Table 1. Expression levels were determined using publicly available RNA-Seq datasets. Introduction Despite advances in treatment options for patients with HER2-expressing tumors, significant unmet medical need remains. Checkpoint inhibition (CPI) therapy has been largely ineffective in HER2-expressing tumors (2+ and 3+ by IHC), likely due to the absence of T cell infiltrate. In contrast, it is well established that HER2-expressing tumors are replete with myeloid cells offering the opportunity for intratumoral immune activation. Local administration, the typical delivery route used for innate immune/myeloid cell agonists, is limited by tumor accessibility and a dependence on abscopal responses. SBT6050 is a novel ImmunoTAC™ therapeutic comprised of a HER2-directed monoclonal antibody conjugated to a potent and highly specific TLR8 agonist, allowing for systemic delivery of a myeloid cell agonist with activity localized to HER2-expressing tumor sites. Conclusions • SBT6050, a HER2-directed monoclonal antibody conjugated to a potent and highly specific TLR8 agonist, activates multiple anti-tumor immune mechanisms in a HER2-dependent manner, allowing for systemic delivery and tumor-localized activity. • SBT6050-S demonstrates robust, durable single agent activity in tumor models with low tumor infiltrating lymphocytes, highlighting the potential for clinical activity with SBT6050 in HER2-expressing malignancies. • SBT6050-S is curative as a single agent in a HER2-expressing xenograft model lacking T, B, and NK cells, demonstrating the potential of myeloid cells to mediate robust efficacy. • The combination of a low dose of SBT6050-S together with trastuzumab in a HER2-positive mouse tumor model enhanced the single agent activity observed with either agent alone. • Collectively, these data support clinical evaluation of SBT6050 as a single agent and in combination with trastuzumab in relevant HER2-expressing tumor types. SBT6050 is currently in late preclinical development for patients with moderate or high HER2- expressing tumors and is projected to enter the clinic later this year. Figure 5: SBT6050 Mouse Surrogate (SBT6050-S) Matches the Functional Profile of SBT6050 on Human Myeloid Cells Figure 7: SBT6050-S Induces Robust Single Agent Tumor Clearance in T, B, and NK Cell Deficient Mice SBT6050, a HER2-Directed TLR8 Therapeutic, is a Systemically Administered, Tumor-Targeted Human Myeloid Cell Agonist Heather Metz, Monica Childs, Jamie Brevik, Damion Winship, Ty Brender, Michael Comeau, Jenny R Chang, Jeffrey Adamo, Ben Setter, Hengyu Xu, Li-Qun Fan, Sean W Smith, Phil Tan, Robert DuBose, Yvette Latchman, Peter Baum and Valerie Odegard Silverback Therapeutics™, Seattle, WA | Contact information: [email protected] Figure 8: Combination of SBT6050-S and Trastuzumab Enhances In Vivo Efficacy The data presented here demonstrate the following: • SBT6050 potently activates human myeloid cells in the presence of HER2-expressing tumor cells with 2+ and 3+ levels of expression. • Activation of myeloid cells by SBT6050 drives an innate immune response for direct tumor killing and can also nucleate a T cell response. • SBT6050 mouse surrogate (SBT6050-S) is efficacious as a single agent in HER2-expressing, tumor-infiltrating lymphocyte (TIL) deficient tumor models. • SBT6050 and trastuzumab recognize distinct epitopes on HER2. • Combination of SBT6050-S and trastuzumab in a mouse tumor model leads to enhanced efficacy compared to either agent alone. Collectively, these data support clinical evaluation of SBT6050 as a single agent and in combination with trastuzumab in relevant HER2-expressing tumor types. Figure 1: SBT6050 is an ImmunoTAC™ Therapeutic Designed for Systemic Administration with TME-Localized Activity Cell Type TLR4 TLR7 TLR8 TLR9 STING RIG-I Myeloid Cells Dendritic Cells +++ +/- ++++ - ++ ++ Macrophages ++++ + +++ - ++ ++ Non-Myeloid Fibroblasts ++ ++ - - +++ +++ Endothelial Cells +++ ++ - - + ++ Tumor HER2 + Tumor Cells - - - - ++ ++ Figure 5. (A) TLR7 RNA expression in mouse myeloid cells is comparable to that of TLR8 in human. RNA expression data obtained from public databases. (B) SBT6050-S mediates HER2-dependent macrophage activation in vitro with a potency similar to SBT6050. A B Figure 6: SBT6050-S Induces Durable Single Agent Efficacy in a T Cell Excluded Syngeneic Model HER2-expressing EMT6 Tumors are Infiltrated by Myeloid Cells, not T Cells A B Tumor (H&E) T Cells Macrophages Robust Single-Agent Anti-Tumor Efficacy 0/8 CR 0/8 CR 4/8 CR Figure 6. (A) IHC of untreated EMT6 tumors. (B) Monotherapy efficacy of established tumors. Unconjugated HER2 mAb denotes SBT6050-S without payload. Mice (n=10) bearing HER2-expressing EMT6 tumors were treated with PBS, 10mg/kg unconjugated HER2 mAb, or 10mg/kg SBT6050-S. Arrows indicate doses administered. (C) Mice cleared of tumors were re-challenged with HER2-expressing or HER2 negative EMT6 tumor cells 60 days after initial tumor clearance. Naïve mice were included as a control for tumor growth. 0/10 CR 0/10 CR 10/10 CR Figure 7. Unconjugated HER2 mAb denotes SBT6050-S without an agonist payload. Isotype control matched to unconjugated HER2 mAb. SCID-Beige mice (n=10) bearing NCI-N87 tumors were treated with 10 mg/kg isotype control, 10mg/kg unconjugated HER2 mAb, or 10mg/kg SBT6050-S. Arrows indicate doses administered. Figure 8. SBT6050-S was administered at 1mg/kg to allow for combinatorial benefit to be observed. SCID mice (n=10) bearing NCI-N87 tumors were treated with the indicated combinations. Unconjugated HER2 mAb denotes SBT6050-S without payload. (A) Isotype controls matched to unconjugated HER2 mAb (1mg/kg) and trastuzumab (5mg/kg). (B) Isotype control for trastuzumab (5mg/kg) + unconjugated HER2 mAb (1mg/kg). (C) Isotype control for trastuzumab (5mg/kg) + SBT6050-S (1mg/kg). (D) trastuzumab (5mg/kg) + isotype control for unconjugated HER2 mAb (1mg/kg). (E) trastuzumab (5mg/kg) + unconjugated HER2 mAb (1mg/kg). (F) trastuzumab (5mg/kg) + SBT6050-S (1mg/kg). Arrows indicate doses administered. Table 1: Human TLR8 Myeloid-Restricted Expression Profile Supports Development of a TLR8-Selective Payload Tumor Cell Line HER2 #/Cell (x10 6 ) IHC Score SKBR3 1.10 3+ NCI-N87 0.65 3+ BT-474 0.47 3+ MDA-453 0.08 2+ ZR-75-1 0.04 1+/2+ MDA-468 <0.02 0 Figure 2. IHC for HER2 and TLR8 performed on a ductal breast carcinoma sample. Figure 2: HER2 And TLR8 Are Adjacent In Human Tumor HER2 TLR8 Figure 3: SBT6050 Designed to Activate Myeloid Cells in the Presence of 2+ and 3+ Levels of HER2 Expression Figure 3. Tumor cell lines were co-cultured with human PBMC and the indicated concentrations of SBT6050. Activation was determined by TNFα production. ADCC Figure 4: SBT6050 Drives a Broad Spectrum of T Cell Dependent and Independent Anti-Tumor Immune Mechanisms Figure 4. (A) Human PBMC were co-cultured with HER2-expressing (BT-474, 3+; MDA-MB-453, 2+) or HER2-negative (MDA-MB-468) tumor cell lines in the presence of SBT6050. Data representative of multiple donors. No activation of PBMC was observed when co-cultured with tumor cells and unconjugated HER2 mAb (data not shown). (B) ADCC was assessed using human PBMC co-cultured with labelled BT-474, MDA-MB-453, or MDA-MB-468 tumor cell lines in the presence of SBT6050, unconjugated HER2 mAb or a negative control conjugate (isotype control mAb conjugated with TLR8 agonist payload) as indicated and 24 hours later analyzed by flow cytometry. Data representative of multiple donors. A B Protection From Tumor Re-challenge is HER2 Independent C ASCO 2020, Abstract #3110 Dendritic cells Macrophages Monocytes 0 2 4 6 8 log2 (TPM+1) Human TLR8 Human TLR7 Mouse TLR7
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Table 1. Expression levels were determined using publicly available RNA-Seq datasets.
Introduction
Despite advances in treatment options for patients with HER2-expressing tumors, significant unmet medical need remains. Checkpoint inhibition (CPI) therapy has been largely ineffective in HER2-expressing tumors (2+ and 3+ by IHC), likely due to the absence of T cell infiltrate. In contrast, it is well established that HER2-expressing tumors are replete with myeloid cells offering the opportunity for intratumoral immune activation. Local administration, the typical delivery route used for innate immune/myeloid cell agonists, is limited by tumor accessibility and a dependence on abscopal responses. SBT6050 is a novel ImmunoTAC™ therapeutic comprised of a HER2-directed monoclonal antibody conjugated to a potent and highly specific TLR8 agonist, allowing for systemic delivery of a myeloid cell agonist with activity localized to HER2-expressing tumor sites.
Conclusions
• SBT6050, a HER2-directed monoclonal antibody conjugated to a potent and highly specific TLR8 agonist, activates multiple anti-tumor immune mechanisms in a HER2-dependent manner, allowing for systemic delivery and tumor-localized activity.
• SBT6050-S demonstrates robust, durable single agent activity in tumor models with low tumor infiltrating lymphocytes, highlighting the potential for clinical activity with SBT6050 in HER2-expressing malignancies.
• SBT6050-S is curative as a single agent in a HER2-expressing xenograft model lacking T, B, and NK cells, demonstrating the potential of myeloid cells to mediate robust efficacy.
• The combination of a low dose of SBT6050-S together with trastuzumab in a HER2-positive mouse tumor model enhanced the single agent activity observed with either agent alone.
• Collectively, these data support clinical evaluation of SBT6050 as a single agent and in combination with trastuzumab in relevant HER2-expressing tumor types.
SBT6050 is currently in late preclinical development for patients with moderate or high HER2-expressing tumors and is projected to enter the clinic later this year.
Figure 5: SBT6050 Mouse Surrogate (SBT6050-S) Matches the Functional Profile of SBT6050 on Human Myeloid Cells
Figure 7: SBT6050-S Induces Robust Single Agent Tumor Clearance in T, B, and NK Cell Deficient Mice
SBT6050, a HER2-Directed TLR8 Therapeutic, is a Systemically Administered, Tumor-Targeted Human Myeloid Cell Agonist Heather Metz, Monica Childs, Jamie Brevik, Damion Winship, Ty Brender, Michael Comeau, Jenny R Chang, Jeffrey Adamo, Ben Setter, Hengyu Xu, Li-Qun Fan, Sean W Smith, Phil Tan, Robert DuBose, Yvette Latchman, Peter Baum and Valerie OdegardSilverback Therapeutics™, Seattle, WA | Contact information: [email protected]
Figure 8: Combination of SBT6050-S and Trastuzumab EnhancesIn Vivo Efficacy
The data presented here demonstrate the following:
• SBT6050 potently activates human myeloid cells in the presence of HER2-expressing tumor cells with 2+ and 3+ levels of expression.
• Activation of myeloid cells by SBT6050 drives an innate immune response for direct tumor killing and can also nucleate a T cell response.
• SBT6050 mouse surrogate (SBT6050-S) is efficacious as a single agent in HER2-expressing, tumor-infiltratinglymphocyte (TIL) deficient tumor models.
• SBT6050 and trastuzumab recognize distinct epitopes on HER2.
• Combination of SBT6050-S and trastuzumab in a mouse tumor model leads to enhanced efficacy compared toeither agent alone.
Collectively, these data support clinical evaluation of SBT6050 as a single agent and in combination with trastuzumab in relevant HER2-expressing tumor types.
Figure 1: SBT6050 is an ImmunoTAC™ Therapeutic Designed for Systemic Administration with TME-Localized Activity
Cell Type TLR4 TLR7 TLR8 TLR9 STING RIG-I
Mye
loid
Cel
ls Dendritic Cells +++ +/- ++++ - ++ ++
Macrophages ++++ + +++ - ++ ++
Non
-Mye
loid Fibroblasts ++ ++ - - +++ +++
Endothelial Cells +++ ++ - - + ++
Tum
or
HER2+ Tumor Cells - - - - ++ ++
Figure 5. (A) TLR7 RNA expression in mouse myeloid cells is comparable to that of TLR8 in human. RNA expression data obtained from public databases. (B) SBT6050-S mediates HER2-dependent macrophage activation in vitro with a potency similar to SBT6050.
A B
Figure 6: SBT6050-S Induces Durable Single Agent Efficacy in a T Cell Excluded Syngeneic Model
HER2-expressing EMT6 Tumors are Infiltrated by Myeloid Cells, not T Cells A
B
Tumor (H&E) T Cells Macrophages
Robust Single-Agent Anti-Tumor Efficacy
0/8 CR 0/8 CR 4/8 CR
Figure 6. (A) IHC of untreated EMT6 tumors. (B) Monotherapy efficacy of established tumors. Unconjugated HER2 mAb denotes SBT6050-S without payload. Mice (n=10) bearing HER2-expressing EMT6 tumors were treated with PBS, 10mg/kg unconjugated HER2 mAb, or 10mg/kg SBT6050-S. Arrows indicate doses administered. (C) Mice cleared of tumors were re-challenged with HER2-expressing or HER2 negative EMT6 tumor cells 60 days after initial tumor clearance. Naïve mice were included as a control for tumor growth.
0/10 CR 0/10 CR 10/10 CR
Figure 7. Unconjugated HER2 mAb denotes SBT6050-S without an agonist payload. Isotype control matched to unconjugated HER2 mAb. SCID-Beige mice (n=10) bearing NCI-N87 tumors were treated with 10 mg/kg isotype control, 10mg/kg unconjugated HER2 mAb, or 10mg/kg SBT6050-S. Arrows indicate doses administered.
Figure 8. SBT6050-S was administered at 1mg/kg to allow for combinatorial benefit to be observed. SCID mice (n=10) bearing NCI-N87 tumors were treated with the indicated combinations. Unconjugated HER2 mAb denotes SBT6050-S without payload. (A) Isotype controls matched to unconjugated HER2 mAb (1mg/kg) and trastuzumab (5mg/kg). (B) Isotype control for trastuzumab (5mg/kg) + unconjugated HER2 mAb (1mg/kg). (C) Isotype control for trastuzumab (5mg/kg) + SBT6050-S (1mg/kg). (D) trastuzumab (5mg/kg) + isotype control for unconjugated HER2 mAb (1mg/kg). (E) trastuzumab (5mg/kg) + unconjugated HER2 mAb (1mg/kg). (F) trastuzumab (5mg/kg) + SBT6050-S (1mg/kg). Arrows indicate doses administered.
Table 1: Human TLR8 Myeloid-Restricted Expression Profile Supports Development of a TLR8-Selective Payload
Tumor Cell Line
HER2 #/Cell (x106)
IHC Score
SKBR3 1.10 3+
NCI-N87 0.65 3+
BT-474 0.47 3+
MDA-453 0.08 2+
ZR-75-1 0.04 1+/2+
MDA-468 <0.02 0
Figure 2. IHC for HER2 and TLR8 performed on a ductal breast carcinoma sample.
Figure 2: HER2 And TLR8 Are Adjacent In Human Tumor
HER2 TLR8
0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0
0
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
C o n c ( n M )
TN
Fa
(p
g/m
L)
S K - B R - 3
N C I - N 8 7
B T - 4 7 4
M D A - 4 5 3
Z R - 7 5 - 1
0
0.220.250.220.19
~ 0.21
E C 5 0 ( n M )
M D A - 4 6 8
0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0
0
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
C o n c ( n M )
TN
Fa
(p
g/m
L)
S K - B R - 3
N C I - N 8 7
B T - 4 7 4
M D A - 4 5 3
Z R - 7 5 - 1
0
0.220.250.220.19
~ 0.21
E C 5 0 ( n M )
M D A - 4 6 8
0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0
0
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
C o n c ( n M )
TN
Fa
(p
g/m
L)
S K - B R - 3
N C I - N 8 7
B T - 4 7 4
M D A - 4 5 3
Z R - 7 5 - 1
0
0.220.250.220.19
~ 0.21
E C 5 0 ( n M )
M D A - 4 6 8
0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0
0
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
C o n c ( n M )
TN
Fa
(p
g/m
L)
S K - B R - 3
N C I - N 8 7
B T - 4 7 4
M D A - 4 5 3
Z R - 7 5 - 1
0
0.220.250.220.19
~ 0.21
E C 5 0 ( n M )
M D A - 4 6 80 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0
0
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
C o n c ( n M )
TN
Fa
(p
g/m
L)
S K - B R - 3
N C I - N 8 7
B T - 4 7 4
M D A - 4 5 3
Z R - 7 5 - 1
0
0.220.250.220.19
~ 0.21
E C 5 0 ( n M )
M D A - 4 6 8
Figure 3: SBT6050 Designed to Activate Myeloid Cells in the Presence of 2+ and 3+ Levels of HER2 Expression
Figure 3. Tumor cell lines were co-cultured with human PBMC and the indicated concentrations of SBT6050. Activation was determined by TNFα production.
ADCC
Figure 4: SBT6050 Drives a Broad Spectrum of T Cell Dependent and Independent Anti-Tumor Immune Mechanisms
Figure 4. (A) Human PBMC were co-cultured with HER2-expressing (BT-474, 3+; MDA-MB-453, 2+) or HER2-negative (MDA-MB-468) tumor cell lines in the presence of SBT6050. Data representative of multiple donors. No activation of PBMC was observed when co-cultured with tumor cells and unconjugated HER2 mAb (data not shown). (B) ADCC was assessed using human PBMC co-cultured with labelled BT-474, MDA-MB-453, or MDA-MB-468 tumor cell lines in the presence of SBT6050, unconjugated HER2 mAb or a negative control conjugate (isotype control mAb conjugated with TLR8 agonist payload) as indicated and 24 hours later analyzed by flow cytometry. Data representative of multiple donors.
A
BProtection From Tumor Re-challenge is HER2 IndependentC
ASCO 2020, Abstract #3110
Dendritic c
ells
Macrophage
s
Monocytes
0
2
4
6
8
log2
(TPM
+1)
Human TLR8
Human TLR7
Mouse TLR7
Related Documents
