HPN601 Is A Protease-Activated EpCAM-Targeting T Cell ...
Transcript of HPN601 Is A Protease-Activated EpCAM-Targeting T Cell ...
HPN601 Is A Protease-Activated EpCAM-Targeting T Cell Engager with an Improved Safety Profile for the Treatment of Solid Tumors
S. Jack Lin, Sony S. Rocha, Kathryn Kwant, Maria Rosalyn Dayao, Tessie M. Ng, Raphaela Rose Banzon, Wade Aaron, Evan Callihan,Maria Gamez-Guerrero, Golzar Hemmati, Kevin J. Wright, Manasi Barath, Yinghua Xiao, Timothy Yu, Patrick Chew, Thomas Evans,Jessica O’Rear, Scott Gatto, Michael Cremin, Stephen Yu, Purbasa Patnaik, Avneel Hundal, Richard Austin, Bryan Lemon, Holger Wesche
Harpoon Therapeutics, Inc.
South San Francisco, CA
November 12, 2020
Disclosure
• All authors are current or former employees and are shareholders of Harpoon Therapeutics
The Need for a Conditionally Active T Cell Engager Prodrug To Target More Broadly Expressed Tumor AntigensPROBLEM:
• T cell engagers are potent, but limited to tumor antigens with restricted normal tissue expression
• Many solid tumor antigens have normal tissue expression liabilities
• Several T cell engager targets have encountered dose-limiting toxicities in the clinic
• Examples: EpCAM, gpA33, B7-H3, CEACAM5
SOLUTION:
• Design a T cell engager prodrug that is active in tumor and spares normal tissues
• Enables targeting of more solid tumor antigens
ProTriTAC Is a T Cell Engager Prodrug Platform Based on Harpoon’s Clinically Validated TriTAC Components
αALB
αTarget
αCD3
TriTAC ProTriTAC
protease linker (red)
masking moiety from αALB (orange)
αALB
αTarget
αCD3
Started with same TriTAC binders
Rearranged binders
Added protease linker and masking moiety
ProTriTAC Links Masking with Half-Life Extension To Improve the Therapeutic Index (TI)
TUMOR
Activation by tumor proteases & T cell-directed killing
Rapid clearance in circulation
CIRCULATION
αALB
αTarget
αCD3
Long-lived prodrug
CIRCULATION
Albumin
EpCAM Is a Broadly Expressed Epithelial Tumor Antigen
• Epithelial Cell Adhesion Molecule (EpCAM, CD326)
• Highly expressed on many solid tumors1
• Marker for circulating tumor cells2
• Therapeutic potential hindered by its normal tissue expression
1. Spizzo, J Clin Pathol 2011. 2. de Wit, Oncotarget 2018. EpCAM IHC images taken from ProteinAtlas.org
CRC
NSCLC
mCRPC
Efficacy of Past EpCAM T Cell Engagers Was Limited Because of On-Target Toxicity in Normal Tissues
T Cell Engager Route of Admin. Clinical Experience
SolitomabSystemic(intravenous)
MTD = 24 µg/dayClinical activity noted at dose levels 2-4x above MTD1
CatumaxomabLocal(intraperitoneal)
Approved for malignant ascites in Europe2
Not tolerated as systemic therapy3
1. Kebenko, OncoImmunol 2018. 2. https://www.ema.europa.eu/en/medicines/human/EPAR/removab. 3. Mau-Sorensen, Cancer Chemother Pharmacol 2015.
• Systemic administration not tolerated, but highest (non-tolerated) doses for solitomab had clinical activity
• Local administration had more success, but cannot target all metastatic tumors
Goal of EpCAM ProTriTAC = systemic administration + local activity in all tumors
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1×106
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Cell V
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U)
SKBR3
H90.2 NCLV
H90.2 CT
-12 -11 -10 -9 -8 -7
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Log of concentration (M)
Cell V
iab
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SKBR3
H13 NCLV
H13 CT
Two EpCAM-Specific Binders Were Chosen for Further Efficacy and Toxicity Assessments In Vivo
ProdrugActive
594x602x
Clinical Candidate Binder(Binds Human/Cyno EpCAM)
Mouse Cross-Reactive Binder(Binds Human/Cyno/Mouse EpCAM)
• Comparable masking observed in functional T cell killing (TDCC) assays
• ProTriTAC with the mouse cross-reactive binder used for TI assessment
ProdrugActive
αALB
αEpCAM
αCD3
EpCAM ProTriTAC Is 3x Less Potent than the Tool TriTACin Shrinking LoVo Colon Tumors in Mice
TriTAC
ProTriTAC
Control
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0.003 mg/kg 0.01 mg/kg 0.03 mg/kg 0.1 mg/kg 0.3 mg/kg
0.03 mg/kg 0.1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kg
0.03 mg/kg
Human T cells
Human LoVo tumor
T Cell Engager
Establishedtumor model
EpCAM ProTriTAC Is 30x Safer than the Tool TriTAC in the Same Tumor-Bearing Mice
Survival:
Clinical Chemistry:
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Dose Level (mg/kg)
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ALT at d15
TriTAC
ProTriTAC
ALT
>30x
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Dose Level (mg/kg)
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AST at d15
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ProTriTAC
AST
>30x
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Dose Level (mg/kg)
Co
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TBIL at d15
TriTAC
ProTriTAC
Bilirubin (Total)
30xTriTAC
ProTriTAC
TriTAC
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Perc
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0.003 mg/kg
0.01 mg/kg
0.03 mg/kg
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0.3 mg/kg
ProTriTAC
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The 30x Improved Safety of EpCAM ProTriTAC Is Further Supported by Mouse Histopathology in the Same Tumor-Bearing Mice
ProTriTAC0.3 mg/kg
TriTAC0.3 mg/kg
Mouse Liver Sections (H&E stain)
ProTriTAC enables better discrimination of tumor vs. normal tissue to reduce on-target tissue damage
Ctrl TriTAC ProTriTAC
Dose level (mg/kg)
0.3 0.003 0.01 0.03 0.1 0.3 0.03 0.1 0.3 1 3
Coagulation necrosis
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Portal fibrosis 10%* 10%* 10%* 10%* 100% 100% 20%* 20%* - - 100%
Bile ductuledilation
- - - - 100% 100% - - - - 100%
Note: percentages represent proportion of animals with the finding, asterisks denote findings were all of minimal severity
Mouse Liver Histopathology Findings
10x Therapeutic Index Expansion Achieved for ProTriTACin a Tumor Xenograft Model in Mice
• TI expansion demonstrated in vivo : efficacy + tox in the same animal
• Preclinical model validated: similar on-target tox in mouse and in human1
Minimum Efficacious Dose
Maximum Tolerated Dose
Therapeutic Index (TI)
TriTAC 0.03 mg/kg 0.03 mg/kg 1
ProTriTAC 0.1 mg/kg 1 mg/kg 10
ProTriTAC Advantage 10x
1. Kebenko, OncoImmunol 2018
EpCAM ProTriTAC with the Clinical Candidate Binder (HPN601) Confirms TI Improvement by Comparing Across Species
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Control
TriTAC
ProTriTAC(HPN601)
Both TriTAC and ProTriTAC dosed at 100 µg/kg
Peak Cytokine Levels
Both TriTAC and ProTriTAC dosed at 30 µg/kg
Established HT29 Tumor Xenograft Model
IL-2
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IL-1
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TriTAC
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ProTriTAC(HPN601)
HPN601 Is Active in Multiple Established Tumor Xenograft Models
Control 30 µg/kg 100 µg/kg 300 µg/kg dosed qdx14
HPAF-II(Pancreatic)
5 10 15 20 25 30 350
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Day, post tumor implantation
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Admix Therapeutic Xenograft HPAFII-007 in NSG Mice
Various Doses of EpCAM-H13 ProTriTAC
Mask 027 Linker 40 QD and QOD
Effect of Treatment on Tumor Volume
GFP TriTAC QD (0.3 mg/kg)
EpCAM-H13 ProTriTAC Mask 027 Linker 40 QD (0.1 mg/kg)
EpCAM-H13 ProTriTAC Mask 027 Linker 40 QD (0.03 mg/kg)
EpCAM-H13 ProTriTAC Mask 027 Linker 40 QD (0.3 mg/kg)
HT-29(Colon)
5 10 15 20 25 30 350
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Day, post tumor implantation
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Admix Therapeutic Xenograft HT29-005 in NSG Mice
EpCAM-H13 ProTriTAC Linker 040
Effect of Treatment on Tumor Volume
EpCAM H13 Pro L040 0.03 mg/kg
EpCAM H13 Pro L040 0.1 mg/kg
EpCAM H13 Pro L040 0.3 mg/kg
GFP TAC 0.1 mg/kg
22Rv1(Prostate)
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Day, post tumor implantation
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Admix Therapeutic Xenograft
22RV1-007 in NSG Mice
HPN601 Effect of Treatment on Tumor Volume
GFP TAC 0.3 mg/kg
HPN601 0.3 mg/kg
HPN601 0.1 mg/kg
HPN601 0.03 mg/kg
H292(Lung)
5 10 15 20 25 300
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Day, post tumor implantation
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Admix Therapeutic Xenograft
NCIH292-007 in NSG Mice
HPN601 Effect of Treatment on Tumor Volume
GFP TAC 0.3 mg/kg
HPN601 0.3 mg/kg
HPN601 0.1 mg/kg
HPN601 0.03 mg/kg
Demonstrates anti-tumor activity and prodrug processing in multiple tumor types
Summary
• ProTriTAC is a new approach to engineer conditionally active T cell engager prodrugs
• HPN601 is an EpCAM-targeting ProTriTAC
• 10x improved TI compared to a constitutively active T cell engager
• Efficacious in multiple EpCAM-expressing xenograft tumor models in vivo
• IND-enabling studies initiated
Acknowledgements
Translational Medicine• Che-Leung Law• Laurie Tatalick• Vaishnavi Ganti
CMC• Susan Dana Jones• Alpana Naresh• Mark Wesson
We thank all other Harpoon staff members who enabled this effort.