HARPOON THERAPEUTICS, INC. TriTAC-XR is an extended-release T cell engager platform that improves safety by minimizing risk of cytokine release syndrome
Kathryn S. Kwant, Sony S. Rocha, Timothy Yu, Golzar Hemmati, Evan Callihan, Subramanian Thothathri, Katrina Stephenson, Raphaela Rose Banzon, Sydney Vollhardt, Wade H. Aaron, Jessica O'Rear, Eric Bragg, Willis Kwong, Hubert Situ, Avneel Hundal, Stephen Yu, Taggra Jackson, Kevin Carlin, Yinghua Xiao, Maria Rosalyn Dayao, Linh To, Nick Bergo, Kevin Wright, Laurie Tatalick, Aparna Shinde, Linda Santiago, Richard Austin, Holger Wesche, Bryan Lemon, S. Jack Lin.
Harpoon Therapeutics Inc., South San Francisco, CA.
• T cell engagers are potent anti-tumor drugs, but they frequently induce cytokine release syndrome (CRS) in patients
• Existing approaches to manage CRS, while effective, can be suboptimal:
o Corticosteroids: blunted T cell response and reduced efficacy
o Step-up dosing: inconvenient, needed after every treatment interruption
o Continuous I.V. dosing: inconvenient, increased infection risks
o Subcutaneous dosing: increased immunogenicity risks
• TriTAC-XR molecules are T cell engager prodrugs that become slowly activated in circulation by systemic proteases
• This extended-release mechanism enables slow build-up of active drug and minimizes induction of cytokines while maintaining efficacy
Introduction
Poster 2861, AACR 2022
Slow build-up of active drug reduces cytokine release while maintaining comparable levels of target cell depletion
• Cyno cross-reactive TriTAC and TriTAC-XR molecules targeting FLT3, CD19, and CD20 were dosed at the indicated concentrations in cyno monkeys by intravenous infusion
• PK, target cell depletion, and cytokine release were measured from the same animals to assess therapeutic index expansion
FLT3
CD19
CD20
(1000 ug/kg, single dose)
(300 ug/kg, single dose)
(30 ug/kg, repeat dose, QWx4)
FLT3 at 1000 µg/kg
CD19 at 300 µg/kg
CD20 at 30 µg/kg
Slow build-up of active drug
PlasmaConcentration(nM)
1000
100
10
1
PlasmaConcentration(nM)
100
10
1
0.1 0
PlasmaConcentration(nM)
100
10
TriTAC
TriTAC-XR (Total drug)TriTAC-XR (Active drug)
1
0.1
0
24
48
72
96
120
144
168
Normalize to Predose (Fraction) of CD20+ (Absolute)Normalize0 to Pre2d4 ose (4F8ractio7n2) of C9D620+ (1A2b0solute)
24
48
72
96
120
144
168
XR vs TT for ATiAmCeR(hpouorst)er no Vehicle
Time (hours)
Time (hours)
Comparable target cell depletion
NormalizedBMFLT3RNA
TriTAC (1 mg/kg)
TriTAC-XR (1 mg/kg)
NormalizedBcellCounts
NormalizedBcellCounts
TriTACTriTAC-XR
24
48
72
96
120
144
168
168
336
504
168
336
504
672
Time (hours)
Time (hours)
Time (hours)
IL-2
IL-6
IL-2
IL-6
IL-2
IL-6
CD19 TriTAC 300 µg/kg
200
Reduced cytokine release
PeakIL-2(pg/ml)
150
100
50
PeakIL-6(pg/ml)
500400300200100
3
80
200
CD19 TriTAC-XR 300 µg/kg
PeakIL-2(pg/ml)
2
1
PeakIL-6(pg/ml)
60
40
20
PeakIL-2(pg/ml)
150
100
50
PeakIL-6(pg/ml)
500400300200100
0
0
0
0
0
0
TriTAC
TriTAC-XR
TriTAC
PK was assessed with two separate ligand binding assays using specific anti-idiotype antibodies: one specific for TriTAC and TriTAC-XR (active drug) and one specific for both active and prodrug forms of TriTAC-XR (total drug). FLT3 target cell depletion was assessed by qPCR of bone marrow samples collected from cyno monkeys at the indicated time points. B cell depletion was assessed by flow cytometry for CD3- / CD20+ cell population from peripheral blood in cyno monkey at the indicated time points. Peak cytokine release was measured by cyno cross-reactive ligand binding assays.
Expansion of Therapeutic Index in Non-Human Primates
TriTAC-XR results in near-constant exposure of active drug even with intravenous dosing
Empirical Cyno PK Profile of CD20 TriTAC-XR
1000
Concentration(nM)
100
10
1
Active drug, 30 ug/kgActive drug, 300 ug/kgTotal drug, 30 ug/kgTotal drug, 300 ug/kg
0.1
0
168
336
504
672
Time (hours)
• TriTAC-XR active drug concentration is relatively constant due to continual conversion of prodrug to active drug
• Empirical PK profile confirms the predicted PK model
TriTAC-XR via intravenous dosing is predicted to have superior PK profile than TriTAC via subcutaneous dosing
Dose 2
Dose 3
Dose 4
1000
Concentration
100
TriTAC (via IV)
TriTAC (via SC)
TriTAC-XR active drug (via IV)
10
1 0
168
336
504
672
Time (hours)
Benefits of TriTAC-XR compared to subcutaneous dosing:
• More gradual dose ramp-up
• Reduced risks for immunogenicity and injection site reactions
Improved PK in Repeat Dose Setting
Pre-dose 2 | Pre-dose 3 | Pre + post-dose 4 |
(trough) | (trough) |
Summary
• PK of TriTAC-XR confirms the slow build-up of active drug with reduced Cmax/Cmin ratio in systemic circulation
• This enhanced PK profile of TriTAC-XR translates to improved therapeutic index, observed across multiple targets in cyno monkeys
• TriTAC-XR and its underlying extended-release mechanism represents a new approach to managing CRS, either alone or in combination with other existing CRS-mitigation approaches
• The expected safety improvements would enable T cell engagers targeting immune cells to broaden its adoption from oncology to autoimmune and other non-oncology diseases
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Disclaimer
Harpoon Therapeutics Inc. published this content on 01 April 2022 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 12 April 2022 07:50:08 UTC.
