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A Single Dose of CD117 Antibody Drug Conjugate Enables Hematopoietic Stem Cell Based Gene Therapy in Nonhuman Primates
Naoya Uchida1, John F. Tisdale1, Robert E. Donahue1, Bradley R Pearse2, Sean M McDonough2, Jennifer
L Proctor2, Cindy Dunbar1, Allen E. Krouse1, Nathaniel S. Linde1, Aylin C. Bonifacino1, Sogun Hong1, Rajiv
Panwar2, Ganapathy Sarma2, Lena Kien2, Kellie Latimer2, Junia Dushime2, Sharon L Hyzy2, Melissa
Brooks2, Rahul Palchaudhuri2, Qing Li2, Pranoti Sawant2, Charlotte F McDonagh2, Anthony E Boitano2,
Michael P Cooke2
2 Magenta Therapeutics, Cambridge, MA
1 National Heart, Lung, and Blood Institute (NHLBI) and National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK), NIH, Bethesda, MD
HSC Based Gene Therapy: The Patient Journey to a Cure
ADC-mediated
conditioning
Opportunity:
• Less toxic conditioning
• Immune preservation
• Avoid secondary malignancy and infertility
• Improve risk benefit profile to broaden access
Targeted Conditioning Using Antibody Drug Conjugates
CD117 (C-kit) is an Ideal Target for ADC-Mediated Conditioning
Rapid internalization
Restricted expression profile
limited systemic toxicity
A single dose of CD117 ADC
enables robust engraftment in mice
Czechowicz, Palchaudhuri et al. Nat Comm 2019
Isotype
ADC
Anti-mCD117
ADC
PBS
Hematopoietic Stem
Cell
Common Myeloid Progenitor Common Lymphoid Progenitor
Megakaryocyte
Platelet
Erythrocyte Mast
Cell Myeloblast
Basophil
Neutrophil
EosinophilMonocyte
Macrophage
Natural killer cell
Small Lymphocyte
T cell B cell
Plasma cell
-16 -15 -14 -13 -12 -11 -100
25
50
75
100
125
Anti-CD117 ADC is Potent on Primary Human and NHP CD34+ Cells
Log [M]
% V
iab
le C
D34+
Human
EC50 = 0.2 pMPrimate
EC50 = 0.1 pM
Hematopoietic Stem Cell Killing Assay
Primate
Isotype
Human
Isotype
A Single Dose of Anti-CD117 ADC Enables Full Depletion of Human CD34+ Cells In Vivo
% Remaining
Relative to Control
0
5
10
15
20
100
200
0.3 1.0Control 3
Isotype
ADC
mg/kg
Human CD34+ Cell Depletion
1
Anti-
CD117Anti-CD117 ADC
3.0
Assess HSC depletion in
bone marrow
Humanized NSG Mice
CD117-ADC
(Single dose, i.v.)
Day 21Day 0
Single Dose of CD117 ADC Selectively Depletes HSCs in Primates
Hematopoietic Stem
Cell Depletion
CD
34
CD90
CD
3
CD20
Baseline
Maintenance of
Lymphocytes
Day 6 Post-
Dose
CD117-ADC Depletes Functional HSC
Pre-dose Day 60
250
500
CF
U (
x10
3)
/ m
L o
f
Bone
Marr
ow
Assess HSC
depletion in
bone marrow
Primates
CD117-ADC
(Single dose, i.v.)
Day 6Day 0
CD117 ADC Is Engineered for Rapid Clearance and Optimal Timing for Graft Infusion
0 1 2 3 4 5 6 70.001
0.01
0.1
1
10
100
1,000
10,000
Plasma ADC
Concentration (ng/ml)
Days Post-Dose
Engineered
CD117-ADC
Rapid Clearance Enables Graft Infusion Within
Days Post Dosing
Lower limit of
detection by ELISA
ADC in
circulation
Effective concentration that is not
cytotoxic to CD117 expressing cells
Wild Type
CD117-ADC
Modeled
Pharmacokinetics
Safe to
infuse graft
t1/2=10hrs
Treatment Schema For Gene-Marked Autologous Transplant in CD117-ADC Conditioned Primates
Single Dose
CD117-ADC
Cohort
Multi-Dose
Busulfan Cohort
(Clinical Regimen)Uchida et al.
Mol Ther 2019
Primate
Primate
Single Dose of Anti-CD117 ADC is Sufficient to Enable Autologous Gene Modified Transplant in Rhesus
Days Post-Transplant
Ne
utr
op
hils
(1
03/u
l)
Lym
ph
ocyte
s (
10
3/u
l)
Pla
tele
ts (
10
5/u
l)
NHP #1
NHP #2
Conditioning
RegimenAnimal Number
Neutrophil
Recovery
Platelet
RecoveryLymphocyte Counts
Days post Transplant Range (103/uL)
CD117 ADCNHP #1 8 10 0.9-4.2
NHP #2 10 11 0.9-4.0
Busulfan Busulfan Cohort*Uchida et al. Mol Ther 2019
8-10 10-15 0.6-20
Days Post-Transplant Days Post-Transplant
Neutrophil Recovery Platelet Recovery Lymphocytes Counts
ANC
500
50,000
-6 1 8 150
200
400
600
20 60 100 140 180-6 1 8 150.01
0.1
1
10
100
20 60 100 140 180 -6 1 8 150.1
1
10
20 60 100 140 180
CD117ADC
11
0 30 60 90 120 150 18010 -3
10 -2
10 -1
100
Peripheral Granulocyte Vector Copy Number is Stable Over Time and Comparable to Historical Data with Busulfan Conditioning
Conditioning
Regimen
Animal
Number
CD34 dose
(x106 cells/kg)
VCN of
infused cells
Peripheral VCN
@ 1-6 months
Anti-CD117 ADCNHP #1 3.3 5 0.01-0.04
NHP #2 1.1 4 0.01-0.05
Busulfan Busulfan Cohort*Uchida et al. Mol Ther 2019
4.1-4.2 8-10 0.004-0.08
Peripheral Granulocyte β-globin Vector Copy Number
Ve
cto
r C
op
y N
um
ber
Days Post-Transplant
NHP #1
NHP #2
VCN range with
busulfan conditioning
CD117-ADC is Well-Tolerated in Primates
No ADC-related changes outside
normal range for:
Aspartate Aminotransferase (AST)
alanine aminotransferase (ALT)
Lactic Acid Dehydrogenase (LDH)
Albumin
Creatinine (Cr)
Blood Urea Nitrogen (BUN)
Total Bilirubin (TBIL)
alkaline phosphatase (ALP)
Glucose
Busulfan Side EffectsOutcomes With CD117-
ADC
Emesis Not observed
Diarrhea Not observed
Mucositis Not observed
Wasting Syndrome Not observed
Seizures Not observed
Veno-occlusive Disease Not observed
Pulmonary Fibrosis Not observed
Conclusions
• The engineered CD117 ADC shows potent activity on human and NHP CD34+ cells ex vivo
• The CD117-ADC robustly depletes rhesus HSCs in vivo, has a favorable safety profile, spares the immune system and is cleared rapidly to allow for optimal timing of graft infusion
• A single dose of the CD117-ADC enables engraftment of β-globin gene modified HSCs in a primate model without chemotherapy
• These results validate the use of CD117-ADC for targeted stem cell depletion prior to transplant and supports development as a new conditioning agent for autologous HSC-based gene therapy approaches
• This targeted approach for safer conditioning could improve the risk benefit profile for patients undergoing transplant and enable more patients to benefit from these potentially curative therapies including gene therapy for sickle cell disease and severe combined immunodeficiency