Abstract AXA-042, a Systemically Administered TLR2/6 agonist, Demonstrates Target Engagement
1047P
and TLR Pathway Activation in Patients with Advanced Solid Tumors.
Ben Tran1, Michael Millward2, Charlotte Rose Lemech3,4, Sophia Frentzas5,6, Daphne Day5,6, Ardian Latifi7, Jayesh Desai 1,Paul Wabnitz7, Phil Kearney7 and Anna Galkin7.
1 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; 2 Linear Clinical Research, Perth, Australia; 3 Scientia Clinical Research, Randwick, Australia; 4 Prince of Wales Clinical School, UNSW Sydney, NSW; 5Department of Medical Oncology, Monash Health, Clayton, VIC, Australia;
6 Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia; 7Axelia Oncology, Melbourne, Victoria, Australia.

BACKGROUNDFigure 1. AXA-042 Whole Blood Gene Signature is Consistent with TLR Pathway Activation and Myeloid Cell Engagement

C1D1

C1D2

C1D2-4-2
02Signature Score

4MAPK Signaling••••

Cytokines: C1D1 pre-dose, 1h, 4h, C1D2;
C2D1 pre-dose, 4h; C3D1 pre-dose, 4hNanostring: C1D1 pre-dose, C1D2, C1D15CYTOF: C1D1 pre-dose, C1D2, C1D15-44-202
Signature Score

IL741642C1D1

C1D15

1C1D1

C1D15

C1D2

C1D15TNF

IFITM282.0
1.5
1.00.532
1C1D154200
C1D26

C1D1

C1D2

C1D1

C1D15

C1D2

C1D15

Figure 3. AXA-042 Impacts Distribution of Immune
Cell Subsets in Patient Whole Blood

23

196

1Pt5

1155 8966

11150 36700

21216382

2

60

10.1

0.1

DDDPre-Pre-Pre-ose

40

1CXCL9TNF03101113

1Pt31361129145

111823

1Pt4

1151115551

118151Pt5

161411788

2022

128231Cycle 1FoldChangeCycle 2Cycle 3Cycle 1

1000000

Cycle 2Cycle 3

10000
1000

10000

1000

30

1

12941

1

12572

4Pt4

1314

1

122242

1111

441

773/F

High grade serous,
platinum-resistantovarian cancer

3

12328

1

1708

315

324h

224h

Metastatic PDAC

341h

71/F

35

ose2

11.2

1.2

Monocytes CD38+ HLA-DR+

2.6

2.9

CD8+ T cells

1.41.4CD8+ Tbet+ T cells

1.5

1.6

CD8+ CD38+ T cells

1.1

1.1

CD4+ T cells

1.00.91.4

1.4

CD4+ CD38+ T cells

0.90.9γδ T cells

2.02.4γδ T cells Tbet+

2.1

2.6γδ T cells CD38+

1.9

2.6NK+

1.7

2.1

NK+ Tbet+

1.8

2.2

NK+ CD38+

1.7

2.1

Treg+

0.9

0.9

1000

Treg+ Tbet+

1.0

1.0

100

Treg+ CD38+

0.9

0.8

C1D2

C1D15

10000
1000
100oseDDDPre-Pre-Pre-4hose4hDPre-ose
DPre-4hDose4hose4hDPre-oseDPre-4h

DPre-Pre-CXCL9Cycle 2

Cycle 3

Cycle 1

10000

100000

Cycle 2

Cycle 3

10000

101pg/mL

5100

Cycle 1

Cycle 3

1000

0.1

100

0.01

10

104h

1

Monocytes

CD4+ Tbet+ T cells

CXCL10Cycle 2

ose

Pt3

IFNγ
Cycle 14h

12D963

Pr
e-14

ose

14h

1

D2

Pre-2

ose1

D

1

Pre-

4

pg/mL

14h

1

ose

Pt24h

6

D245

Pre-1ose

14h

1

D2

Pre-1

D43/Fose1ose2D

1Cycle 3

1100Pre-1pg/mL

1Cycle 2

1010

CSF3

Pt1

Pt5

Metastatic colorectal
adenocarcinoma

IL15Pre-3

IL7

1.1

1000001000001006Cycle 1

1000000

1000004h

14h14h9ose24h

Pt2

1

CSF3

CCL2

ose2

D2Pre-

1ose

1ose44h

174h

2

D

1

Pre-

1

ose2

D

1

Pre-

Pt1

1pg/mLCXCL10

pg/mL

7IFNy

pg/mL

Prior Linesof Therapy

1.223
Fold Change

1

Neutrophils

Tbet+ γδ T Cells

B.

21

A. Heat Map displaying kinetics of cytokine and chemokine induction in individual patient whole blood samples collected pre-dose orat indicated time points post infusion on C1D1. Data is shown as fold change relative to C1D1 pre-dose timepoint. B. Representative
cytokine and chemokine induction 4h post AXA-042 infusion in individual patients across Cycles 1, 2 and 3. Cytokine data for n=5
patients was available for Cycles 1-2 and n=3 patients for Cycle 3 at time of data cut-off. Data is shown as pg/mL.

01

1

15Tbet+ CD8+ T Cells
FoldChange

2
Fold Change

1310115

Tbet+ NK Cells
3
Fold Change

56

A.

4h

164h1ose610D202

1Pre-3410ose

Pt4

1100

4h

Pt3

2

D

1132

Pre-

1617ose

16

1

D

12

pg/mL

11228

Cycle 3

Pr
e-

166

11Cycle 2

100

4h

166

110ose

1

21000

4h

41648

Cycle 1

1000

D94

9Cycle 3

Pre-734

180ose54h

10Cycle 2D

514h24h

Metastatic mucinous
appendiceal
adenocarcinoma (AMN)

2IL15Pre-1ose3Pt21h69/F

Metastatic GIST

C1D24C1D1

D226

Cycle 1100

pg/mL186

Cycle 34h1Cycle 2ose5ose50/M

300
C1D20.010000

4h44Cycle 1100000

ose249B.

4h

1D60/F

C1D154Fold Change-202
Signature Score

Pre-CCL2pg/mL

Pt1Pre-PD BIOMARKER COLLECTION TIMEPOINTS

IL624hPharmacodynamic (PD) effects of AXA-042
Preliminary AXA-042 anti-tumor efficacy

2

Fold Change

C1D15-41004h••TNFa1h

EXPLORATORY ENDPOINTSA.

osePharmacokinetic parameters of AXA-042
Immunogenicity of AXA-042

C1D2

FCGR2A

S100A82.5

C1D2IL6D••C1D1C1D120

Metastatic ovariangranulosa tumor (GCT)

1C1D1583Figure 2. AXA-042 Cytokine/Chemokine Induction is Transient and Reproducible Across Cycles

COHORT 1 PATIENT CHARACTERISTICS
Cancer Type

2A. Volcano plot displaying differentially expressed genes on Cycle 1 Day 2 (C1D2) relative to C1D1 pre-dose timepoint in whole blood samples collected from AXA-042 treated patients (n=4). Genes withsignificance P-value < 0.05 and absolute fold change > 1 (log2) are labelled. B. Box plots displaying Pathway Signature Scores for whole blood samples collected on C1D1 (pre-dose), C1D2 and C1D15. Min
and max values are indicated C. Representative examples of AXA-042 differentially expressed genes across individual patients (n=4). Data is shown as fold change relative to C1D1 (pre-dose) timepoint.

IV once every 3-weeks

Age/Gender

C1D2

Fold Change-6

10NFκB Signaling

Log2FC (Day2 vs Day 1)

30C1D1IFNAR1

DLT period =Cycle 1 (21 days)

SECONDARY ENDPOINTSC1D15Fold Change-505Signature Score

C1D1AXA-042

Safety and Tolerability of AXA-042

1CSF3R-10Pre-•20C1D2C1D1Subjects with advanced metastatic solid tumors
3+3 design
Dose Level 3

PRIMARY ENDPOINTS

4C1D15C1D15C1D15Dose Level 110Galkin et al. Cancer Res (2022) 82:3502

Dose Level 220

A MULTI-CENTER OPEN-LABEL DOSE ESCALATION,DOSE EXPANSION PHASE 1 STUDY

CD14TLR13C1D1C1D2••TLR23Fold Change

C1D1C.

Fold Change

Cytokine and Chemokine Signaling

Myeloid Compartment

Fold Change

AXA-042 induces a pro-inflammatory
cytokine/ chemokine release by tumorlocalized monocytes/ macrophages (1),increases tumor cell killing and antigen
release (2), enhances DC activation (3)and potentiates T cell response tocheckpoint blockade (4).

B.

Fold Change

A.

Fold Change•AXA-042 is a novel synthetic potent
and selective TLR2/6 agonist
designed for systemic delivery to reengage the innate immune response.

Significance, -log10(P)•RESULTS

2101

AMN

15GCTGISTA. Impact of AXA-042 treatment on whole blood immune cellsubsets in GCT patient on C1D2 and C1D15. B. Impact of AXA-042
treatment on Tbet+ γδ T cell, CD8+ T cell and NK cell subsets acrossthree independent patients in cohort 1. Data in both panels isshown as Fold Change relative to C1D1 pre-dose timepoint

ACKNOWLEDGEMENTS

CONCLUSIONS

The authors would like to acknowledge the patients and their caregivers for theirsupport, and the investigators and their study teams for their contributions. We
also thank Nic West and team at Griffith University (Australia) for the wholeblood Nanostring gene expression analysis; Teiko.Bio (USA) for the whole blood
CYTOF data analysis and ViRemics (Singapore) for plasma cytokine profiling.

• Systemic administration of AXA-042 demonstrates strong engagement of the TLR signaling pathway as reflected by on-target inductionof gene expression and cytokines/chemokines associated with myeloid cell activation in patient whole blood samples.
• AXA-042 target engagement response is transient and reproducible across treatment cycles.
• AXA-042 transient TLR2 engagement enhances proportion of Tbet+ peripheral T- and NK- cell subsets in subsets of patients on C1D15.

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