketOvarianCancer

PancreaticCancer

RESPONSE ASSESSMENTS■■ Anti-tumor response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines■■ Assessments to be performed at baseline and every 6 weeks for first 6 months and then every 12 weeks thereafter until confirmed progression disease or patient withdrawal

SAFETY ASSESSMENTS■■ Adverse events will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03■■ To be assessed continuously during the study and for 30 days after the last treatment

ENTRY CRITERIAKEY INCLUSION CRITERIA■■ Histologically proven relapsed / refractory advanced, unresectable solid tumor ■■ Measurable disease as per RECIST 1.1 criteria■■ Identification of archival tumor sample for LIF expression analysis■■ ECOG 0 or 1■■ Weight > 37.5 kg■■ Life expectancy ≥ 12 weeks■■ Men and women ≥ 18 years of age■■ Adequate organ function■■ Signed Informed Consent

KEY EXCLUSION CRITERIA■■ Symptomatic or unstable brain metastasis■■ Prior systemic therapy within 4 weeks of study entry■■ Prior radiation therapy or significant surgery within 21 days to study entry■■ Ascites or pleural effusion requiring large volume para- or pleurocentesis within 4 weeks of study entry ■■ Patients currently receiving immunosuppressive therapy, except inhaled corticosteroids ■■ Uncontrolled or clinically significant cardiovascular or pulmonary disease■■ Grade 3 or 4 peripheral neuropathy (NCI CTCAE v4.03)■■ Vaccination with live virus vaccine 4 weeks from initiation■■ Positive for hepatitis B or C or HIV ■■ Second primary malignancy not in remission > 2 years■■ Therapeutic anticoagulation for a thromboembolic event

REFERENCES1. Yue X et al. Cancer Cell Microenvironment 2015 PMID: 26807429. 2. Nicola NA et al. Cytokine Growth Factor Rev 2015 PMID: 26187859. 3. Morales-Prieto DM et al. The Scientific World Journal 2013 PMID: 24288470. 4. Jeannin P et al. Immunotherapy 2011 PMID: 21524164. 5. Yu H et al. Nature Communications 2014 PMID: 4203416. 6. Liu S et al. J of Clinical Investigations 2013 PMID: 24270418. 7. Albrengues J et al. Cell Reports 2014 PMID: 24857661. 8. Li X et al. Oncotarget 2014 PMID: 24553191.