Tumor Targeted Immunostimulants; A Promising Approach to ...€¦ · Sutro Platform Enables Rapid & Precise Optimization of single species ADCs • ADCs produced in a few days •

Tumor Targeted Immunostimulants; A Promising Approach to In Situ Immunization

Trevor Hallam CSOMarch 4, 2020

Forward Looking Statements

• This presentation and the accompanying oral presentation contain “forward-looking” statements that are based on our management’sbeliefs and assumptions and on information currently available to management. Forward-looking statements include all statements other than statements of historical fact contained in this presentation, including information concerning our future financial performance, business plans and objectives, current and future clinical and preclinical activities, timing and success of our ongoing and planned clinical trials and related data, the timing of announcements, updates and results of our clinical trials and related data, timing and success of our planned development activities, our ability to obtain and maintain regulatory approval, the potential therapeutic benefits and economic value of our product candidates, potential growth opportunities, financing plans, competitive position, industry environment and potential market opportunities.

• Forward-looking statements are subject to known and unknown risks, uncertainties, assumptions and other factors. It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements we may make. These factors, together with those that may be described in greater detail under the heading “Risk Factors” contained in our most recent Annual Report on Form 10-K and other reports the company files from time to time with the Securities and Exchange Commission, may cause our actual results, performance or achievements to differ materially and adversely from those anticipated or implied by our forward-looking statements.

• You should not rely upon forward-looking statements as predictions of future events. Although our management believes that the expectations reflected in our forward-looking statements are reasonable, we cannot guarantee that the future results, levels of activity, performance or events and circumstances described in the forward-looking statements will be achieved or occur. Moreover, neither we nor our management assume responsibility for the accuracy and completeness of the forward-looking statements. We undertake no obligation to publicly update any forward-looking statements for any reason after the date of this presentation to conform thesestatements to actual results or to changes in our expectations, except as required by law.

• This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions, and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk.

• Solely for convenience, the trademarks and tradenames referred to in this presentation appear without the ® and ™ symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights, or the right of the applicable licensor to these trademarks and tradenames.

2 NON-CONFIDENTIAL

Sutro Clinical Pipeline Owned and Partnered Programs

PROGRAM DISCOVERY PRECLINICAL PHASE 1 PHASE 2/3 MILESTONE COMMERCIAL RIGHTS

FolRα - targeting ADCSTRO-002

CD74 – targeting ADCSTRO-001

Multiple Oncology & I/O Programs

BCMA – targeting ADCCC-99712

Bispecific ADC

Cytokine Derivatives

PD1-LAG3

BCMA-CD3

PD1-TIM3

Additional Clinical Data Expected in 1H20

Additional Clinical Data Expected in 1H20

Trial Enrolling BMS Worldwide Rights

Worldwide Rights

(a)

(a) BMS automatically obtained worldwide rights to the BCMA - targeting ADC---the first collaboration product candidate to achieve IND clearance in the United States. Additionally, there are three programs to which BMS currently has ex-U.S. rights and Sutro currently has U.S. rights. Sutro is eligible for milestones and royalties on each of the four product candidates.

(b) EMD Serono is the U.S. healthcare business of Merck KGaA, Darmstadt, Germany.

Multiple Myeloma (Orphan Drug Designation);Lymphomas: DLBCL, Mantle Cell, Follicular

Ovarian and Endometrial Cancer

Oncology

Multiple Myeloma

Multiple Myeloma

ImmunoOncology

ImmunoOncology

Oncology & Autoimmune

Oncology

3

Oncology (b)

(a)

GMP supply in process

NON-CONFIDENTIAL

Input DNA

Ribosomes

Cell-free environment

Sutro’s XpressCF+TM Platform: Incorporation of Non-natural Amino Acids

Protein

NNN

mRNA NNN UAA

Stop

MJ tRNACF Engineered MJ TyrRS

nnAA

+

RF1

Zimmerman et al Bioconj Chem 2014, 25, 351-361.Yin and Stephenson et al Nature Sci Reports 2017, 7 (1) 3027.

NON-CONFIDENTIAL4

Wholly Owned Manufacturing Advantage –XpressCF™Accelerating the development of potential best-in-class protein therapeutics

Potential Best-in-Class Protein Therapeutics Differentiated Attributes of XpressCF™

• Rapid generation of diverse protein structures enables empirical assessment and selection of optimal candidates

• Can accelerate time to IND by 9 - 15 months compared to conventional technologies

• Homogeneous drug products generated precisely according to specifications

• Cell-free protein production process generates homogenous products from DNA sequences in <24 hours

• Consistent production method used across scale-up — from discovery to commercial manufacturing

• Enables site-specific, efficient and complete conjugation to non-natural amino acids

Bispecifics Cytokine-basedI/O Therapeutics

ADCs

NON-CONFIDENTIAL5

Sutro Platform Enables Rapid & PreciseOptimization of single species ADCs

• ADCs produced in a few days

• Structure-Activity optimization allows screening for

• Optimal Antibody discovery

• Sites of drug-linker attachment

• Optimal combination of sites

• Precise Drug/Antibody Ratio

• Refinement of linker and warhead attributes

• Good product stability

Specific Conjugation-Optimized Sites Drives Superior Therapeutic Index with First and Best-in Class potential

NON-CONFIDENTIAL6

STRO-002: FolRα ADCPotential Best-in-Class ADC for Ovarian and Endometrial Cancers

NON-CONFIDENTIAL7

STRO-002: Overcoming Therapeutic Window Limitations of 1st Generation ADCs

STRO-002 Properties Implications for Best-in-Class Potential

• Homogeneous ADC product generated from Sutro’s XpressCF™ platform.

• Optimized cytotoxin positioning and consistent drug-antibody ratio (DAR = 4)

• Potent and Sutro proprietary hemiasterlin-derivative warhead

• Cleavable linker warhead designed for optimized pharmacology

• Potential for improved therapeutic index through homogeneous delivery of cytotoxin to tumor.

• Many designs tested to identify STRO-002, the candidate with potential for best potency and safety

• Efficacious, potent killing of tumor cells

• Rapid clearance of toxic catabolite after release & cell killing in tumor; potential for improved safety

No ocular toxicity observed in NHP study

NON-CONFIDENTIAL8

Negative10%

Low10%

Medium16%High

64%

Negative7%

Low15%

Medium24%

High54%

Ovarian Endometrial

STRO-002: Targeting FolRα in Ovarian and Endometrial Cancers

FolRαü Clinically validated target + site directed conjugation

resulting in homogeneous ADC

ü Expressed on a variety of tumor types

ü Limited expression in normal tissue FolRα expressed in more than 90% of evaluated ovarian and endometrial cancer tissue samples(a)

(a) Source: Sutro Biopharma report, Expression Of Folate Receptor Alpha In Ovarian And Endometrial Cancer Samples, TR-TPPD-0039-V1.0, dated March 12, 2018.

FolRα Expression Appears to Correlate with Disease Progression in Ovarian Cancer

NON-CONFIDENTIAL9

STRO-002 in Ovarian CancerDesign features facilitate improved potency and specificity

STRO-002 Demonstrates More Potent Cell Killing Compared to the Benchmark and Has Minimal Off-Target Activity

Source: Sutro Biopharma report, STRO-002 Cell Killing Compared to SP8435, TR-TPPD-0021-V1.0, dated May 18, 2018.

NON-CONFIDENTIAL10

STRO-002: A Potentially Superior FolRα ADC Improved stability can widen therapeutic index

* not detectable

Day 0 Day 1 Day 3 Day 70

50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC209 Levels

Plasm

a Level (n

g/m

l)


50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC334 (DM4) Levels

Plasm

a Level (n

g/m

l)

Tumor Levels (ng/g) Plasma Levels (ng/ml)


50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC209 Levels

Plasm

a Level (n

g/m

l)


50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC334 (DM4) Levels

Plasm

a Level (n

g/m

l)



50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC209 Levels

Plasm

a Level (n

g/m

l)Day 0 Day 1 Day 3 Day 7

0

50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC334 (DM4) Levels

Plasm

a Level (n

g/m

l)


* * *Day 0 Day 1 Day 3 Day 7

0

50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC209 Levels

Plasm

a Level (n

g/m

l)


50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC334 (DM4) Levels

Plasm

a Level (n

g/m

l)



50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC209 Levels

Plasm

a Level (n

g/m

l)


50

100

150

0

1

2

3

4

Tu

mo

r L

evel

(n

g/g

)

SC334 (DM4) Levels

Plasm

a Level (n

g/m

l)


*

Mouse Tumor Model – Free Warhead in Tumor vs. Blood After Dosing

STRO-002 Free Warhead

Heterogeneous BenchmarkFree Warhead

no observable warhead*

No Evidence of STRO-002 Free Warhead Circulating in the Blood Post DosingNo evidence of Free Warhead Accumulation in FolRa Negative Tumors

Source: Sutro Biopharma report, In Vivo Catabolite Profiling for SP8193 and SP8435 in Tumor and Plasma, TR-PHRM-0036-V1.1, dated January 8, 2018.

* not detectable

Day 0Day 1Day 3Day 70

50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)

Tumor Levels (ng/g)Plasma Levels (ng/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)



50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)


*** Day 0Day 1Day 3Day 70

50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)



50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)


*

Mouse Tumor Model –Free Warhead in Tumor vs. Blood After Dosing



no observable warhead *

* not detectable


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)



50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)



50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)


*** Day 0Day 1Day 3Day 70

50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)



50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC209 Levels

Pla

sma

Lev

el (

ng

/ml)


50

100

150

0

1

2

3

4

Tu

mo

r Level (n

g/g

)

SC334 (DM4) Levels

Pla

sma

Lev

el (

ng

/ml)


*

Mouse Tumor Model –Free Warhead in Tumor vs. Blood After Dosing



no observable warhead *

NON-CONFIDENTIAL11

Part 1 — Dose Escalation (1 Cohort: Ovarian) Part 2 — Dose Expansion (2 Cohorts)

STRO-002 Phase 1 Clinical Trial DesignSi

ngle

Age

ntCo

mbi

natio

n St

udie

s An

ticip

ated

Dose Level n

FPD in 1Q19

MTD-2

MTD-1

MTD

n = 3 - 6

n = 1 - 6 RP2D

RP2D

n = 40 Ovarian

n = 40 Endometrial

TBD Endometrial + Combo Therapy

TBD Ovarian + Combo Therapy

Up to:

Anticipated combination study

Dose Level 1-3

Dose Level 4

2.9 mg/kg

0.5 -1.8 mg/kg

Dose Level 5

Dose Level 6

4.3 mg/kg

6.0 mg/kg

• First Patient Dosed March 2019• STRO-002 given by IV infusion

on Day 1 of 21-day cycles

NON-CONFIDENTIAL12

13

• STRO-002 has been well tolerated • No DLTs or infusion reactions have been observed• No ocular toxicity observed; No prophylactic corticosteroid eye drops

being utilized• MTD not yet determined

• Dose escalation continuing at 6.0 mg/kg • Preliminary evidence of clinical benefit and anti-tumor activity

• One confirmed PR by RECIST 1.1 (Cycle 5) with a confirmed CA-125 response

• Five patients have stable disease per RECIST 1.1 (confirmed & unconfirmed) in first 13 patients

STRO-002 Phase 1 Emerging Clinical Data in Ovarian Cancer (All Comers)

Data as of Oct 15, 2019Presented at AACR-NCI-EORTC 2019

NON-CONFIDENTIAL

STRO-002 in combination with Avelumab resulted in complete remission of animals bearing MC38-FolRα tumors

• Markedly enhanced anti-tumor activity observed with combination treatments compared to either single agent alone

• Combination treatment extended median survival compared to single agent therapy• Combination treatment significantly increased infiltration of CD8+ T Cells into

tumor; T cell infiltration not seen with either single agent therapy

0 20 40 60 80 100 1200

500

1000

1500

2000

Days post treatment

Tum

or s

ize

(mm

3 )

Tumor Growth Curves

Vehicle

15 mg/kg STRO-002 (single)

20 mg/kg Avelumab (q3dx3)

Combination

0 25 50 75 100 1250

25

50

75

100

Days post treatment

Per

cent

sur

viva

l

Survival

Vehicle



Combination

A B

0 20 40 60 80 100 1200

500

1000

1500

2000

Days post treatment

Tum

or s

ize

(mm

3 )

Tumor Growth Curves

Vehicle



Combination

0 25 50 75 100 1250

25

50

75

100

Days post treatment

Per

cent

sur

viva

l

Survival

Vehicle



Combination

NON-CONFIDENTIAL14

STRO-002 Stimulation of The Immune System is Mediated by Hemiasterlin and is FolRa Dependent

STRO-002 Induces ICD Markers only in FolRa Positive Cells

STRO-002 Induces Immunogenic Cell Death STRO-002 Activates MonocytesFolRa positive cells FolRa negative cells

FolRa positive cells FolRa negative Cells

medium Hemiasterlin aFolRa STRO-002 aGFP ADC0

2

4

6

HM

GB

1 C

once

ntra

tion

(fol

d ch

ange

ove

r m

ediu

m)

HMGB1 Release

medium Hemiasterlin aFolRa STRO-002 aGFP ADC0

1

2

3

4

Geo

met

ric

MFI

(F

old

Cha

nge

Ove

r M

ediu

m)

Calreticulin Expression

• Tumor targeted immunogenic cell death (ICD) induces activation of monocytes in the tumor microenvironment

• Calreticulin and HMGB1 are markers of ICD and can enhance APC activation, recruitment and tumor antigen uptake

• Tumor ICD promotes innate immune activation and synergy with PD1 checkpoints

0.0001 0.01 1 100 10000

0

20

40

60

80

nM

CD86+(%

ofC

D14+)

Baseline = 0.9%

aFolRa STRO-002

0.0001 0.01 1 100 10000

0

20

40

60

80

nM

CD86+(%

ofC

D14+)

Baseline = 1.1%

aGFP ADCHemiasterlin

NON-CONFIDENTIAL15

Intratumoral (IT) dosing of synthetic Toll-like Receptor agonists (TLRs) under evaluation as potential new cancer therapies

• Challenges:• Despite localized (IT) injection, cytokine storm is a dose limiting toxicity.• IT administration is limited to external or cutaneous tumor indications.

Immune cell

Several Clinical trials with TLR agonists have shown promise with tumor regression and abscopal effects; however limited by I.T. administration

NON-CONFIDENTIAL16

TLR4 and TLR7/8 Agonists Synergistically Activate Dendritic CellsFurther enhancement seen with CPIs or ICD Inducers

• Cytoxan (cyclophosphamide) induces ICD which promotes DC proliferation.• HMGN1 and R848 synergistically activate DCs through TLR4 and TLR7/8, respectively• Triplet treatment enhanced tumor infiltrating DC activation and increased infiltration of

CD4+ and CD8+ T cells. • Tumor-free mice treated were resistant to subsequent challenge with CT26, indicating

protective immunity

Would a Dual Conjugate of A Tumor Targeting Antibody and TLR4 and TLR7/8 Agonists Act As an In Situ Vaccine?

Nie et al (2017)

www.nature.com/scientificreports/

4Scientific RepoRts | 7: 14186 | DOI:10.1038/s41598-017-14655-8

To investigate whether the therapeutic antitumor effect of TheraVac consisting of CY, R848, and HMGN1 was due to generation of antitumor immunity, neutralizing anti-CD4, anti-CD8, or anti-NK1.1 antibody was used together with TheraVac. As shown in Fig. 4, CT26 tumor growth was halted by TheraVac. Simultaneous adminis-tration of anti-CD4 or anti-CD8 antibody almost completely nullified the therapeutic effect of TheraVac, demon-strating that both CD4 and CD8 T cells are required for the manifestation of the antitumor effect of TheraVac. In contrast, simultaneous administration of anti-NK1.1 antibody did not affect the therapeutic antitumor effect of TheraVac, suggesting that NK cells did not contribute significantly.

Given the DC-activating effects of R848 and HMGN16,27 as shown by data in Fig. 1, we hypothesized that tDCs might mature and migrate to the draining lymph nodes (LN) after TheraVac therapy. To examine this possibility, Balb/c mice harboring large CT26 tumors were injected i.t. with FITC-labeled ovalbumin and subsequently treated with PBS, CY, CY + R848, or the TheraVac combination. Twenty-four hours after treatment, draining LNs were harvested, sliced, and enzymatically digested to make single cell suspensions. The cell suspensions were immunostained with various fluorochrome-conjugated antibodies against mouse CD11c, CD80, and CD86, and analyzed on a BD LSR II flow cytometer. Gating on DCs (CD11c+) that were FITC+ showed that CT26-bearing mice treated with TheraVac had the highest number of FITC+ DCs in the draining inguinal LNs, followed by mice treated with CY + R848 (Fig. 5A), demonstrating that TheraVac treatment resulted in homing of tDCs into the draining LN. Mice treated with CY alone did not signifi-cantly promote tDC homing to the draining inguinal LN (Fig. 5A). Comparison of the levels of costimu-latory molecule expression by CD11+ DCs revealed that DCs in the draining LNs of CT26-bearing mice treated with TheraVac exhibited the highest levels of CD80 and CD86 (Fig. 5B). DCs in the draining LN of CT26-bearing mice treated with CY + R848 also had higher expression of CD80 and CD86, whereas treat-ment with CY alone did not upregulate DC expression of CD80 and CD86 (Fig. 5B). We propose that the

Figure 2. Establishment of a triple combination regimen for the treatment of mice harboring large CT26 colon tumors. (A and B) Balb/c mice (female, 8 week-old, n = 5) were inoculated s.c. with 2 × 105/mouse of CT26 cells in the right flank on day 1 and the formation of tumors were monitored. When tumors reached approximately 1 cm in diameter (day 12), the mice treated with one dose of i.p. Cytoxan (CY, 2 mg/mouse) on day 12 (blue arrow) and/or four i.t. injections of R848 (10 µg/injection/tumor) or HMGN1 (N1, 10 µg/injection/tumor) on day 12, 15, 19, and 22 (black arrows) in various combinations. Tumor growth (A mean ± SD) and survival (B) were monitored and plotted (blue circle = PBS, red circle = CY, green circle = CY + R848, purple circle = CY + R848 + N1). The photo image of one mouse of each group on day 21 is also included (A). Shown are the results of one experiment representative of three. (C–E) Ten CT26-free mice resulted from treatment with the combination of CY + R848 + HMGN1 in (A and B were s.c. inoculated with 2 × 105/mouse of CT26 cells in the right flank and identical amount of 4T1 cells in the left flank. The appearance (C) and growth (D) of solid tumors were monitored for up to five weeks. The formation of 4T1 tumors but not CT26 tumors were confirmed by photographing of the naked flank regions of three randomly chosen euthanized mice (E). (F) Three groups (G1-G3) of female Balb/c mice (8 week-old, n = 5) were inoculated s.c. with 2 × 105/mouse of CT26 cells in the right flank on day 1. On day 5, mice in G3 were inoculated s.c. with 2 × 105/mouse of CT26 cells in the left flank. Mice were treated with PBS (G1) or a combination (G2 and G3) of one i.p. Cytoxan (CY, 2 mg/mouse, blue arrow) and four i.t. injections of R848 and HMGN1 (each at 10 µg/injection/tumor, black arrows) into the right tumors twice weekly starting on day 12. Tumor growth (mean ± SD) was monitored and plotted (RT and LT = right and left tumor, respectively). *p < 0.05 and **p < 0.01 when compared with PBS-treated group.











Triplet of Cytoxan, R848 and HMGN1• Cy: Cytoxan • R848: TLR7/8 agonist • HMGN1: TLR4 agonist

NON-CONFIDENTIAL17

Systemic Administration of TLR7/8-agonist Resulted in Tumor Growth Inhibition but with Transient BW loss

• Anti-tumor activity of TLR7/8 agonist : IT dosing > IV or SC (systemic) dosing.

• Transient BW loss during 1st week in all treated groups (IT, IV, and SC dosing).

TLR7/8 Agonist q4d X 2IT = intratumoralSC = subcutaneousIV = intravenous

0 5 10 15 20 250

3

6

9

12

Days post treatment

Fold

Cha

nge

(Tum

or S

ize)

Tumor Growth Curves

Vehicle (IT) - Treated

Vehicle (IT) - Contralateral

2 mg/kg SC501 (IT) - Treated

2 mg/kg SC501 (IT) - Contralateral

2 mg/kg SC501 (SC)

2 mg/kg SC501 (IV)

0 5 10 15 20 25-15

-10

-5

0

5

10

Days post treatmentB

ody

wei

ght c

hang

e (%

)

Body Weight Change

Vehicle

2 mg/kg SC501 (IT)

2 mg/kg SC501 (SC)

2 mg/kg SC501 (IV)

← ~93% TGI

← ~80% TGI(abscopal effect)

MC38-hFolRα model

Vehicle IT - (R) Treated

Vehicle IT - (L) Contralateral

2 mg/kg TLR7a IT - (R) Treated

2 mg/kg TLR7a IT - (L) Contralateral

2 mg/kg TLR7a SC

2 mg/kg TLR7a IV

Limitations of IT dosing – leakage and systemic exposure - drive, at least in part, efficacy but also toxicity.

NON-CONFIDENTIAL18

Sutro’s FolR𝜶 ISAC product concept promises to preserve efficacy and improve tolerability

FolRα Ab conjugated to TLR7/8 agonist via cleavable linker

FolRα ISAC (Immune Stimulator Antibody Conjugate)

Site-Specific Conjugation Technology Allows For Optimization of Pharmacological Properties

NON-CONFIDENTIAL19

Combination of FolR𝜶 ISAC and FolR𝜶 ADC Results in Tumor Regressions and No Tumor Growth Upon Re-challenge

Part 2: Tumor re-challenge in ISAC/ADC tumor-free mice (no additional treatment administered)

10 mg/kg single-dose

Part 1: Evaluation of ISAC/ADC combination

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days post implantation

Tum

or s

ize

(mm

3 )

Control

FolRα ISACα + FolR ADC (previously treated)

0 5 10 15 20 25 30 350

500

1000

1500

2000

Days post treatment

Tum

or s

ize

(mm

3 )

Vehicle

FolRα ISAC

FolRα ADC

FolRα ISAC + FolRα ADC

• FolR𝜶 ISAC (immune stimulator antibody conjugate) product concept supported by impressive in vivo anti-tumor activity and good tolerability with 1/40th dose of free TLR agonist

• Combination of ADC and ISAC gave greater anti-tumor response with evidence of regressions.• No tumor re-growth in survivors upon tumor re-implantation, suggest FolR𝛼 ISAC/ADC-related

innate and adaptive immune mechanisms drive anti-tumor response.

NON-CONFIDENTIAL20

ADC to iADC: Combining Synergistic Mechanisms in a Single Molecule

ADC iADC

= linker-hemiasterlin= linker-TLR agonist

• Specific conjugations to specifically positioned sites• Optimal stoichiometry (absolute DAR and ratio of each payload)

• Enables optimal efficacy and tolerability

• Process options enabled allowing use of single nnAA or two different nnAAs• Both process paths result in a single molecular species iADC

NON-CONFIDENTIAL21

Combining ADC and Immune Agonists Can Break Tumor Tolerance and Elicit Protective Immunity in a single therapy

iADC approach can elicit protective tumor immunity by two mechanisms:1. Tumor targeted immunogenic cell death

• Induce tumor killing that alerts immune response2. Directly activate immune cells (i.e. dendritic cells)

• Demonstrates tumor immunity in vivo

ADC + immune stim

Some patients will require multiple therapies to enable cancer immunity,an iADC combines multiple MOAs into a single tumor targeted therapy

NON-CONFIDENTIAL22

Superior Anti-Tumor Memory Response with Single Dose of a Prototype 4+2 FolRα iADC

All treated animals that achieved CR were re-challenged with MC38-hFolRacells

0 20 40 60 800

500

1000

1500

2000

Rechallenge

Days

Tum

or s

ize

(mm

3 )

Naive (n=12)

Treated (n=8)

0 10 20 30 40 50 60

0

500

1000

1500

2000

2500

Days post treatment

Tum

or s

ize

(mm

3 )

Vehicle

CR: 0/9

0 10 20 30 40 50 60

0

500

1000

1500

2000

2500

Days post treatment

Tum

or s

ize

(mm

3 )

aFolRa ISACTLR7i DAR2

CR: 0/8

0 10 20 30 40 50 60

0

500

1000

1500

2000

2500

Days post treatment

Tum

or s

ize

(mm

3 )

aFolRa ADC(hemiasterlin DAR4)

CR: 3/8

0 10 20 30 40 50 60

0

500

1000

1500

2000

2500

Days post treatment

Tum

or s

ize

(mm

3 )

aFolRa iADC(Hemiasterlin DAR4; TLR7i DAR2)

CR: 5/7

FolRα iADC showed enhanced activity vs. ADC alone based on higher number of animals with complete responses and durable anti-tumor immunity

NON-CONFIDENTIAL23

A new precedentTurning a tumour into a vaccine in situ…..

• This program is one of a number of approaches at Sutro exploring whether systemically administered TME-targeting of conjugated combination payloads can set up a sustained and robust anti-tumor immune response

• In our illustrated case a targeted cytotoxin, our proprietary hemiasterlin, that stimulates immunogenic cell death, provides a synergistic stimulation of memory responses when paired together with TLR agonists.

• This systemically delivered trigger for the immune system induces an adaptive and protective response …….”an immunization triggered in situ ”

NON-CONFIDENTIAL24

Headquarters310 Utah Ave.Suite 150South San Francisco, CA 94080

Manufacturing Plant870 Industrial RoadSan Carlos, CA 94070

Phone: 650.392.8412Fax: 650.872.8924Web: www.sutrobio.com

Additional Offices240 E. Grand AveSouth San Francisco, CA 94080

[email protected]

Documents

Tumor Targeted Immunostimulants; A Promising Approach to ...€¦ · Sutro Platform Enables Rapid & Precise Optimization of single species ADCs • ADCs produced in a few days •